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1
Khurana, Simran, Sharmistha Chakraborty, Minh Lam, Yu Liu, Yu-Ting Su, Xuan Zhao, Moin A. Saleem, Peter W. Mathieson, Leslie A. Bruggeman, and Hung-Ying Kao. "Familial Focal Segmental Glomerulosclerosis (FSGS)-linked α-Actinin 4 (ACTN4) Protein Mutants Lose Ability to Activate Transcription by Nuclear Hormone Receptors." Journal of Biological Chemistry 287, no. 15 (February 17, 2012): 12027–35. http://dx.doi.org/10.1074/jbc.m112.345421.
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Mutations in α-actinin 4 (ACTN4) are linked to familial forms of focal segmental glomerulosclerosis (FSGS), a kidney disease characterized by proteinuria due to podocyte injury. The mechanisms underlying ACTN4 mutant-associated FSGS are not completely understood. Although α-actinins are better known to cross-link actin filaments and modulate cytoskeletal organization, we have previously shown that ACTN4 interacts with transcription factors including estrogen receptor and MEF2s and potentiates their transcriptional activity. Nuclear receptors including retinoic acid receptor (RAR) have been proposed to play a protective role in podocytes. We show here that ACTN4 interacts with and enhances transcriptional activation by RARα. In addition, FSGS-linked ACTN4 mutants not only mislocalized to the cytoplasm, but also lost their ability to associate with nuclear receptors. Consequently, FSGS-linked ACTN4 mutants failed to potentiate transcriptional activation by nuclear hormone receptors in podocytes. In addition, overexpression of these mutants suppressed the transcriptional activity mediated by endogenous wild-type ACTN4 possibly by a cytoplasmic sequestration mechanism. Our data provide the first link between FSGS-linked ACTN4 mutants and transcriptional activation by nuclear receptor such as RARα and peroxisome proliferator-activated receptor γ.
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NAGARAJAN, Raman P., Feifei CHEN, Wei LI, Eva VIG, Maureen A. HARRINGTON, Harikrishna NAKSHATRI, and Yan CHEN. "Repression of transforming-growth-factor-β-mediated transcription by nuclear factor κB." Biochemical Journal 348, no. 3 (June 7, 2000): 591–96. http://dx.doi.org/10.1042/bj3480591.
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Activation of transforming growth factor-β (TGF-β) and activin receptors leads to phosphorylation of Sma- and Mad-related protein 2 (Smad2) and Smad3, which function as transcription factors to regulate gene expression. Smad7 is a regulatory protein which is able to inhibit TGF-β and activin signalling in a negative-feedback loop, mediated by a direct regulation by Smad3 and Smad4 via a Smad-binding element (SBE) in the Smad7 promoter. Interestingly, we found that the Smad7 promoter was also regulated by nuclear factor ĸB (NF-ĸB), a transcription factor which plays an important role in inflammation and the immune response. Expression of NF-ĸB p65 subunit was able to inhibit the Smad7 promoter activity, and this inhibition could be reversed by co-expression of IĸB, an inhibitor of NF-ĸB. In addition, the inhibitory activity of p65 was observed in a minimal promoter that contained only the Smad7 SBE and a TATA box, without any consensus NF-ĸB binding site. This inhibitory effect appeared to be common to other TGF-β- and activin-responsive promoters, since p65 also inhibited the forkhead-activin-signal-transducer-2-mediated activation of a Xenopus Mix.2 promoter, as well as the Smad3-mediated activation of 3TP-lux which contains PMA-responsive elements and a plasminogen-activator-inhibitor-1 promoter. Activation of endogenous NF-ĸB by tumour necrosis factor-α (TNF-α) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells. In human hepatoma HepG2 cells, TNF-α was able to inhibit TGF-β- and activin-mediated transcriptional activation. Furthermore, overexpression of the transcription co-activator p300 could abrogate the inhibitory effect of NF-ĸB on the Smad7 promoter. Taken together, these data have indicated a novel mode of crosstalk between the Smad and the NF-ĸB signalling cascades at the transcriptional level by competing for a limiting pool of transcription co-activators.
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Zhou, Xiaoming, Joan D. Ferraris, Qi Cai, Anupam Agarwal, and Maurice B. Burg. "Increased reactive oxygen species contribute to high NaCl-induced activation of the osmoregulatory transcription factor TonEBP/OREBP." American Journal of Physiology-Renal Physiology 289, no. 2 (August 2005): F377—F385. http://dx.doi.org/10.1152/ajprenal.00463.2004.
