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1
Huang, Zhongting, Haibin He, Feng Qiu, and Hailong Qian. "Expression and Prognosis Value of the KLF Family Members in Colorectal Cancer." Journal of Oncology 2022 (March 19, 2022): 1–13. http://dx.doi.org/10.1155/2022/6571272.
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Krüppel-like factors (KLFs) are some kind of transcriptional regulator that regulates a broad range of cellular functions and has been linked to the development of certain malignancies. KLF expression patterns and prognostic values in colorectal cancer (CRC) have, however, been investigated rarely. To investigate the differential expression, predictive value, and gene mutations of KLFs in CRC patients, we used various online analytic tools, including ONCOMINE, TCGA, cBioPortal, and the TIMER database. KLF2-6, KLF8-10, KLF12-15, and KLF17 mRNA expression levels were dramatically downregulated in CRC tissues, but KLF1, KLF7, and KLF16 mRNA expression levels were significantly elevated in CRC tissues. According to the findings of Cox regression analysis, upregulation of KLF3, KLF5, and KLF6 and downregulation of KLF15 were linked with a better prognosis in CRC. For functional enrichment, our findings revealed that KLF members are involved in a variety of cancer-related biological processes. In colon cancer and rectal cancer, KLFs were also shown to be associated with a variety of immune cells. The findings of this research reveal that KLF family members’ mRNA expression levels are possible prognostic indicators for patients with CRC.
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Moi, Paolo, Loredana Porcu, Maria G. Marini, Isadora Asunis, Maria G. Loi, Tohru Ikuta, and Antonio Cao. "Differential Modulation of the β-Like Globin Genes by KLFs Isolated with a γ-Globin CACCC Bait." Blood 106, no. 11 (November 16, 2005): 3637. http://dx.doi.org/10.1182/blood.v106.11.3637.3637.
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Abstract The globin CACCC boxes are absolutely required for the appropriate regulation of the β-like globin genes. While the β-globin CACCC box binds EKLF/KLF1, a likely adult switching factor, analogous factors, interacting with the γ-globin gene and predicted to regulate the fetal stage of hemoglobin switching, have so far been elusive. By using yeast one hybrid assay, we have isolated four KLFs, KLF1, 2, 4, and 6, that bound the γ-CACCC bait. To establish their role in globin regulation and in the switching of hemoglobins, these factors were compared to four other KLFs already established or putative globin regulators, KLF3, 11, 13 and 16, mainly evaluating their ability to bind and transactivate the ε-, γ- and β-globin gene. γ-CACCC binding at variable intensities was confirmed in band shift assay for all four isolated KLFs, for KLF3 and, faintly, for KLF13. The ε- and β-CACCC were bound by the same factors with similar affinities with the exception of KLF3 and KLF13 that bound stronger to the β- and ε- than to the γ-CACCC box. On the other hand, KLF11 and 16 did not produce any specific complex in band shift assays with anyone of the globin CACCC boxes. More relevant differences were observed among the factors in the transactivation of single and dual luciferase reporters in both K562 and MEL cells. In these assays, most factors presented peculiar modulatory properties and specific promoter tropism. Several factors presented bidirectional activity displaying in the same time the capacity to stimulate and repress different globin promoters. KLF1 and 4 were the strongest stimulators of the β-globin promoter in both cell lines, whereas KLF2 activated the β-promoter only in K562 cells. KLF1 and especially KLF4 consistently repressed ε-globin expression especially in MEL cells. KLF3 behaved always as a general globin repressor in MEL cells, but acted as a weak stimulator of the γ- and ε-promoter in K562 cells. KLF4 was the strongest inhibitor of the ε-globin gene. KLF13 significantly stimulated the γ-promoter in both cell lines, whereas KLF3, 4 and 6 showed statistically significant stimulation only in MEL cells. By RT-PCR analysis we found that KLFs were highly variable in their tissue expression and that KLF1, 3 and 13 had the highest expression in erythroid tissues. Thus the level of tissue expression should ultimately determine which factors are really active in physiological conditions. Taken together our binding and expression studies suggest that several KLFs have the potential to modulate the activity of the globin genes and that the resulting globin expression will depend on the vectorial sum of the relative activities of the factors expressed at any given time of development. Furthermore, as some KLFs, like KLF1 and 4, exert opposite effects on fetal and adult globin genes, their role in hemoglobin switching may be direct and not only dependent on their ability to mediate promoter competition for the LCR.
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Sue, Nancy, Briony H. A. Jack, Sally A. Eaton, Richard C. M. Pearson, Alister P. W. Funnell, Jeremy Turner, Robert Czolij, et al. "Targeted Disruption of the Basic Krüppel-Like Factor Gene (Klf3) Reveals a Role in Adipogenesis." Molecular and Cellular Biology 28, no. 12 (April 7, 2008): 3967–78. http://dx.doi.org/10.1128/mcb.01942-07.
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ABSTRACT Krüppel-like factors (KLFs) recognize CACCC and GC-rich sequences in gene regulatory elements. Here, we describe the disruption of the murine basic Krüppel-like factor gene (Bklf or Klf3). Klf3 knockout mice have less white adipose tissue, and their fat pads contain smaller and fewer cells. Adipocyte differentiation is altered in murine embryonic fibroblasts from Klf3 knockouts. Klf3 expression was studied in the 3T3-L1 cellular system. Adipocyte differentiation is accompanied by a decline in Klf3 expression, and forced overexpression of Klf3 blocks 3T3-L1 differentiation. Klf3 represses transcription by recruiting C-terminal binding protein (CtBP) corepressors. CtBPs bind NADH and may function as metabolic sensors. A Klf3 mutant that does not bind CtBP cannot block adipogenesis. Other KLFs, Klf2, Klf5, and Klf15, also regulate adipogenesis, and functional CACCC elements occur in key adipogenic genes, including in the C/ebpα promoter. We find that C/ebpα is derepressed in Klf3 and Ctbp knockout fibroblasts and adipocytes from Klf3 knockout mice. Chromatin immunoprecipitations confirm that Klf3 binds the C/ebpα promoter in vivo. These results implicate Klf3 and CtBP in controlling adipogenesis.
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Allen, Kristi L., Mukesh K. Jain, and Keith R. McCrae. "KLF2 and KLF4 Are Essential Mediators of the Anti-Thrombotic Effects of Statins in the Presence of Antiphospholipid/Anti-ß2GPI Antibodies,." Blood 118, no. 21 (November 18, 2011): 3272. http://dx.doi.org/10.1182/blood.v118.21.3272.3272.
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Abstract Abstract 3272 Antiphospholipid syndrome (APS) is characterized by thrombosis and/or recurrent pregnancy loss in the presence of antiphospholipid antibodies (APLA). The majority of APLA are directed against phospholipid binding proteins, particularly β2GPI. Anti-ß2GPI antibodies activate endothelial cells and monocytes in a β2GPI-dependent manner through a pathway that involves NF-κB and leads to increased expression of adhesion molecules, tissue factor and proinflammatory cytokines. Krüppel-like factors (KLFs) regulate endothelial cell and monocyte responses to inflammatory stimuli; increased expression of these transcription factors inhibits proinflammatory and procoagulant gene expression, and maintains vascular homeostasis. We recently reported that anti-ß2GPI antibodies decrease the expression of KLF2 and KLF4 in endothelial cells (Allen et al, Blood 2011), promoting endothelial cell activation. Subsequent studies demonstrate that these antibodies decrease expression of KLF2 in monocytes as well. Statins have been proposed as a potential alternative to anticoagulation for APS patients, and stimulate the expression of KLFs. We hypothesized that the ability of statins to block endothelial cell activation in response to anti-β2GPI antibodies was mediated by KLFs. Treatment of endothelial cells and monocytes with 100 nM fluvastatin, lovastatin, or simvastatin upregulated KLF2 and KLF4 mRNA, even in the presence of anti-ß2GPI antibodies. In parallel, statin treatment inhibited the anti-β2GPI antibody-mediated induction of E-selectin, VCAM-1, and TF mRNA in endothelial cells, and ICAM-1 and TF mRNA in human monocytes. To assess the dependence of these effects on KLF expression, endothelial cells were pretreated with KLF2 or KLF4 siRNA prior to treatment with statins. siRNA-mediated inhibition of KLF expression completely blocked the ability of statins to prevent anti-β2GPI antibody-induced endothelial cell activation, as measured by adhesion molecule and TF mRNA levels and expression of E-selectin on the endothelial cell surface. Taken together, these data demonstrate that KLFs are critical modulators of the effects of statins on endothelial cells, and that increased expression of KLFs may represent a mechanism by which these drugs inhibit the activation of endothelial cells and monocytes by APLA/anti-β2GPI antibodies. Disclosures: No relevant conflicts of interest to declare.
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Natesampillai, Sekar, Jason Kerkvliet, Peter C. K. Leung, and Johannes D. Veldhuis. "Regulation of Kruppel-like factor 4, 9, and 13 genes and the steroidogenic genes LDLR, StAR, and CYP11A in ovarian granulosa cells." American Journal of Physiology-Endocrinology and Metabolism 294, no. 2 (February 2008): E385—E391. http://dx.doi.org/10.1152/ajpendo.00480.2007.
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Kruppel-like factors (KLFs) are important Sp1-like eukaryotic transcriptional proteins. The LDLR, StAR, and CYP11A genes exhibit GC-rich Sp1-like sites, which have the potential to bind KLFs in multiprotein complexes. We now report that KLF4, KLF9, and KLF13 transcripts are expressed in and regulate ovarian cells. KLF4 and 13, but not KLF9, mRNA expression was induced and then repressed over time ( P < 0.001). Combined LH and IGF-I stimulation increased KLF4 mRNA at 2 h ( P < 0.01), whereas LH decreased KLF13 mRNA at 6 h ( P < 0.05), and IGF-I reduced KLF13 at 24 h ( P < 0.01) compared with untreated control. KLF9 was not regulated by either hormone. Transient transfection of KLF4, KLF9, and KLF13 suppressed LDLR/luc, StAR/luc, and CYP11A/luc by 80–90% ( P < 0.001). Histone-deacetylase (HDAC) inhibitors stimulated LDLR/luc five- to sixfold and StAR/luc and CYP11A/luc activity twofold ( P < 0.001) and partially reversed suppression by all three KLFs ( P < 0.001). Deletion of the zinc finger domain of KLF13 abrogated repression of LDLR/luc. Lentiviral overexpression of the KLF13 gene suppressed LDLR mRNA ( P < 0.001) and CYP11A mRNA ( P = 0.003) but increased StAR mRNA ( P = 0.007). Collectively, these data suggest that KLFs may recruit inhibitory complexes containing HDAC corepressors, thereby repressing LDLR and CYP11A transcription. Conversely, KLF13 may recruit unknown coactivators or stabilize StAR mRNA, thereby explaining enhancement of in situ StAR gene expression. These data introduce new potent gonadal transregulators of genes encoding proteins that mediate sterol uptake and steroid biosynthesis.
6
Stratopoulos, Apostolos, Alexandra Kolliopoulou, Kariofyllis Karamperis, Anne John, Kyriaki Kydonopoulou, George Esftathiou, Argyro Sgourou, et al. "Genomic variants in members of the Krüppel-like factor gene family are associated with disease severity and hydroxyurea treatment efficacy in β-hemoglobinopathies patients." Pharmacogenomics 20, no. 11 (July 2019): 791–801. http://dx.doi.org/10.2217/pgs-2019-0063.
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Aim: β-Type hemoglobinopathies are characterized by vast phenotypic diversity as far as disease severity is concerned, while differences have also been observed in hydroxyurea (HU) treatment efficacy. These differences are partly attributed to the residual expression of fetal hemoglobin (HbF) in adulthood. The Krüppel-like family of transcription factors (KLFs) are a set of zinc finger DNA-binding proteins which play a major role in HbF regulation. Here, we explored the possible association of variants in KLF gene family members with response to HU treatment efficacy and disease severity in β-hemoglobinopathies patients. Materials & methods: Six tag single nucleotide polymorphisms, located in four KLF genes, namely KLF3, KLF4, KLF9 and KLF10, were analyzed in 110 β-thalassemia major patients (TDT), 18 nontransfusion dependent β-thalassemia patients (NTDT), 82 sickle cell disease/β-thalassemia compound heterozygous patients and 85 healthy individuals as controls. Results: Our findings show that a KLF4 genomic variant (rs2236599) is associated with HU treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients and two KLF10 genomic variants (rs980112, rs3191333) are associated with persistent HbF levels in NTDT patients. Conclusion: Our findings provide evidence that genomic variants located in KLF10 gene may be considered as potential prognostic biomarkers of β-thalassemia clinical severity and an additional variant in KLF4 gene as a pharmacogenomic biomarker, predicting response to HU treatment.
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Morris, Valerie A., Carrie Cummings, Brendan Korb, Sean M. Boaglio, and Vivian Oehler. "Krüppel-like Factors KLF4 and KLF2 Regulate microRNA-150 Expression in Myeloid Leukemias." Blood 124, no. 21 (December 6, 2014): 874. http://dx.doi.org/10.1182/blood.v124.21.874.874.
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Abstract Background: Acute myeloid leukemia (AML) is characterized by increased self-renewal of leukemia stem/progenitor cells and failure of differentiation to mature myeloid cells. MicroRNAs (miRNAs) are small single stranded non-coding RNAs 19 to 24 nucleotides in length that regulate expression of tens to hundreds of genes via mRNA degradation or translational repression. MiRNA contributions to normal hematopoiesis have been described and deletion of key miRNA processing enzymes in murine and human cells suggests that miRNA loss contributes to the cancer phenotype and aberrant differentiation in leukemia. By combining observations of miRNA expression in normal hematopoietic progenitor cells and patient AML cells and high-throughput lentiviral expression library screening approaches in AML cell lines we have identified candidate miRNAs that contribute to altered proliferation and differentiation in AML cells. We have previously established 1) that miR-150 expression is decreased in a large subset of primary patient AML samples, in particular poor risk cytogenetic groups, 2) and that miR-150 re-expression induces myeloid differentiation and decreases cell proliferation of normal hematopoietic progenitor cells and AML cell lines and primary patient cells in part through downregulation of MYB expression. MiR-150 loss is relevant in other hematopoietic and solid tumor malignancies where re-expression inhibits cell proliferation, promotes apoptosis and induces reversal of endothelial to mesenchymal transition. Transcription factors are important regulators of myeloid differentiation and cell proliferation. Moreover, as highlighted by recent sequencing of the AML genome, alterations in myeloid transcription factors through mutation, gene rearrangement, and altered expression play a significant role in leukemogenesis. Consequently, we have focused on how myeloid transcription factors regulate miRNA expression, specifically for miR-150. Results: Using 5’RACE from healthy bone marrow RNA, we identified a major transcription start site at 214 basepairs upstream of the pre-miR-150 hairpin. We identified the minimal miR-150 promoter region as -266 to +259 basepairs from the major transcription start site using miR-150 promoter truncation luciferase constructs assayed in myeloid leukemia cell lines (THP-1, K562, and KG1a) and a lymphoid leukemia cell line (Jurkat). We identified DNA binding sites for the Krüppel-like factor (KLF) family of transcription factors that are necessary for miR-150 promoter activity using site-directed DNA mutagenesis of the luciferase reporters. KLFs regulate proliferation, differentiation, pluripotency, migration and inflammation. Depending on cell type and context, KLFs can function as tumor suppressors or oncogenes. To identify which KLF isoforms regulate miR-150 expression, we assayed the ability of KLFs 2, 3, 4, 5, 6, 7, 9, and 10 to induce miR-150 promoter activity using the luciferase reporters and endogenous miR-150 expression by quantitative PCR. KLF2 and KLF4 overexpression increased miR-150 promoter activity in luciferase assays 50-fold and 450-fold respectively in K562 cells. Furthermore, KLF2 and KLF4 induced endogenous miR-150 expression 20-fold and 100-fold respectively as detected by quantitative PCR in both THP-1 and K562 cells. Prior work has established that KLF2 and KLF4 regulate the differentiation of monocytes. We then confirmed that KLF2 and KLF4 overexpression promotes myeloid differentiation of THP-1 cells by flow cytometry and gene expression that was partially reversed by inhibition of miR-150 expression. Conclusions: Previous studies have determined that KLF2 and KLF4 expression are decreased or absent in a significant subset of AML cases. Our observations suggest that loss of KLF2 and KLF4 expression contributes to decreased miR-150 expression which in turn alters cell proliferation and differentiation. Other studies have implicated the cell cycle inhibitor p21WAF1/CIP1 and altered PPAR gamma signaling downstream of KLF4. Nonetheless, our mechanistic understanding is limited. Our work suggests that the loss of miR-150 and other miRNAs downstream of these transcription factors also contributes. Understanding the interactions between KLFs, miR-150 and other miRNAs has broader significance as KLF2 and KLF4 expression is altered in other hematopoietic and solid tumors. Disclosures No relevant conflicts of interest to declare.
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Goswami, Sandeep, Chandrani Sarkar, Wendy L. Frankel, Sujit Basu, and Debanjan Chakroborty. "Abstract 2415: Loss of Krüppel-like factor 4 facilitates disruption of epithelial barrier function in gastric cancer and promotes metastasis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2415. http://dx.doi.org/10.1158/1538-7445.am2022-2415.
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Abstract Stomach or gastric cancer (GC) is one of the most common malignancies observed in men and women worldwide. It is also a leading cause of cancer-related deaths. The disease is potentially curable when diagnosed early with survival records of more than 90%. This number, however, sharply declines to less than 20% when diagnosed at advanced stages. Therefore identification of functional molecular markers that can predict the progression of the disease is of utmost importance as early diagnosis enhances the chances of successful therapeutic intervention. Krüppel-like Factors (KLFs) are a family of evolutionarily conserved transcriptional regulators with zinc finger DNA binding domains. KLFs have been shown to play important roles both in normal development as well as in disease progression. In cancers, KLFs have been reported to regulate diverse cellular processes like cell growth, proliferation and differentiation. Of the 17 KLFs identified to date, KLF4 and KLF 5 show significantly altered expression in GC tissues compared to normal gastric tissues (TCGA sample analysis of gene expression pattern for KLFs). WhileKLF5 typically pro-proliferative and acts as a tumor promoter, KLF4 has been both oncogenic and tumor-suppressive. KLF4 downregulation is associated with a poor prognosis in GC. However, the specific role of KLF4 in GC progression has not been fully elucidated. Using human GC tissues, orthotropic gastric tumors developed in athymic nude mice, and in vitro functional assays, we hereby report that loss of KLF4 in GC disrupts tight junction stability of epithelial cells. Loss of KLF4 expression correlates with altered expression of tight junction proteins such as claudins and ZO1 in GC. Altered expression of these proteins results in disruption of epithelial barrier integrity leading to cell detachment and metastasis. Therefore, our work indicates that loss of KLF4 observed in GC may promote cell metastasis and can serve as a prognostic marker for GC metastasis. The knowledge generated from this study not only imparts insight into the pathogenesis of GC metastasis but also will be helpful in the development of newer treatment strategies in the future. Citation Format: Sandeep Goswami, Chandrani Sarkar, Wendy L. Frankel, Sujit Basu, Debanjan Chakroborty. Loss of Krüppel-like factor 4 facilitates disruption of epithelial barrier function in gastric cancer and promotes metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2415.
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Alder, Jonathan K., Robert W. Georgantas, Richard L. Hildreth, Xiaobing Yu, and Curt I. Civin. "Kruppel-Like Factor 4 Upregulates p21 and Downregulates Proliferation of Human and Mouse HSPCs, but Is Not Essential for Mouse HSPC Repopulation." Blood 108, no. 11 (November 16, 2006): 1317. http://dx.doi.org/10.1182/blood.v108.11.1317.1317.
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Abstract Several Kruppel-like factor family members, including KLF1, KLF2, KLF3, and KLF6 have pivotal roles in hematopoiesis. Experiments in zebrafish have suggested that KLF4 may play a similar role. Here we found that enforced expression of KLF4 in hematopoietic cells induced cell cycle arrest without triggering apoptosis. Based on the high levels of expression of KLF4 in mouse and human hematopoietic stem-progenitor cells (HSPCs), we hypothesized and demonstrated that KLF4 regulates proliferation of these cells through regulation of p21cip1/waf1 (p21). Nevertheless, KLF4−/− mouse fetal liver cells had normal numbers of all mature lineages and provided radioprotection, similar to wild type (wt) controls. Furthermore, in long-term competitive repopulation assays, KLF4−/− mouse HSPCs demonstrated hematopoietic potency equivalent to wt. We found that KLF2 is expressed at higher levels than KLF4 in mouse HSPCs and is a more potent activator of p21, suggesting that KLF2 (and/or other KLF family members) may play a compensatory role in KLF4−/− HSPCs. Thus, although is not essential for their normal development and function, KLF4 expression is sufficient to induce p21-mediated cell cycle arrest in hematopoietic cells.
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Ilsley, Melissa, Kevin R. Gillinder, Graham Magor, Merlin Crossley, and Andrew C. Perkins. "Fine-Tuning Erythropoiesis By Competition Between Krüppel-like Factors for Promoters and Enhancers." Blood 128, no. 22 (December 2, 2016): 1036. http://dx.doi.org/10.1182/blood.v128.22.1036.1036.
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Abstract Krüppel-like factors (KLF) are a group of 17 transcription factors with highly conserved DNA-binding domains that contain three C-terminal C2H2-type zinc fingers and a variable N-terminal domain responsible for recruiting cofactors 1. KLFs participate in diverse roles in stem cell renewal, early patterning, organogenesis and tissue homeostasis. Krüppel-like factor 1 (KLF1) is an erythroid-specific KLF responsible for coordinating many aspects of terminal erythroid differentiation 2. It functions as a transcriptional activator by recruiting cofactors such as p300 and chromatin modifiers such as Brg1 via N-terminal transactivation domains 3. Krüppel-like factor 3 (KLF3) acts as a transcriptional repressor via recruitment of C-terminal binding proteins 4. In erythropoiesis, KLF1 directly activates KLF3 via an erythroid-specific promoter 5. Some KLF1 target genes are upregulated in Klf3-/- fetal liver suggesting possible competition between the two factors for promoter/enhancer occupancy. We generated three independent clones of the erythroid cell line, J2E, by retroviral transduction of a tamoxifen-inducible version of Klf3 (Klf3-ERTM) as previously described 6. Using next-generation sequencing of newly synthesised RNA (4sU-labeling), we show KLF3 induction leads to immediate repression of a set of ~580 genes; a subset of these (54) are also directly induced by KLF1 in K1-ER cells, suggesting antagonistic regulation. Indeed, ChIP-seq revealed KLF1 and KLF3 bind many of the same regulatory sites within the erythroid cell genome. KLF3 also binds an independent set of promoters which are not bound by KLF1, suggesting it also plays a KLF1-independent role in maintenance of gene repression. By de novo motif discovery we confirm KLF3 binds preferably to a extended CACCC motif, R-CCM-CRC-CCN, so the DNA-binding specificity in vivo is indistinguishable from the KLF1 binding specificity 7, and is independent of co-operating DNA-binding proteins or cofactors. Using Q-PCR of KLF1 ChIPed DNA in J2E-Klf3ER cells, we show that overexpression of KLF3 directly displaces KLF1 from many key target sites such as the E2f2 enhancer and this leads to down regulation of gene expression. This is the first proof that KLF1 and KLF3 directly compete for key promoters and enhancers which drive erythroid cell proliferation and differentiation. We propose KLF3 acts to 'fine-tune' transcription in erythropoiesis by repressing genes activated by KLF1 and that this negative feedback system is necessary for precise control over the generation of erythrocytes. It also works independently of KLF1 perhaps via competition for binding with other KLF/SP factors. References: 1. van Vliet J, Crofts LA, Quinlan KG, Czolij R, Perkins AC, Crossley M. Human KLF17 is a new member of the Sp/KLF family of transcription factors. Genomics. 2006;87(4):474-482. 2. Tallack MR, Magor GW, Dartigues B, et al. Novel roles for KLF1 in erythropoiesis revealed by mRNA-seq. Genome Res. 2012. 3. Perkins A, Xu X, Higgs DR, et al. "Kruppeling" erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants unveiled by genomic sequencing. Blood. 2016. 4. Dewi V, Kwok A, Lee S, et al. Phosphorylation of Kruppel-like factor 3 (KLF3/BKLF) and C-terminal binding protein 2 (CtBP2) by homeodomain-interacting protein kinase 2 (HIPK2) modulates KLF3 DNA binding and activity. J Biol Chem. 2015;290(13):8591-8605. 5. Funnell AP, Maloney CA, Thompson LJ, et al. Erythroid Kruppel-like factor directly activates the basic Kruppel-like factor gene in erythroid cells. Mol Cell Biol. 2007;27(7):2777-2790. 6. Coghill E, Eccleston S, Fox V, et al. Erythroid Kruppel-like factor (EKLF) coordinates erythroid cell proliferation and hemoglobinization in cell lines derived from EKLF null mice. Blood. 2001;97(6):1861-1868. 7. Tallack MR, Whitington T, Yuen WS, et al. A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells. Genome Res. 2010;20(8):1052-1063. Disclosures Perkins: Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria.