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The signaling pathways leading to high NaCl-induced activation of the transcription factor tonicity-responsive enhancer binding protein/osmotic response element binding protein (TonEBP/OREBP) remain incompletely understood. High NaCl has been reported to produce oxidative stress. Reactive oxygen species (ROS), which are a component of oxidative stress, contribute to regulation of transcription factors. The present study was undertaken to test whether the high NaCl-induced increase in ROS contributes to tonicity-dependent activation of TonEBP/OREBP. Human embryonic kidney 293 cells were used as a model. We find that raising NaCl increases ROS, including superoxide. N-acetylcysteine (NAC), an antioxidant, and MnTBAP, an inhibitor of superoxide, reduce high NaCl-induced superoxide activity and suppress both high NaCl-induced increase in TonEBP/OREBP transcriptional activity and high NaCl-induced increase in expression of BGT1mRNA, a transcriptional target of TonEBP/OREBP. Catalase, which decomposes hydrogen peroxide, does not have these effects, whether applied exogenously or overexpressed within the cells. Furthermore, NAC and MnTBAP, but not catalase, blunt high NaCl-induced increase in TonEBP/OREBP transactivation. NG-monomethyl-l-arginine, a general inhibitor of nitric oxide synthase, has no significant effect on either high NaCl-induced increase in superoxide or TonEBP/OREBP transcriptional activity, suggesting that the effects of ROS do not involve nitric oxide. Ouabain, an inhibitor of Na-K-ATPase, attenuates high NaCl-induced superoxide activity and inhibits TonEBP/OREBP transcriptional activity. We conclude that the high NaCl-induced increase in ROS, including superoxide, contributes to activation of TonEBP/OREBP by increasing its transactivation.
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MacDougald, O. A., and D. B. Jump. "Identification of functional cis-acting elements within the rat liver S14 promoter." Biochemical Journal 280, no. 3 (December 15, 1991): 761–67. http://dx.doi.org/10.1042/bj2800761.
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The structure of DNAase I hypersensitive site 1 (Hss-1), located adjacent to the 5′ end of the rat liver S14 gene, is regulated by tissue-specific factors, and its formation correlates with the transcriptional activation of the S14 gene. We propose that tissue-specific trans-acting factors interacting with key cis-linked elements within this site function in the initiation of S14 gene transcription. To examine this hypothesis we used DNAase I footprint, gel shift and in vitro transcriptional analyses to identify cis-linked elements that function in the control of S14 gene transcription. Binding of rat liver nuclear proteins to the S14 promoter (from -8 to -464 bp) produced four DNAase I footprints (designated A-D). Gel shift studies showed that DNA-protein binding was tissue- and sequence-specific, differentially heat-sensitive, and abolished by proteinase K. The function of the four cis-acting elements was assessed by using an in vitro transcription initiation assay in which the S14 promoter was fused to a reporter gene (G-free cassette). Deletion studies showed that nuclear factors binding to regions A (-48 to -63 bp), B (-88 to -113 bp) and D (-286 to -310 bp) enhanced the rate of initiation of transcription, while proteins binding to region C (-227 to -244 bp) suppressed the rate of initiation of transcription. Based on oligonucleotide competition studies, we suggest that hepatic NF-1 (or a related protein) binding to the A region enhances the rate of initiation of S14 gene transcription. Since trans-acting factors interacting with regions B and D are found in liver but not in spleen or kidney, we suggest that the proteins interacting with these regions may be involved in the tissue-specific augmentation of S14 gene transcription.
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Matsuda, Miyuki, Kouichi Tamura, Hiromichi Wakui, Toru Dejima, Akinobu Maeda, Masato Ohsawa, Tomohiko Kanaoka, et al. "Involvement of Runx3 in the basal transcriptional activation of the mouse angiotensin II type 1 receptor-associated protein gene." Physiological Genomics 43, no. 14 (July 2011): 884–94. http://dx.doi.org/10.1152/physiolgenomics.00005.2011.