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McConnell, Beth B., and Vincent W. Yang. "Mammalian Krüppel-Like Factors in Health and Diseases." Physiological Reviews 90, no. 4 (October 2010): 1337–81. http://dx.doi.org/10.1152/physrev.00058.2009.
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The Krüppel-like factor (KLF) family of transcription factors regulates diverse biological processes that include proliferation, differentiation, growth, development, survival, and responses to external stress. Seventeen mammalian KLFs have been identified, and numerous studies have been published that describe their basic biology and contribution to human diseases. KLF proteins have received much attention because of their involvement in the development and homeostasis of numerous organ systems. KLFs are critical regulators of physiological systems that include the cardiovascular, digestive, respiratory, hematological, and immune systems and are involved in disorders such as obesity, cardiovascular disease, cancer, and inflammatory conditions. Furthermore, KLFs play an important role in reprogramming somatic cells into induced pluripotent stem (iPS) cells and maintaining the pluripotent state of embryonic stem cells. As research on KLF proteins progresses, additional KLF functions and associations with disease are likely to be discovered. Here, we review the current knowledge of KLF proteins and describe common attributes of their biochemical and physiological functions and their pathophysiological roles.
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Allen, Kristi L., Mukesh K. Jain, and Keith R. McCrae. "Decreased Expression of KLF2 and KLF4 Induced by Antiphospholipid Antibodies Promotes NF-Kb-Mediated Endothelial Cell Activation and Is Modulated by CBP/p300." Blood 116, no. 21 (November 19, 2010): 4315. http://dx.doi.org/10.1182/blood.v116.21.4315.4315.
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Abstract Abstract 4315 Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy loss in the presence of antiphospholipid antibodies (APLA). These antibodies are directed primarily against phospholipid-bound β2-glycoprotein I (β2GPI). Anti-β2GPI antibodies activate endothelial cells, enhancing the expression of adhesion molecules and tissue factor, and the secretion of proinflammatory cytokines. Krüppel-like factors (KLF) regulate endothelial cell inflammatory responses. KLF2 and KLF4 mediate anti-atherosclerotic and anti-inflammatory effects in endothelial cells, and we have hypothesized that alterations in the expression or activity of KLF2 or KLF4 may modulate the endothelial cell response to APLA. In preliminary studies, we have observed that endothelial cell activation induced by APLA/anti-β2GPI antibodies inhibits the expression of KLF2 and KLF4, and as demonstrated by our laboratory and others, is accompanied by activation of NF-kB. However, forced expression of KLF2 or KLF4 by plasmid-mediated transfection of endothelial cells inhibits neither the phosphorylation of ser536 of the p65 subunit of NF-kB, nor the nuclear translocation of p65 in response to APLA/anti-β2GPI antibodies. Despite the lack of effect on forced KLF2 or KLF4 expression in endothelial cells on p65 phosphorylation, expression of either of these factors inhibits NF-κB transcriptional activity with corresponding inhibition of cellular activation as measured by inhibition of cell-surface E-selectin expression as well as E-selectin promoter activity. Inhibition of NF-kB transcriptional activity by KLF2 and KLF4 appears to be due to recruitment of the CBP/p300 cofactor away from NF-kB by KLF2 or KLF4, since augmenting the cellular pool of CBP/p300 by transfection restores NF-κB activity and endothelial cell activation responses. Similarly, treatment of APLA-activated endothelial cells with CBP/p300 siRNA inhibits NF-kB transcriptional activity regardless of the levels of KLF2 or KLF4. These data suggest that APLA inhibit KLF expression and that these changes promote the acquisition of a prothrombotic endothelial cell phenotype. CBP/p300 may serve as a molecular switch that determines the relative antithrombotic activities of KLFs versus the prothrombotic, inflammatory responses induced by NF-kB in APLA/anti-β2GPI antibody activated endothelial cells. Disclosures: No relevant conflicts of interest to declare.
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Samak, Mostafa, Andreas Kues, Diana Kaltenborn, Lina Klösener, Matthias Mietsch, Giulia Germena, and Rabea Hinkel. "Dysregulation of Krüppel-Like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes." International Journal of Molecular Sciences 24, no. 3 (January 27, 2023): 2482. http://dx.doi.org/10.3390/ijms24032482.
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Cardiovascular complications are the main cause of morbidity and mortality from diabetes. Herein, vascular inflammation is a major pathological manifestation. We previously characterized the cardiac microvascular inflammatory phenotype in diabetic patients and highlighted micro-RNA 92a (miR-92a) as a driver of endothelial dysfunction. In this article, we further dissect the molecular underlying of these findings by addressing anti-inflammatory Krüppel-like factors 2 and 4 (KLF2 and KLF4). We show that KLF2 dysregulation in diabetes correlates with greater monocyte adhesion as well as migratory defects in cardiac microvascular endothelial cells. We also describe, for the first time, a role for myocyte enhancer factor 2D (MEF2D) in cardiac microvascular dysfunction in diabetes. We show that both KLFs 2 and 4, as well as MEF2D, are dysregulated in human and porcine models of diabetes. Furthermore, we prove a direct interaction between miR-92a and all three targets. Altogether, our data strongly qualify miR-92a as a potential therapeutic target for diabetes-associated cardiovascular disease.
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Cao, Zhuoxiao, Xinghui Sun, Basak Icli, Akm Khyrul Wara, and Mark W. Feinberg. "Role of Krüppel-like factors in leukocyte development, function, and disease." Blood 116, no. 22 (November 25, 2010): 4404–14. http://dx.doi.org/10.1182/blood-2010-05-285353.
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Abstract The Krüppel-like transcription factor (KLF) family participates in diverse aspects of cellular growth, development, differentiation, and activation. Recently, several groups have identified new connections between the function of these factors and leukocyte responses in health and disease. Gene targeting of individual KLFs in mice has uncovered novel and unexpected physiologic roles among myeloid and lymphocyte cell lineage maturation, particularly in the bone marrow niche and blood. In addition, several KLF family members are downstream targets of stimuli and signaling pathways critical to T-cell trafficking, T regulatory cell differentiation or suppressor function, monocyte/macrophage activation or renewal, and B memory cell maturation or activation. Indeed, KLFs have been implicated in subtypes of leukemia, lymphoma, autoimmunity, and in acute and chronic inflammatory disease states, such as atherosclerosis, diabetes, and airway inflammation, raising the possibility that KLFs and their upstream signals are of therapeutic interest. This review focuses on the relevant literature of Krüppel-like factors in leukocyte biology and their implications in clinical settings.
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Simmen, R. C. M., J. M. P. Pabona, M. C. Velarde, C. Simmons, O. Rahal, and F. A. Simmen. "The emerging role of Krüppel-like factors in endocrine-responsive cancers of female reproductive tissues." Journal of Endocrinology 204, no. 3 (October 15, 2009): 223–31. http://dx.doi.org/10.1677/joe-09-0329.
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Krüppel-like factors (KLFs), of which there are currently 17 known protein members, belong to the specificity protein (Sp) family of transcription factors and are characterized by the presence of Cys2/His2 zinc finger motifs in their carboxy-terminal domains that confer preferential binding to GC/GT-rich sequences in gene promoter and enhancer regions. While previously regarded to simply function as silencers of Sp1 transactivity, many KLFs are now shown to be relevant to human cancers by their newly identified abilities to mediate crosstalk with signaling pathways involved in the control of cell proliferation, apoptosis, migration, and differentiation. Several KLFs act as tumor suppressors and/or oncogenes under distinct cellular contexts, underscoring their prognostic potential for cancer survival and outcome. Recent studies suggest that a number of KLFs can influence steroid hormone signaling through transcriptional networks involving steroid hormone receptors and members of the nuclear receptor family of transcription factors. Since inappropriate sensitivity or resistance to steroid hormone actions underlies endocrine-related malignancies, we consider the intriguing possibility that dysregulation of expression and/or activity of KLF members is linked to the pathogenesis of endometrial and breast cancers. In this review, we focus on recently described mechanisms of actions of several KLFs (KLF4, KLF5, KLF6, and KLF9) in cancers of the mammary gland and uterus. We suggest that understanding the mode of actions of KLFs and their functional networks may lead to the development of novel therapeutics to improve current prospects for cancer prevention and cure.
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Basu, Priyadarshi, Tina K. Lung, Wafaa Lemsaddek, Thanh Giang Sargent, David C. Williams, Mohua Basu, Latasha C. Redmond, Jerry B. Lingrel, Jack L. Haar, and Joyce A. Lloyd. "EKLF and KLF2 have compensatory roles in embryonic β-globin gene expression and primitive erythropoiesis." Blood 110, no. 9 (November 1, 2007): 3417–25. http://dx.doi.org/10.1182/blood-2006-11-057307.
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Abstract The Krüppel-like C2/H2 zinc finger transcription factors (KLFs) control development and differentiation. Erythroid Krüppel-like factor (EKLF or KLF1) regulates adult β-globin gene expression and is necessary for normal definitive erythropoiesis. KLF2 is required for normal embryonic Ey- and βh1-, but not adult βglobin, gene expression in mice. Both EKLF and KLF2 play roles in primitive erythroid cell development. To investigate potential interactions between these genes, EKLF/KLF2 double-mutant embryos were analyzed. EKLF−/−KLF2−/− mice appear anemic at embryonic day 10.5 (E10.5) and die before E11.5, whereas single-knockout EKLF−/− or KLF2−/− embryos are grossly normal at E10.5 and die later than EKLF−/−KLF2−/− embryos. At E10.5, Ey- and βh1-globin mRNA is greatly reduced in EKLF−/−KLF2−/−, compared with EKLF−/− or KLF2−/− embryos, consistent with the observed anemia. Light and electron microscopic analyses of E9.5 EKLF−/−KLF2−/− yolk sacs, and cytospins, indicate that erythroid and endothelial cells are morphologically more abnormal than in either single knockout. EKLF−/−KLF2−/− erythroid cells are markedly irregularly shaped, suggesting membrane abnormalities. EKLF and KLF2 may have coordinate roles in a common progenitor to erythroid and endothelial cells. The data indicate that EKLF and KLF2 have redundant functions in embryonic β-like globin gene expression, primitive erythropoiesis, and endothelial development.
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Basu, Priyadarshi, Pamela E. Morris, Jack L. Haar, Maqsood A. Wani, Jerry B. Lingrel, Karin M. L. Gaensler, and Joyce A. Lloyd. "KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic β-like globin genes in vivo." Blood 106, no. 7 (October 1, 2005): 2566–71. http://dx.doi.org/10.1182/blood-2005-02-0674.
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AbstractThe Krüppel-like factors (KLFs) are a family of C2/H2 zinc finger DNA-binding proteins that are important in controlling developmental programs. Erythroid Krüppel-like factor (EKLF or KLF1) positively regulates the β-globin gene in definitive erythroid cells. KLF2 (LKLF) is closely related to EKLF and is expressed in erythroid cells. KLF2-/- mice die between embryonic day 12.5 (E12.5) and E14.5, because of severe intraembryonic hemorrhaging. They also display growth retardation and anemia. We investigated the expression of the β-like globin genes in KLF2 knockout mice. Our results show that KLF2-/- mice have a significant reduction of murine embryonic Ey- and βh1-globin but not ζ-globin gene expression in the E10.5 yolk sac, compared with wild-type mice. The expression of the adult βmaj- and βmin-globin genes is unaffected in the fetal livers of E12.5 embryos. In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic ϵ-globin gene but not the adult β-globin gene, suggesting that this developmental-stage-specific role is evolutionarily conserved. KLF2 also plays a role in the maturation and/or stability of erythroid cells in the yolk sac. KLF2-/- embryos have a significantly increased number of primitive erythroid cells undergoing apoptotic cell death. (Blood. 2005;106: 2566-2571)
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Salmon, Jessica M., Casie Leigh Reed, Maddyson Bender, Helen Lorraine Mitchell, Vanessa Fox, Graham William Magor, Matthew Sweet, and Andrew Charles Perkins. "KLF3 Represses the Inflammatory Response in Macrophages." Blood 136, Supplement 1 (November 5, 2020): 36. http://dx.doi.org/10.1182/blood-2020-142373.
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Krüppel-like factors (KLFs) are a family of transcription factors that play essential roles in the development and differentiation of the hematopoietic system. These transcription factors possess highly conserved C-terminal zinc-finger motifs, which enable their binding to GC-rich, or CACC-box, motifs in promoter and enhancer regions of target genes. The N-terminal domains of these proteins are more varied and mediate the recruitment of various co-factors, which can form a complex with either activator or repressor function. Acting primarily as a gene repressor through its recruitment of CtBPs and histone deacetylases (HDACs) [1], we have recently shown that KLF3 competes with KLF1 bound sites in the genome to repress gene expression during erythropoiesis [2]. However, the function of Klf3 in other lineages has been less well studied. This widely expressed transcription factor has reported roles in the differentiation of marginal zone B cells, eosinophil function and inflammation [3]. We utilised the Klf3-null mouse model [4] to more closely examine the role of Klf3 in innate inflammatory cells. These mice exhibit elevated white cell counts, including monocytes (Figure 1A), and inflammation of the skin. Conditional knockout of Klf4 in myeloid cells leads to a deficiency of inflammatory macrophages [5]. To test our hypothesis KLF3 normally represses inflammation, perhaps by antagonising the action of KLF4, bone-marrow derived macrophages (BMDM) were generated from wild-type or Klf3-null mice and stimulated with the bacterial toxin lipopolysaccharide (LPS). In wild type BMDM, LPS induces Klf3 gene expression and activation then delayed repression of target genes such as Lgals3 (galectin-3) over a 21 hour time course (Figure 1B). Quantitative real-time PCR and mRNA-seq of WT v Klf3-null macrophages identified ~100 differentially expressed genes involved in proliferation, macrophage activation and inflammation. We transduced the monocyte cell line, RAW264.7 (that expresses Klf4, Klf3 and Klf2), with a retroviral vector expressing a tamoxifen-inducible KLF3-ER fusion construct. KLF3 induced cell cycle arrest and macrophage differentiation. We will report on KLF3-induced gene expression changes (repression and activation), and ChIP-seq for KLF3, in RAW cells. The results shed light on the mechanism by which KLF3 normally represses monocyte/macrophage responses to infection. This study highlights the importance of key transcriptional regulators that tightly control gene expression during inflammation. Loss of Klf3 leads to alterations in this process, resulting in hyper-activation of inflammatory macrophages, increased white cell counts and inflammation of the skin. A greater knowledge of the inflammatory process and how it is regulated is important for our understanding of acute infection and inflammatory disease. Further studies are planned to investigate the role of the KLF3 transcription factor in response to inflammation in vivo. References: 1. Pearson, R., et al., Kruppel-like transcription factors: A functional family. Int J Biochem Cell Biol, 2007. W2. Ilsley, M.D., et al., Kruppel-like factors compete for promoters and enhancers to fine-tune transcription. Nucleic Acids Res, 2017. 45(11): p. 6572-6588. W3. Knights, A.J., et al., Kruppel-like factor 3 (KLF3) suppresses NF-kappaB-driven inflammation in mice. J Biol Chem, 2020. 295(18): p. 6080-6091. W4. Sue, N., et al., Targeted disruption of the basic Kruppel-like factor gene (Klf3) reveals a role in adipogenesis. Mol Cell Biol, 2008. 28(12): p. 3967-78. W5. Alder, J.K., et al., Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol, 2008. 180(8): p. 5645-52. Figure 1: Elevated WCC (A) and inflammatory markers (B) in BMDM after LPS stimulation. 1. Total WCC in adult mice (3-6 months old) of the indicated genotypes. There is a statistically significant increase in the WCC in Klf3-/- v wild type mice (P<0.001 by student's t test). B. Time course (hours) after LPS stimulation of confluent BMDM. Klf3 is induced 3-fold by LPS and KLF3-target genes such as Lgals3 are not fully repressed by 21 hours in knockout mice. Figure 1 Disclosures Perkins: Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Tallack, Michael, Thomas Whitington, Brooke Gardiner, Eleanor Wainwright, Janelle Keys, Marion Monet, Ehsan Nourbakhsh, et al. "Klf1 Regulatory Networks in Primary Erythroid Cells." Blood 114, no. 22 (November 20, 2009): 1462. http://dx.doi.org/10.1182/blood.v114.22.1462.1462.
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Abstract Abstract 1462 Poster Board I-485 Klf1/Eklf regulates a diverse suite of genes to direct erythroid cell differentiation from bi-potent progenitors. To determine the local cis-regulatory contexts and transcription factor networks in which Klf1 works, we performed Klf1 ChIP-seq using the SOLiD deep sequencing platform. We mapped more than 10 million unique 35mer tags and found ∼1500 sites in the genome of primary fetal liver erythroid cells are occupied by endogenous Klf1. Many reside within well characterised erythroid gene promoters (e.g. b-globin) or enhancers (e.g. E2f2 intron 1), but some are >100kb from any known gene. We tested a number of Klf1 bound promoter and intragenic sites for activity in erythroid cell lines and zebrafish. Our data suggests Klf1 directly regulates most aspects of terminal erythroid differentiation including synthesis of the hemoglobin tetramer, construction of a deformable red cell membrane and cytoskeleton, bimodal regulation of proliferation, and co-ordination of anti-apoptosis and enucleation pathways. Additionally, we suggest new mechanisms for Klf1 co-operation with other transcription factors such as those of the gata, ets and myb families based on over-representation and spatial constraints of their binding motifs in the vicinity of Klf1-bound promoters and enhancers. Finally, we have identified a group of ∼100 Klf1-occupied sites in fetal liver which overlap with Klf4-occupied sites in ES cells defined by Klf4 ChIP-seq. These sites are associated with genes controlling the cell cycle and proliferation and are Klf4-dependent in skin, gut and ES cells, suggesting a global paradigm for Klfs as regulators of differentiation in many, if not all, cell types. Disclosures No relevant conflicts of interest to declare.
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Xiong, Qunli, Zhiwei Zhang, Yang Yang, Yongfeng Xu, Ying Zhou, Su Zhang, Jinlu Liu, Ying Zheng, and Qing Zhu. "Krüppel-like Factor 6 Suppresses the Progression of Pancreatic Cancer by Upregulating Activating Transcription Factor 3." Journal of Clinical Medicine 12, no. 1 (December 27, 2022): 200. http://dx.doi.org/10.3390/jcm12010200.
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Background: As a member of the Krüppel-like factor (KLFs) family, Krüppel-like factor 6 (KLF6) plays a critical role in regulating key cellular functions. Presently, scholars have proved the important role of KLF6 in the tumorigenesis of certain cancers through a large number of experiments. However, gaps still remain in our knowledge of the role of KLF6 in pancreatic cancer (PAAD). Therefore, this paper mainly investigates the role of KLF6 in the progression of pancreatic cancer. Methods: The expression pattern of KLF6 in pancreatic cancer was explored in pancreatic cancer tissues and cell lines. Then, we investigated the prognostic value of KLF6 in pancreatic cancer by immunohistochemical assays. Next, Cell Counting Kit-8 (CCK8) and clone information assays were employed to explore the proliferation of PAAD affected by KLF6. The metastasis and epithelial-mesenchymal transition (EMT) abilities affected by KLF6 were identified through transwell invasion as well as migration assays and western blots. Finally, the TRRUST tool was used to analyze the potential targeted genes of KLF6. The results were verified by Quantificational Real-time Polymerase Chain Reaction (qRT-PCR), western blot and rescue assays. Results: KLF6 expresses lowly in pancreatic cancer compared to corresponding normal tissues and relates to poor survival times. Overexpression of KLF6 inhibits the proliferation, metastasis, and EMT progression in pancreatic cancer cells. Further studies suggest that KLF6 could upregulate ATF3 in PAAD. Conclusions: Our results suggest that KLF6 can be a useful factor in predicting the prognosis of PAAD patients and that it inhibits the progression of pancreatic cancer by upregulating activating transcription factor 3 (ATF3).
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Hiroi, Toyoko, Clayton B. Deming, Haige Zhao, Baranda S. Hansen, Elisabeth K. Arkenbout, Thomas J. Myers, William J. Riordan, Michael A. McDevitt, and Jeffrey J. Rade. "Bortezomib Improves Endothelial Thromboresistance Via Induction of KLF Transcription Factors." Blood 112, no. 11 (November 16, 2008): 1890. http://dx.doi.org/10.1182/blood.v112.11.1890.1890.
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Abstract Background: Patients with multiple myeloma (MM) are at high risk for venothromboembolic events (VTE). Recent studies, however, suggest that MM patients treated with bortezomib, an approved proteasome inhibitor with potent NF-kB inhibitory effects, appear to have a lower risk of VTE compared to those treated with other therapies. We hypothesize that this could be due to a beneficial effect of bortezomib on endothelial thromboresistance. Methods and Results: Human umbilical vein endothelial cells (HUVECs) were incubated with bortezomib for 20 hours and changes in the expression of a panel of coagulation and inflammation-related genes measured by qPCR. Bortezomib stimulated baseline expression of anticoagulant genes (thrombomodulin (TM), eNOS and tissue factor pathway inhibitor), suppressed baseline expression of pro-coagulant genes (vWF and protease activated receptor-1) and suppressed cytokine-mediated induction of E-selectin, VCAM-1 and tissue factor. Most pronounced, was the dose-dependent upregulation of TM, a member of the protein C anticoagulant pathway (229 ± 15% and 341 ± 7% of control, at 5 nM and 10 nM bortezomib, respectively, p <0.0001). Induction of TM gene expression was paralleled by a significant upregulation of TM protein expression, assessed by Western blot analysis, and by an increased capacity to generate activated protein C (205 ± 5% of control with 5 nM bortezomib, p <0.0001). Bortezomib-induced TM upregulation was blocked by cycloheximide, suggesting that induction of a transcriptional pathway, and not simply inhibition of the NF-kB pathway, was required. We therefore examined the effects of bortezomib on the expression of several Krüppel like transcription factors (KLFs) that are known to be important regulators of TM expression and endothelial thromboresistance. Bortezomib significantly upregulated the expression of KLF2, KLF4 and KLF6 in HUVECs (18 ± 1, 8 ± 1 and 2 ± 0.1-fold of control, respectively, p <0.0001 for each) following a 5 nM exposure for 20 hours. Knock-down experiments using small interfering RNAs revealed that KLF2 and KLF4, but not KLF6, play critical and synergistic roles in mediating bortezomib-induced TM upregulation. To determine the in vivo significance of these findings, mice were administered ascending doses of bortezomib for 7 days and TM expression measured in selected tissue. Compared to controls, a dose of 0.8 mg/kg bortezomib ip increased TM gene and protein expression in the liver by 7.0 ± 1.1 and 9.5 ± 2.9-fold, respectively (p <0.0001 for each) and TM gene expression in the kidney by 2.5 ± 0.2-fold (p <0.0001). There was no significant change in TM expression observed in heart and lung tissue. Paralleling changes in TM expression, expression of the KLF2 and KLF4 genes was also increased in the liver (2.1 ± 0.3 and 6.2 ± 1.5-fold of controls, respectively, p <0.001 for each) and kidney (1.9 ± 0.2 and 2.9 ± 0.3-fold of controls, respectively, p <0.01 for each), but not in heart or lung tissue. Conclusions: Bortezomib markedly stimulates endothelial TM expression, both in vitro and in vivo in a tissue-specific manner. TM upregulation appears dependent on the induction of KLF2 and KLF4 transcription factors rather than by inhibition of the NFkB pathways. Our findings provide a rationale for further studies of bortezomib-induced enhancement of endothelial thromboresistance in patients with MM and may help explain why these patients are reduced risk for VTE.
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Itakura, Meiji, Masato Shingoji, and Toshihiko Iizasa. "Expressions of KLF2 and chemokine receptor CCR7 in pulmonary adenocarcinoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e21054-e21054. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21054.
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e21054 Background: Chemokines and chemokine receptors not only have the powerful ability in cancer metastasis and tumorigenesis, but also act as anti-tumorgenic ability. Lung Krueppel-like factor (LKLF, KLF2) is a member of the family of the Krueppel-like factors (KLFs). KLF2 was initially described as a lung-specific transcription factor. KLF2 is reported to regulate some malignant cells. We examined and evaluated the effect of KLF2 on pulmonary adenocarcinoma and the relationship of their mRNA expression with CCR7, EGFR and p53 genetical mutations in pulmonary adenocarcinoma. Methods: 120 patients of stage I to IV with pulmonary adenocarcinoma were included in this retrospective analysis. The expression of CCR7 and KLF2 mRNA expression in surgically resected pulmonary adenocarcinoma specimens were examined and evaluated the relation to prognosis, the effect of EGFR and p53 genetical mutations. Results: High mRNA expression of KLF2 in lung cancer patients indicated significantly good prognosis than the groups of low expressions (p= 0.0066, HR= 2.008, 95% CI of ratio 1.215 to 3.319). The expression of KLF2 mRNA had relationships with CCR7 mRNA expression in pulmonary adenocarcinoma. Moreover the mRNA expression of KLF2 in pulmonary adenocarcinoma specimens was influenced by the mutation of p53 mutation in lung cancer specimens. There was no significant difference within KLF2 mRNA expression quantities of EGFR mutation positive and negative group. Conclusions: We propose KLF2 as clinical good prognostic factors and that KLF2 has strong relation with CCR7 and p53 genetical mutation mRNA expression in pulmonary adenocarcinoma.
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Laub, Friedrich, Lei Lei, Hideaki Sumiyoshi, Daisuke Kajimura, Cecilia Dragomir, Silvia Smaldone, Adam C. Puche, et al. "Transcription Factor KLF7 Is Important for Neuronal Morphogenesis in Selected Regions of the Nervous System." Molecular and Cellular Biology 25, no. 13 (July 1, 2005): 5699–711. http://dx.doi.org/10.1128/mcb.25.13.5699-5711.2005.
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ABSTRACT The Krüppel-like transcription factors (KLFs) are important regulators of cell proliferation and differentiation in several different organ systems. The mouse Klf7 gene is strongly active in postmitotic neuroblasts of the developing nervous system, and the corresponding protein stimulates transcription of the cyclin-dependent kinase inhibitor p21 waf/cip gene. Here we report that loss of KLF7 activity in mice leads to neonatal lethality and a complex phenotype which is associated with deficits in neurite outgrowth and axonal misprojection at selected anatomical locations of the nervous system. Affected axon pathways include those of the olfactory and visual systems, the cerebral cortex, and the hippocampus. In situ hybridizations and immunoblots correlated loss of KLF7 activity in the olfactory epithelium with significant downregulation of the p21 waf/cip and p27 kip1 genes. Cotransfection experiments extended the last finding by documenting KLF7's ability to transactivate a reporter gene construct driven by the proximal promoter of p27 kip1 . Consistent with emerging evidence for a role of Cip/Kip proteins in cytoskeletal dynamics, we also documented p21waf/cip and p27kip1 accumulation in the cytoplasm of differentiating olfactory sensory neurons. KLF7 activity might therefore control neuronal morphogenesis in part by optimizing the levels of molecules that promote axon outgrowth.
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Wu, Kaikai, Zhiying Jia, Qi’ai Wang, Zhenlin Wei, Zunchun Zhou, and Xiaolin Liu. "Identification, expression analysis, and the regulating function on C/EBPs of KLF10 in Dalian purple sea urchin, Strongylocentrotus nudus." Genome 60, no. 10 (October 2017): 837–49. http://dx.doi.org/10.1139/gen-2017-0033.
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Accumulating evidence indicates that Krüppel-like factors (KLFs) play important roles in fat biology via the regulation of CCAAT/enhancer binding proteins (C/EBPs). However, KLFs and C/EBPs have not been identified from Strongylocentrotus nudus, and their roles in this species are not clear. In this study, the full-length cDNA of S. nudus KLF10 (SnKLF10) and three cDNA fragments of S. nudus C/EBPs (SnC/EBPs) were obtained. Examination of tissue distribution and expression patterns during gonadal development implied that SnKLF10 and SnC/EBPs play important roles in gonadal lipogenesis. The presence of transcription factor-binding sites (TFBSs) for KLFs in SnC/EBPs, and the results of an over-expression assay, revealed that SnKLF10 negatively regulates the transcription of SnC/EBPs. In addition, the core promoter regions of SnC/EBPs were determined, and multiple TFBSs for transcription factor (TFs) were identified, which are potential regulators of SnC/EBP transcription. Taken together, these results suggest that SnC/EBP genes are potential targets of SnKLF10, and that SnKLF10 plays a role in lipogenesis by repressing the transcription of SnC/EBPs. These findings provide information for further studies of KLF10 in invertebrates and provide new insight into the regulatory mechanisms of C/EBP transcription.
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Sangwung, Panjamaporn, Guangjin Zhou, Yuan Lu, Xudong Liao, Benlian Wang, Stephanie M. Mutchler, Megan Miller, Mark R. Chance, Adam C. Straub, and Mukesh K. Jain. "Regulation of endothelial hemoglobin alpha expression by Kruppel-like factors." Vascular Medicine 22, no. 5 (August 19, 2017): 363–69. http://dx.doi.org/10.1177/1358863x17722211.
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Hemoglobin subunit alpha (HBA) expression in endothelial cells (ECs) has recently been shown to control vascular tone and function. We sought to elucidate the transcriptional regulation of HBA expression in the EC. Gain of KLF2 or KLF4 function studies led to significant induction of HBA in ECs. An opposite effect was observed in ECs isolated from animals with endothelial-specific ablation of Klf2, Klf4 or both. Promoter reporter assays demonstrated that KLF2/KLF4 transactivated the hemoglobin alpha promoter, an effect that was abrogated following mutation of all four putative KLF-binding sites. Fine promoter mutational studies localized three out of four KLF-binding sites (sites 2, 3, and 4) as critical for the transactivation of the HBA promoter by KLF2/KLF4. Chromatin immunoprecipitation studies showed that KLF4 bound to the HBA promoter in ECs. Thus, KLF2 and KLF4 serve as important regulators that promote HBA expression in the endothelium.
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Allen, Kristi L., Anne Hamik, Mukesh K. Jain, and Keith R. McCrae. "Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors." Blood 117, no. 23 (June 9, 2011): 6383–91. http://dx.doi.org/10.1182/blood-2010-10-313072.
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Abstract Antiphospholipid syndrome is characterized by thrombosis and/or recurrent pregnancy loss in the presence of antiphospholipid antibodies (APLAs). The majority of APLAs are directed against phospholipid-binding proteins, particularly β2-glycoprotein I (β2GPI). Anti-β2GPI antibodies activate endothelial cells in a β2GPI-dependent manner through a pathway that involves NF-κB. Krüppel-like factors (KLFs) play a critical role in regulating the endothelial response to inflammatory stimuli. We hypothesized that activation of endothelial cells by APLA/anti-β2GPI antibodies might be associated with decreased expression of KLFs, which in turn might facilitate cellular activation mediated through NF-κB. Our experimental results confirmed this hypothesis, demonstrating markedly decreased expression of KLF2 and KLF4 after incubation of cells with APLA/anti-β2GPI antibodies. Restoration of KLF2 or KLF4 levels inhibited NF-κB transcriptional activity and blocked APLA/anti-β2GPI–mediated endothelial activation despite NF-κB p65 phosphorylation. Chromatin immunoprecipitation analysis demonstrated that inhibition of NF-κB transcriptional activity by KLFs reflects sequestration of the cotranscriptional activator CBP/p300, making this cofactor unavailable to NF-κB. These findings suggest that the endothelial response to APLA/anti-β2GPI antibodies reflects competition between KLFs and NF-κB for their common cofactor, CBP/p300. Taken together, these observations are the first to implicate the KLFs as novel participants in the endothelial proinflammatory response to APLA/anti-β2GPI antibodies.
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Kuneš, Pavel, Zdeňka Holubcová, and Jan Krejsek. "Occurrence and Significance of the Nuclear Transcription Factor Krüppel-Like Factor 4 (KLF4) in the Vessel Wall." Acta Medica (Hradec Kralove, Czech Republic) 52, no. 4 (2009): 135–39. http://dx.doi.org/10.14712/18059694.2016.119.
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Practically all mammalian cells including human can switch, according to micro- or macroenvironmental conditions, from states of cellular quiescence to inflammatory activation and vice versa. Along with recent knowledge, cellular quiescence is not a passive, but a highly active state with broad engagement of the cell synthetic and secretory machinery. Inflammatory activation is a beneficial process in cases of infection; however, if its control fails, it may degrade into autoimmune diseases or cancer growth. Control over cellular quiescence is exerted predominantly by a set of zincfinger transcription proteins, referred to as Krüppel-like factors (KLFs). This review article offers recent information concerning activities of Krüppel-like factor 4 in the vascular wall.
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Perkins, Andrew C., and Melissa R. Gardiner. "Zebrafish KLF4 Is Essential for Primitive Haematopoiesis." Blood 106, no. 11 (November 16, 2005): 1746. http://dx.doi.org/10.1182/blood.v106.11.1746.1746.
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Abstract Gene knockout studies of Krüppel-like factors (KLFs) in mice have demonstrated key roles in organogenesis. EKLF (Klf1) plays an essential role in definitive erythropoiesis and b-globin gene expression, but primitive (yolk sac) erythropoiesis and embryonic globin gene expression are essentially normal. Since expression of embryonic globin genes is dependent upon proximal CACC box elements, additional KLFs must function during the embryonic wave of erythropoiesis. A number of KLFs have been described in zebrafish. One of these, zKLF4, the homologue of neptune, a Xenopus Laevis KLF expressed in the ventral blood island, cement and hatching glands, is an early marker of lateral plate mesoderm (LPM). From 1 somite and prior to expression of scl and flk1, there is a continuous rim of expression of zKLF4 2–3 cells wide within the LPM extending from the postero-lateral boundary of the polster to the tail. Expression in the posterior lateral plate persists as it migrates medially in a zipper-like movement to generate the intermediate cell mass (ICM), the site of embryonic haematopoiesis. zKLF4 is also expressed in a patch of dorsal mesendodermal cells from 70% epiboly which are fated to become the polster. Morpholino knockdown of zKLF4 results in moderate anaemia which resolves as definitive erythropoiesis replaces primitive erythropoiesis at 48–72 hpf. zKLF4 morphants show a down-regulation in the expression of GATA-1 (>100 fold) and embryonic globin (>10 fold) by real time RT-PCR. Both are expressed during the primitive wave of haematopoiesis. In addition there is a dramatic up-regulation (>100 fold) in the level of cmyb expression in zKLF4 morphant compared to control embryos at 72 hpf, which is consistent with expansion of the secondary definitive wave of erythropoiesis, possibly in response to anemia. These results suggest mammalian KLF orthologs of zKLF4, either KLF4 or KLF2, may play roles in primitive erythropoiesis and embryonic globin gene expression in mice or man.
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Sousa, Luis, Ines Pankonien, Luka A. Clarke, Iris Silva, Karl Kunzelmann, and Margarida D. Amaral. "KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway." Cells 9, no. 7 (July 2, 2020): 1607. http://dx.doi.org/10.3390/cells9071607.
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Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.
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Fernandez-Zapico, Martin E., Gwen A. Lomberk, Shoichiro Tsuji, Cathrine J. DeMars, Michael R. Bardsley, Yi-Hui Lin, Luciana L. Almada, et al. "A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth." Biochemical Journal 435, no. 2 (March 29, 2011): 529–37. http://dx.doi.org/10.1042/bj20100773.
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SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cell-cycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRAS-mediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.
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Kalra, Inderdeep S., Md M. Alam, and Betty S. Pace. "Transcriptional Regulation of γ-Globin Gene Expression by KLF4." Blood 116, no. 21 (November 19, 2010): 645. http://dx.doi.org/10.1182/blood.v116.21.645.645.
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Abstract Abstract 645 Kruppel-like factors (KLFs) are a family of Cys2His2 zinc-finger DNA binding proteins that regulate gene expression through CACCC/GC/GT box binding in various gene promoters. The CACCC element is also critical for developmental regulation of the human γ-globin and β-globin genes; therefore studies to identify transcription factors that bind the CACCC element to alter gene expression are desirable. By microarray-based gene profiling, we identified two Kruppel-like factors, KLF4 and KLF12 whose expression levels decreased simultaneously with γ-globin silencing during in vitro erythroid maturation. Subsequent reverse transcription quantitative PCR (RT-qPCR) analysis confirmed KLF4 and KLF12 mRNA levels decreased 56-fold and 16-fold respectively in erythroid progenitors from day 7 to day 28 with over 90% γ-globin gene silencing. The effects of known fetal hemoglobin inducers hemin (50μM) and sodium butyrate (2mM) on KLF factor expression was tested in K562 cells. Hemin and sodium butyrate increased KLF4 3-fold (p<0.05) and 13-fold (p<0.01) respectively while KLF12 was only induced by butyrate. Likewise, hemin treatment of KU812 leukemia cells, which actively express γ-globin and β-globin, produced a 7-fold increase in KLF4 (p<0.05) while KLF12 levels were not changed suggesting KLF4 may be directly involved in γ-globin gene regulation. To characterize its role further siRNA-mediated loss of function studies were performed in K562 cells. A 60% knockdown of KLF4 expression produced 40% attenuation of γ-globin transcription (p<0.05). To confirm this effect, rescue experiments were performed as follows: K562 cells were treated with 100nM siKLF4 alone or in combination with the pMT3-KLF4 expression vector (10 and 20μg) for 48 hrs. The 40% knockdown of γ-globin expression produced by siKLF4 was rescued to baseline levels after enforced pMT3-KLF4 expression (p<0.05). To establish whether KLF4 directly stimulates γ-globin promoter activity, we performed co-transfection of pMT3-KLF4 and the Gγ-promoter (-1500 to +36) cloned into the pGL4.17 Luc2/neo vector; a dose-dependent increase in luciferase activity (2- to 5-fold; p<0.001) was observed. Furthermore, enforced expression of pMT3-KLF4 augmented endogenous γ-globin expression 2-fold (p<0.01). Collectively, these studies suggest that KLF4 acts as a trans-activator of γ-globin gene transcription. To address the physiological relevance of these findings, studies were extended to human primary erythroid cells grown in a two-phase liquid culture system. At day 11 when γ-globin gene expression was maximal, siKLF4 treatment produced a 60% decrease in γ/β-globin mRNA levels (p<0.001). By contrast, enforced pMT3-KLF4 expression enhanced γ/β-globin 1.5-fold at day 11 and day 28 (after γ-globin silencing); HbF levels were induced 1.5-fold (p<0.05) which was demonstrated by enzyme-linked immunosorbent assay. To gain insights into the molecular mechanism of KLF4-mediated γ-globin regulation, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP) were completed. Since CREB binding protein (CBP) is known to function as a co-activator for KLF1, 4 and 13, we also tested its role in γ-globin gene regulation. EMSA performed with K562 nuclear extract and a [γ-32P] labeled γ-CACC probe (-155 to -132 relative to the γ-globin cap site) produced three DNA-protein complexes; the addition of KLF4 or CBP antibody resulted in a marked decrease in intensity of all complexes suggesting these factors bind the γ-CACC element. ChIP assay demonstrated 10-fold and 20-fold chromatin enrichment with KLF4 and CBP antibody respectively (p<0.001) confirming in vivo binding at the γ-CACC region. Lastly, co-immunoprecipitation established protein-protein interaction between KLF4 and CBP in K562 cells. Future studies will investigate the role of CBP in KLF4-mediated γ-globin regulation which will provide molecular targets for fetal hemoglobin induction and treatment of sickle cell anemia and β-thalassemia. Disclosures: No relevant conflicts of interest to declare.
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Burns, Audrea, Chun-Shik Park, Takeshi Yamada, Monica Puppi, Lei Lei, and Daniel Lacroazza. "The role of KLF7 in hematopoiesis and lymphopoiesis (160.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 160.2. http://dx.doi.org/10.4049/jimmunol.186.supp.160.2.
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Abstract Krüppel-like factors (KLFs) are transcription factors that possess important roles in cell development and differentiation through the regulation of proliferation. Similar to KLF4, KLF7 regulates genes that control cell cycle arrest, specifically increasing p21 expression and downregulating cyclin D1. Based on our previous findings that KLF4 is important in hematopoiesis and negatively regulates CD8+ T cell proliferation, we hypothesize that KLF7 may also be important in hematopoiesis and T cell function. To test this hypothesis, qRT-PCR analysis of lineage negative, progenitor, and mature T cell subsets was performed. KLF7 mRNA expression increases throughout lineage commitment with the highest expression being in erythrocytes and mature T cells. Clonogenic assays revealed a decreased number of common myeloid progenitors (CMP) induced by ectopic expression of KLF7, which suggests that KLF7 is important for regulating commitment to a CMP fate. Further, to test whether KLF7 is important for effector T cell proliferation, KLF7-/- and KLF7+/+ fetal liver cells were transplanted into lethally irradiated congenic recipients (due to neonatal lethality) respectively. Although CFSE dilution assays demonstrated that CD4+ and CD8+ T cell proliferation was similar, thymic T cells from KLF7-/- recipients showed a developmental block from the DP to CD4SP and CD8SP stages in the thymus. Our findings suggest that KLF7 plays important roles in hematopoiesis and T cell development.
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Kotlyarov, Stanislav, and Anna Kotlyarova. "Participation of Krüppel-like Factors in Atherogenesis." Metabolites 13, no. 3 (March 19, 2023): 448. http://dx.doi.org/10.3390/metabo13030448.
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Atherosclerosis is an important problem in modern medicine, the keys to understanding many aspects of which are still not available to clinicians. Atherosclerosis develops as a result of a complex chain of events in which many cells of the vascular wall and peripheral blood flow are involved. Endothelial cells, which line the vascular wall in a monolayer, play an important role in vascular biology. A growing body of evidence strengthens the understanding of the multifaceted functions of endothelial cells, which not only organize the barrier between blood flow and tissues but also act as regulators of hemodynamics and play an important role in regulating the function of other cells in the vascular wall. Krüppel-like factors (KLFs) perform several biological functions in various cells of the vascular wall. The large family of KLFs in humans includes 18 members, among which KLF2 and KLF4 are at the crossroads between endothelial cell mechanobiology and immunometabolism, which play important roles in both the normal vascular wall and atherosclerosis.
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Moi, Paolo, Giuseppina Maria Marini, Loredana Porcu, Isadora Asunis, Maria Giuseppina Loi, Lisa Anna Cabriolu, and Antonio Cao. "Regulation of the Human α-Globin Genes by GKLF." Blood 112, no. 11 (November 16, 2008): 1867. http://dx.doi.org/10.1182/blood.v112.11.1867.1867.
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Abstract EKLF and related Krueppel-like factors (KLFs) are variably implicated in the regulation of the β- and β-like globin genes. Prompted by the observation that four KLF sites are distributed in the human α-globin promoter, we investigated if any of the β-globin cluster regulating KLFs could also act to modulate the expression of the α-globin genes. We found that, among the globin regulating KLFs (EKLF, LKLF, BKLF, GKLF, KLF6, FKLF and FKLF2), only GKLF and BKLF bound specifically to three out of four KLF sites. In K562 cells, over-expressed GKLF transactivated at high levels a α-globin-luciferase reporter and its action was impaired by point mutations of the KLF sites that disrupted GKLFDNA binding. In K562 cells stably transfected with a Tet-off regulated GKLF expression cassette, GKLF induction stimulated the expression of the endogenous α-globin genes. In a complementary assay in K562 cells, knocking down GKLF expression with small interfering RNAs caused a parallel decrease in the transcription of the α-globin genes. All experiments combined support a main regulatory role of GKLF in the control of α-globin gene expression.
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Li, Jun-Chen, Qiu-Han Chen, Rui Jian, Jiang-Rong Zhou, Yun Xu, Fang Lu, Jun-Qiao Li, and Hao Zhang. "The Partial Role of KLF4 and KLF5 in Gastrointestinal Tumors." Gastroenterology Research and Practice 2021 (July 27, 2021): 1–13. http://dx.doi.org/10.1155/2021/2425356.
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Background. KLF4 and KLF5 are members of the KLF transcription factor family, which play an important role in many gastrointestinal tumors. To gain a deeper insight into its function and role, bioinformatics was used to analyze the function and role of KLF4 and KLF5 in gastrointestinal tumors. Methods. Data were collected from several online databases. Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN database analysis, Kaplan-Meier Plotter analysis, LOGpc system, the Pathology Atlas, and the STRING website were used to analyze the data. We download relevant data from TCGA and then perform GO enrichment and KEGG enrichment analysis. The effects of KLF5 on gastric cancer cell proliferation were measured by CCK-8 assay. The effect of KLF5 on the expression of CyclinD1 and MMP9 was detected by Western blot. Results. KLF4 and KLF5 were differentially expressed in normal and tumor tissues of the gastrointestinal tract, and their differential expression is related to several genes or pathways. KEGG analysis showed that KLF5 was coexpressed with endocytosis-related genes. KLF5 promotes the proliferation of gastric cancer cells and the expression of metastasis-related molecules. Conclusion. KLF4 and KLF5 are of great significance for developing gastrointestinal tumors and can be used as therapeutic targets.
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Ulfhammer, Erik, Pia Larsson, Mia Magnusson, Lena Karlsson, Niklas Bergh, and Sverker Jern. "Dependence of Proximal GC Boxes and Binding Transcription Factors in the Regulation of Basal and Valproic Acid-Induced Expression of t-PA." International Journal of Vascular Medicine 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/7928681.
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Objective.Endothelial tissue-type plasminogen activator (t-PA) release is a pivotal response to protect the circulation from occluding thrombosis. We have shown that the t-PA gene is epigenetically regulated and greatly induced by the histone deacetylase (HDAC) inhibitor valproic acid (VPA). We now investigated involvement of known t-PA promoter regulatory elements and evaluated dependence of potential interacting transcription factors/cofactors.Methods.A reporter vector with an insert, separately mutated at either the t-PA promoter CRE or GC box II or GC box III elements, was transfected into HT-1080 and HUVECs and challenged with VPA. HUVECs were targeted with siRNA against histone acetyl transferases (HAT) and selected transcription factors from the Sp/KLF family.Results.An intact VPA-response was observed with CRE mutated constructs, whereas mutation of GC boxes II and III reduced the magnitude of the induction by 54 and 79% in HT-1080 and 49 and 50% in HUVECs, respectively. An attenuated induction of t-PA mRNA was observed after Sp2, Sp4, and KLF5 depletion. KLF2 and p300 (HAT) were identified as positive regulators of basal t-PA expression and Sp4 and KLF9 as repressors.Conclusion.VPA-induced t-PA expression is dependent on the proximal GC boxes in the t-PA promoter and may involve interactions with Sp2, Sp4, and KLF5.
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Goldstein, Bree G., Hann-Hsiang Chao, Yizeng Yang, Yuliya A. Yermolina, John W. Tobias, and Jonathan P. Katz. "Overexpression of Krüppel-like factor 5 in esophageal epithelia in vivo leads to increased proliferation in basal but not suprabasal cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 6 (June 2007): G1784—G1792. http://dx.doi.org/10.1152/ajpgi.00541.2006.
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Krüppel-like factor 5 ( Klf5; also called IKLF or BTEB2), a zinc-finger transcription factor with proproliferative and transforming properties in vitro, is expressed in proliferating cells of gastrointestinal tract epithelia, including in basal cells of the esophagus. Thus, Klf5 is an excellent candidate to regulate esophageal epithelial proliferation in vivo. Nonetheless, the function of Klf5 in esophageal epithelial homeostasis and tumorigenesis in vivo has not previously been determined. Here, we used the ED- L2 promoter of the Epstein-Barr virus to express Klf5 throughout esophageal epithelia. ED-L2/ Klf5 transgenic mice were born at the appropriate Mendelian ratio, survived to at least 1 yr of age, and showed no evidence of esophageal dysplasia or cancer. Staining for bromodeoxyuridine (BrdU) demonstrated increased proliferation in the basal layer of ED-L2/ Klf5 mice, but no proliferation was seen in suprabasal cells, despite ectopic expression of Klf5 in these cells. Notably, expression of the KLF family member Klf4, which binds the same DNA sequences as Klf5 and which inhibits proliferation and promotes differentiation, was not altered in ED-L2/ Klf5 transgenic mice. In primary esophageal keratinocytes that overexpressed Klf5, expression of Klf4 still inhibited proliferation and promoted differentiation, providing a possible mechanism for the persistence of keratinocyte differentiation in ED-L2/ Klf5 mice. To identify additional targets for Klf5 in esophageal epithelia, we performed functional genomic analyses and identified a total of 15 differentially expressed genes. In summary, while Klf5 positively regulates proliferation in basal cells, it is not sufficient to maintain proliferation in the esophageal epithelium.
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Abe, Makoto, Naoya Saeki, Yuki Ikeda, and Shinsuke Ohba. "Kruppel-like Factors in Skeletal Physiology and Pathologies." International Journal of Molecular Sciences 23, no. 23 (December 2, 2022): 15174. http://dx.doi.org/10.3390/ijms232315174.
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Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. Currently, 17 murine and human KLFs are known to play crucial roles in the regulation of transcription, cell proliferation, cellular differentiation, stem cell maintenance, and tissue and organ pathogenesis. Recent evidence has shown that many KLF family molecules affect skeletal cells and regulate their differentiation and function. This review summarizes the current understanding of the unique roles of each KLF in skeletal cells during normal development and skeletal pathologies.
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Perkins, Andrew C., Dinushka Gunaratnam, Melissa R. Gardiner, and Kathleen C. Robinson. "Klf12 Is Required for Vessel Organization in Zebrafish Embryos." Blood 106, no. 11 (November 16, 2005): 3695. http://dx.doi.org/10.1182/blood.v106.11.3695.3695.
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Abstract The process of forming a lumenised vessel from an angioblast cord is a crucial part of both vasculogenesis and angiogenesis. The Krüppel like factors (klfs) are a family of zinc finger transcription factors which play important roles in many aspects of differentiation. Klf2 knockout mice die in utero from haemorrhaging due to arterial wall defects. Due to the similarity of vascular and haematopoietic systems to those of mammals, the zebrafish was chosen as a model in which to study the function of klf12, the only zebrafish representative of the repressor subfamily of mammalian klfs which includes klf3, klf8 and klf12. Klf12 is first detected by WISH at 12 somites in the lateral plate mesoderm (LPM) and continues in these cells as they from the ICM at 18–22hpf, the site of vasculogenesis and haematopoiesis. From 24hpf klf12 is expressed in short stripes extending from the ICM dorsally towards the notochord. This expression pattern is similar but not identical to that of fli1 and flk1, two vascular markers. Expression subsequently decreases and is absent by 30hpf. Targeted knockdown of klf12 by translantion-inhibiting and splicing morpholinos (MOs) produces a vascular defect. At 24hpf morphants display correct expression of primitive blood, kidney and vascular markers such as gata1, βE3globin, biklf, pax2.1 and fli1. However, circulation is absent in 65% of embryos at 48 hpf and reduced in most, as seen by both brightfield microscopy and fluorescent microbead microangiography. Embryos also display a slower heartbeat, pericardial oedema and oedema over the yolk/duct of Cuvier, all likely to be secondary effects due to the circulatory defect. Injection of klf12 MOs into fli1-eGFP transgenic embryos reveals correct differentiation of endothelial cells, but disorganised angiogenesis. In summary, klf12 morphants display correct specification of angioblasts and differentiation of endothelial cells but a defect in tubulogenesis of endothelial cords.
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Syafruddin, Saiful E., M. Aiman Mohtar, Wan Fahmi Wan Mohamad Nazarie, and Teck Yew Low. "Two Sides of the Same Coin: The Roles of KLF6 in Physiology and Pathophysiology." Biomolecules 10, no. 10 (September 28, 2020): 1378. http://dx.doi.org/10.3390/biom10101378.
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The Krüppel-like factors (KLFs) family of proteins control several key biological processes that include proliferation, differentiation, metabolism, apoptosis and inflammation. Dysregulation of KLF functions have been shown to disrupt cellular homeostasis and contribute to disease development. KLF6 is a relevant example; a range of functional and expression assays suggested that the dysregulation of KLF6 contributes to the onset of cancer, inflammation-associated diseases as well as cardiovascular diseases. KLF6 expression is either suppressed or elevated depending on the disease, and this is largely due to alternative splicing events producing KLF6 isoforms with specialised functions. Hence, the aim of this review is to discuss the known aspects of KLF6 biology that covers the gene and protein architecture, gene regulation, post-translational modifications and functions of KLF6 in health and diseases. We put special emphasis on the equivocal roles of its full-length and spliced variants. We also deliberate on the therapeutic strategies of KLF6 and its associated signalling pathways. Finally, we provide compelling basic and clinical questions to enhance the knowledge and research on elucidating the roles of KLF6 in physiological and pathophysiological processes.
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Morris, Valerie A., Carrie L. Cummings, Brendan Korb, Sean Boaglio, and Vivian G. Oehler. "Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets." Molecular and Cellular Biology 36, no. 4 (December 7, 2015): 559–73. http://dx.doi.org/10.1128/mcb.00712-15.
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Acute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Krüppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression.
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Yang, Xuexian O., Raymond T. Doty, Justin S. Hicks, and Dennis M. Willerford. "Regulation of T-cell receptor Dβ1 promoter by KLF5 through reiterated GC-rich motifs." Blood 101, no. 11 (June 1, 2003): 4492–99. http://dx.doi.org/10.1182/blood-2002-08-2579.
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Abstract Rearrangement of T-cell receptor (TCR) and immunoglobulin genes by a common V(D)J recombination machinery is regulated by developmentally specific chromatin changes at the target locus, a process associated with transcription. At the TCRβ locus, the Eβ enhancer and the Dβ1 promoter regulate germline transcription originating near the TCR Dβ1 gene segment. The Dβ1 promoter contains 3 GC-rich motifs that bind a common set of nuclear proteins from pro–T-cell lines. Mutations that diminish the binding of nuclear proteins also diminish the activity of the Dβ1 promoter in transcriptional reporter assays. Using a yeast one-hybrid approach, 3 Krüppel-like factors—KLF3, KLF5, and KLF6—and a novel zinc finger protein were identified in a thymus library, all of which bound the GC-rich motif in a sequence-specific manner. Of these genes, KLF5 mRNA was expressed in a restricted manner in lymphoid cells and tissues, with highest expression in pro–T-cell lines and Rag-deficient thymocytes. Antibody supershift studies and chromatin immunoprecipitation assay confirmed that KLF5 bound the Dβ1 promoter. In reporter gene assays, KLF5 but not KLF6 efficiently transactivated the Dβ1 promoter, whereas a dominant-negative KLF5 construct inhibited reporter expression. These data suggest that reiterated GC motifs contribute to germline TCRβ transcription through binding of KLF5 and other Krüppel family members and that restricted expression of KLF5 may contribute to lineage-specific regulation of germline TCRβ transcription.
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Kalra, Inderdeep S., Wei Li, Shalini Muralidhar, and Betty Pace. "Role of KLF4 and KLF12 in γ-Globin Gene Regulation." Blood 114, no. 22 (November 20, 2009): 4075. http://dx.doi.org/10.1182/blood.v114.22.4075.4075.
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Abstract Abstract 4075 Poster Board III-1010 Kruppel-like factors (KLFs) are a family of Cys2His2 zinc-finger DNA binding proteins that regulate gene expression through CACCC/GC/GT box binding in gene promoters. The CACCC element is critical for the developmental regulation of the human γ-globin and β-globin genes and studies are being done to ferret out various factors that bind this region and modulate gene activity. We recently identified two Kruppel-like factors, KLF4 and KLF12 whose expression levels decreased based on microarray-based gene profiling, concomitantly with decreased γ-globin expression during erythroid maturation. Decreased expression of both factors was further confirmed using quantitative PCR (qPCR) analysis. KLF4 and KLF12 mRNA levels decreased 56-fold and 16-fold respectively by day 28 compared to levels in day 7 erythroid progenitors. We next determined if KLF4 and KLF12 bind the γ-globin CACC box by electrophoretic mobility shift assay (EMSA) using nuclear proteins extracted from K562 cells and a [γ-32P] labeled γ-CACC probe located between -155 to -132 relative to the γ-globin gene cap site. Three DNA-protein complexes were observed. The specificity of these interactions was confirmed by competition reactions in which preincubation with excess unlabelled γ-CACC oligonucleotide effectively abolished the formation of all DNA/protein complexes; addition of nonspecific oligonucleotide had no effect on binding activity. Addition of polyclonal KLF4 or KLF12 antibodies to the EMSA reaction resulted in a marked decrease in intensity of all DNA-protein complexes suggesting both KLF4 and KLF12 are present. Additional studies were performed to determine the effect of the known fetal hemoglobin inducer hemin on KLF gene expression in K562 cells. Hemin stimulated γ-globin transcription while increasing KLF4 and KLF12 66-fold and 4-fold respectively (p<0.05). Hemin treatment in KU812 erythroleukemia cells which actively transcribe both γ- and β-globin, also produced a 10-fold increase (p<0.05) in KLF4; KLF12 levels were not changed. Our preliminary data suggest these KLFs might play a role in γ-globin regulation. siRNA mediated gene silencing studies are underway to determine if KLF4 and/or KLF12 play a direct role in γ-globin gene regulation. This mechanism could provide important molecular targets for fetal hemoglobin reactivation. This will be highly significant towards developing therapeutic strategies for hemoglobinopathies like sickle cell anemia and β-thalassemia. Disclosures: No relevant conflicts of interest to declare.
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Xu, Bing, Xiangmeng Wang, Peng Li, Wei Li, Huijuan Dong, Yong Zhou, and Yanyan Li. "KLF4 induces apoptosis in T-ALL through the BCL2/BCLXL pathway." Blood 122, no. 21 (November 15, 2013): 4902. http://dx.doi.org/10.1182/blood.v122.21.4902.4902.
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Abstract KLF4, also known as GKLF (gut KLF), is a member of the KLF zinc finger-containing transcription factor family. Klf4 together with Oct4, Sox2, and c-Mycare widely referred to as ‘Yamanaka factors’ because mouse somatic cells can be reprogrammed into pluripotent stem cells following their ectopic expression. The transcription factor Kruppel-like factor 4 (KLF4) may induce tumorigenesis or suppress tumor growth in a tissue-dependent manner. In T cell leukemia and pre-B cell lymphoma cells, KLF4 acts as a tumor suppressor. We found that over expression of KLF4 induced human acute T cell lymphoblastic leukemia (T-ALL) cell lines to undergo apoptosis through the BCL2/BCLXL pathway, and we confirmed KLF4-induced apoptosis in primary samples from T-ALL patients. We further characterized KLF4 function in human early and mature T cells. Our analysis uncovered that KLF4 suppressed the transcription of other T cell-associated genes in T-ALL. Disclosures: No relevant conflicts of interest to declare.
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Schuettpelz, Laura, Felipe Giuste, Priya Gopalan, and Daniel Link. "Kruppel Like Factor 7 Suppresses Hematopoietic Stem and Progenitor Cell Function." Blood 118, no. 21 (November 18, 2011): 2356. http://dx.doi.org/10.1182/blood.v118.21.2356.2356.
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Abstract Abstract 2356 Kruppel like factor 7 (KLF7) expression is an independent predictor of poor outcome in pediatric acute lymphoblastic leukemia (Flotho, et al; Blood 2007). In addition, KLF7 overexpression is associated with Imatinib-resistant CML (Cammarata, et al; Clinical Leukemia 2007). The kruppel like factor (KLF) family of transcription factors are involved in regulating cellular growth and differentiation in multiple tissue types. KLF7 is important for neurogenesis, and mice lacking KLF7 die perinatally with severe neurologic defects (Laub, et al; Mol Cell Biol 2005). While no specific role for KLF7 in hematopoiesis has been previously reported, loss of the closely related family member KLF6 is associated with defective blood cell production (Matsumoto, et al; Blood 2006), and other KLF family members are involved in multiple aspects of hematopoiesis. Targets of KLF7 include known regulators of hematopoietic stem and progenitor cell (HSPC) function including TRKA, Cebp/a, and CDKN1A (p21). Normal HSPCs appear to have a low level of KLF7 expression based on RNA expression profiling of populations enriched for these cells. Given these findings, we hypothesized that KLF7 may play a role in regulating normal HSPC function, and may contribute to leukemogenesis or resistance to therapy. To test this hypothesis, we first analyzed the effect of the loss of KLF7 on hematopoiesis. Specifically, we generated Klf7−/− fetal liver chimeras and characterized their hematopoiesis. Long-term multilineage engraftment of Klf7−/− cells was comparable to control cells. Moreover, HSC self-renewal, as assessed by serial transplantation was not effected by the loss of KLF7. To model the effect of KLF7 overexpression on HSPC function, we generated retroviral and lentiviral vectors that express KLF7. KLF7 expression in wild type bone marrow cells transduced with KLF7 retrovirus was increased approximately 10-fold. Overexpression of KLF7 was associated with a marked suppression of myeloid progenitor cell growth, as assessed using colony-forming cell assays. Relative to the initial transduction efficiency, the number of myeloid colonies produced from KLF7-transduced cells compared to vector-alone transduced cells was reduced 5.7 ± 1.9 fold. We next assessed short- and long-term engraftment of KLF7-transduced cells by bone marrow transplantation. In experiments using bone marrow cells transduced with high efficiency (≥ 60% transduced cells), overexpression of KLF7 resulted in impaired radioprotection. Whereas all (12 of 12) recipients transplanted with control transduced cells survived, only 42% (5 out of 12) of recipients of KLF7 transduced cells survived more than two weeks after transplantation (P < 0.003). When these experiments were performed with a reduced multiplicity of infection to achieve a lower transduction efficiency, all recipient mice survived at least 3 months. Whereas control-transduced cells were readily detected at near input levels (on average, 40% of nucleated blood cells), minimal contribution of KLF7-transduced cells was observed in all lineages except T cells. Interestingly, KLF7-transduced T cells were present at near input levels. In summary, our show that KLF7 is not required for normal HSPC function. However, overexpression of KLF7 leads to a marked suppression of the short- and long-term repopulating activity of HSPC with the exception cells in the T cell lineage. Whether KLF7 expression contributes to T cell leukemogenesis through suppression of other hematopoietic lineages will require further study. Disclosures: No relevant conflicts of interest to declare.
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Funnell, Alister P. W., Christopher A. Maloney, Lucinda J. Thompson, Janelle Keys, Michael Tallack, Andrew C. Perkins, and Merlin Crossley. "Erythroid Krüppel-Like Factor Directly Activates the Basic Krüppel-Like Factor Gene in Erythroid Cells." Molecular and Cellular Biology 27, no. 7 (February 5, 2007): 2777–90. http://dx.doi.org/10.1128/mcb.01658-06.
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ABSTRACT The Sp/Krüppel-like factor (Sp/Klf) family is comprised of around 25 zinc finger transcription factors that recognize CACCC boxes and GC-rich elements. We have investigated basic Krüppel-like factor (Bklf/Klf3) and show that in erythroid tissues its expression is highly dependent on another family member, erythroid Krüppel-like factor (Eklf/Klf1). We observe that Bklf mRNA is significantly reduced in erythroid tissues from Eklf-null murine embryos. We find that Bklf is driven primarily by two promoters, a ubiquitously active GC-rich upstream promoter, 1a, and an erythroid downstream promoter, 1b. Transcripts from the two promoters encode identical proteins. Interestingly, both the ubiquitous and the erythroid promoter are dependent on Eklf in erythroid cells. Eklf also activates both promoters in transient assays. Experiments utilizing an inducible form of Eklf demonstrate activation of the endogenous Bklf gene in the presence of an inhibitor of protein synthesis. The kinetics of activation are also consistent with Bklf being a direct Eklf target. Chromatin immunoprecipitation assays confirm that Eklf associates with both Bklf promoters. Eklf is typically an activator of transcription, whereas Bklf is noted as a repressor. Our results support the hypothesis that feedback cross-regulation occurs within the Sp/Klf family in vivo.
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Leisegang, Matthias S., Sofia-Iris Bibli, Stefan Günther, Beatrice Pflüger-Müller, James A. Oo, Cindy Höper, Sandra Seredinski, et al. "Pleiotropic effects of laminar flow and statins depend on the Krüppel-like factor-induced lncRNA MANTIS." European Heart Journal 40, no. 30 (June 21, 2019): 2523–33. http://dx.doi.org/10.1093/eurheartj/ehz393.
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Abstract Aims To assess the functional relevance and therapeutic potential of the pro-angiogenic long non-coding RNA MANTIS in vascular disease development. Methods and results RNA sequencing, CRISPR activation, overexpression, and RNAi demonstrated that MANTIS, especially its Alu-element, limits endothelial ICAM-1 expression in different types of endothelial cells. Loss of MANTIS increased endothelial monocyte adhesion in an ICAM-1-dependent manner. MANTIS reduced the binding of the SWI/SNF chromatin remodelling factor BRG1 at the ICAM-1 promoter. The expression of MANTIS was induced by laminar flow and HMG-CoA-reductase inhibitors (statins) through mechanisms involving epigenetic rearrangements and the transcription factors KLF2 and KLF4. Mutation of the KLF binding motifs in the MANTIS promoter blocked the flow-induced MANTIS expression. Importantly, the expression of MANTIS in human carotid artery endarterectomy material was lower compared with healthy vessels and this effect was prevented by statin therapy. Interestingly, the protective effects of statins were mediated in part through MANTIS, which was required to facilitate the atorvastatin-induced changes in endothelial gene expression. Moreover, the beneficial endothelial effects of statins in culture models (spheroid outgrowth, proliferation, telomerase activity, and vascular organ culture) were lost upon knockdown of MANTIS. Conclusion MANTIS is tightly regulated by the transcription factors KLF2 and KLF4 and limits the ICAM-1 mediated monocyte adhesion to endothelial cells and thus potentially atherosclerosis development in humans. The beneficial effects of statin treatment and laminar flow are dependent on MANTIS.
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Gillinder, Kevin R., Graham Magor, Charles Bell, Melissa D. Ilsley, Stephen Huang, and Andrew Perkins. "KLF1 Acts As a Pioneer Transcription Factor to Open Chromatin and Facilitate Recruitment of GATA1." Blood 132, Supplement 1 (November 29, 2018): 501. http://dx.doi.org/10.1182/blood-2018-99-119608.
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Abstract Only a small subset of transcription factors (TFs) can act as pioneer factors; i.e. those that can 'open' otherwise 'closed' chromatin to facilitate assembly of TF complexes and co-factors to enable transcription. The KLF/SP family of TFs bind to a 9-10 bp consensus motif in DNA to activate or repress target gene expression. We have studied the potential for KLF1, which is essential for erythropoiesis, to provide a pioneering function in erythroid progentior cells. Previous ChIP-seq studies have shown KLF1 binds a few thousand enhancers and promoters to activate erythroid cell gene expression 1. It often binds near to other key erythroid TFs such as GATA1 and SCL/TAL1, so is likely to work in concert with them in some contexts. We have employed an inducible stable KLF1-ERTM construct to rescue gene expression and differentiation of Klf1-/- erythroid cell lines 2. We employed ChIP-seq, ATAC-seq and DNAse1 HS to show KLF1 can bind to closed sites in chromatin and induce an open state. We show this is essential for recruitment of the settler transcription, GATA1, at certain co-bound sites but not others. This pioneering function occurs at ~300 key erythroid enhancers and super-enhancers such the one at -26kb in the a-globin LCR and one within the body of the E2f2 gene 3 but rarely at promoters. We further show that two different neomorphic mutations in the KLF1 DNA-binding domain lead to ectopic pioneering (opening of closed chromatin) and aberrant gene activation 4. We generated a series of N-terminal deletions in KLF1 and employed ATAC-seq to map the domain/s within KLF1 responsible for the pioneering activity and show it is distinct from DNA-binding activity. The domain is responsible for bromodomain protein recruitment, the likely effector of chromatin remodelling. We have also examined whether KLF3, which acts as a transcription repressor via recruitment of the co-repressor, CtBP2, can force the closure of otherwise open chromatin 5. We find it cannot. Rather, KLF3 (and likely other members of this subclade) works via active recruitment of co-repressors rather than rendering chromatin inaccessible. This likely enables rapid reactivation of pioneered enhancers without the need to reprogram chromatin. This work has broad implications for how the KLF/SP family of TFs work in vivo to reprogram cells and direct differentiation. We will present data for such activity in non-erythroid cell systems. References:Tallack MR, Whitington T, Yuen WS, et al. A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells. Genome Res. 2010;20(8):1052-1063.Coghill E, Eccleston S, Fox V, et al. Erythroid Kruppel-like factor (EKLF) coordinates erythroid cell proliferation and hemoglobinization in cell lines derived from EKLF null mice. Blood. 2001;97(6):1861-1868.Tallack MR, Keys JR, Humbert PO, Perkins AC. EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2. J Biol Chem. 2009;284(31):20966-20974.Gillinder KR, Ilsley MD, Nebor D, et al. Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability. Nucleic Acids Res. 2017;45(3):1130-1143.Turner J, Crossley M. Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators. Embo J. 1998;17(17):5129-5140. Disclosures Perkins: Novartis Oncology: Honoraria.
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Zinghirino, Federica, Xena Giada Pappalardo, Angela Messina, Francesca Guarino, and Vito De Pinto. "Is the Secret of VDAC Isoforms in Their Gene Regulation? Characterization of Human VDAC Genes Expression Profile, Promoter Activity, and Transcriptional Regulators." International Journal of Molecular Sciences 21, no. 19 (October 7, 2020): 7388. http://dx.doi.org/10.3390/ijms21197388.
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VDACs (voltage-dependent anion-selective channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to VDACs’ presence. In higher eukaryotes, three isoforms are raised during the evolution: they have the same exon–intron organization, and the proteins show the same channel-forming activity. We provide a comprehensive analysis of the three human VDAC genes (VDAC1–3), their expression profiles, promoter activity, and potential transcriptional regulators. VDAC isoforms are broadly but also specifically expressed in various human tissues at different levels, with a predominance of VDAC1 and VDAC2 over VDAC3. However, an RNA-seq cap analysis gene expression (CAGE) approach revealed a higher level of transcription activation of VDAC3 gene. We experimentally confirmed this information by reporter assay of VDACs promoter activity. Transcription factor binding sites (TFBSs) distribution in the promoters were investigated. The main regulators common to the three VDAC genes were identified as E2F-myc activator/cell cycle (E2FF), Nuclear respiratory factor 1 (NRF1), Krueppel-like transcription factors (KLFS), E-box binding factors (EBOX) transcription factor family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each VDAC gene isoform were identified, supporting the results in the literature, indicating a general role of VDAC1, as an actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. For the first time, we propose a comparative analysis of human VDAC promoters to investigate their specific biological functions. Bioinformatics and experimental results confirm the essential role of the VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoform gene.
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Mallipattu, Sandeep K., Chelsea C. Estrada, and John C. He. "The critical role of Krüppel-like factors in kidney disease." American Journal of Physiology-Renal Physiology 312, no. 2 (February 1, 2017): F259—F265. http://dx.doi.org/10.1152/ajprenal.00550.2016.
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Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors critical to mammalian embryonic development, regeneration, and human disease. There is emerging evidence that KLFs play a vital role in key physiological processes in the kidney, ranging from maintenance of glomerular filtration barrier to tubulointerstitial inflammation to progression of kidney fibrosis. Seventeen members of the KLF family have been identified, and several have been well characterized in the kidney. Although they may share some overlap in their downstream targets, their structure and function remain distinct. This review highlights our current knowledge of KLFs in the kidney, which includes their pattern of expression and their function in regulating key biological processes. We will also critically examine the currently available literature on KLFs in the kidney and offer some key areas in need of further investigation.