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We previously cloned a molecule that interacts with angiotensin II type 1 (AT1) receptor to exert an inhibitory function on AT1 receptor signaling that we named ATRAP/ Agtrap (for AT1 receptor-associated protein). In the present study we examined the regulation of basal ATRAP gene expression using renal distal convoluted tubule cells. We found that serum starvation upregulated basal expression of ATRAP gene, a response that required de novo mRNA and protein synthesis. Luciferase assay revealed that the proximal promoter region directs transcription and that a putative binding site of runt-related transcription factors (RBE) is important for transcriptional activation. The results of RBE-decoy transfection and endogenous knockdown by small interference RNA showed that the runt-related transcription factor Runx3 is involved in ATRAP gene expression. Chromatin immunoprecipitation assay also supported the binding of Runx3 to the ATRAP promoter in renal distal convoluted tubule cells. Immunohistochemistry demonstrated the expression of Runx3 and ATRAP proteins in the distal convoluted and connecting tubules of the kidney in consecutive sections. Furthermore, the Runx3 immunostaining was decreased together with a concomitant suppression of ATRAP expression in the affected kidney after 7 days of unilateral ureteral obstruction. These findings indicate that Runx3 plays a role in ATRAP gene expression in renal distal tubular cells both in vitro and in vivo.
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Pecorino, L. T., A. L. Darrow, and S. Strickland. "In vitro analysis of the tissue plasminogen activator promoter reveals a GC box-binding activity present in murine brain but undetectable in kidney and liver." Molecular and Cellular Biology 11, no. 6 (June 1991): 3139–47. http://dx.doi.org/10.1128/mcb.11.6.3139.
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Tissue plasminogen activator (t-PA) mRNA levels are high in murine brain, lower in kidney, and undetectable in liver. Differences in t-PA mRNA levels are regulated in part at the transcriptional level. Brain, kidney, and liver nuclear extracts direct regulated transcription from the murine t-PA promoter in a manner that reflects the relative levels of t-PA gene expression in these tissues in vivo. Analysis of mutants has defined two GC box motifs as important elements for regulated transcription in vitro. Upon investigation of protein-DNA binding, we detected an activity in brain extracts which was not detected in kidney or liver extracts. An Sp1-like factor also binds to this region in all three tissue types. DNA interference experiments show that the brain-enriched binding activity and the Sp1-like factor contact the same GC-rich sequences. These studies provide additional evidence that brain-enriched DNA-binding activities can interact with sequences also recognized by ubiquitous transcription factors.
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Pecorino, L. T., A. L. Darrow, and S. Strickland. "In vitro analysis of the tissue plasminogen activator promoter reveals a GC box-binding activity present in murine brain but undetectable in kidney and liver." Molecular and Cellular Biology 11, no. 6 (June 1991): 3139–47. http://dx.doi.org/10.1128/mcb.11.6.3139-3147.1991.
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Tissue plasminogen activator (t-PA) mRNA levels are high in murine brain, lower in kidney, and undetectable in liver. Differences in t-PA mRNA levels are regulated in part at the transcriptional level. Brain, kidney, and liver nuclear extracts direct regulated transcription from the murine t-PA promoter in a manner that reflects the relative levels of t-PA gene expression in these tissues in vivo. Analysis of mutants has defined two GC box motifs as important elements for regulated transcription in vitro. Upon investigation of protein-DNA binding, we detected an activity in brain extracts which was not detected in kidney or liver extracts. An Sp1-like factor also binds to this region in all three tissue types. DNA interference experiments show that the brain-enriched binding activity and the Sp1-like factor contact the same GC-rich sequences. These studies provide additional evidence that brain-enriched DNA-binding activities can interact with sequences also recognized by ubiquitous transcription factors.
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Chan, Siu Chiu, Ying Zhang, Annie Shao, Svetlana Avdulov, Jeremy Herrera, Karam Aboudehen, Marco Pontoglio, and Peter Igarashi. "Mechanism of Fibrosis in HNF1B-Related Autosomal Dominant Tubulointerstitial Kidney Disease." Journal of the American Society of Nephrology 29, no. 10 (August 10, 2018): 2493–509. http://dx.doi.org/10.1681/asn.2018040437.
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BackgroundMutation of HNF1B, the gene encoding transcription factor HNF-1β, is one cause of autosomal dominant tubulointerstitial kidney disease, a syndrome characterized by tubular cysts, renal fibrosis, and progressive decline in renal function. HNF-1β has also been implicated in epithelial–mesenchymal transition (EMT) pathways, and sustained EMT is associated with tissue fibrosis. The mechanism whereby mutated HNF1B leads to tubulointerstitial fibrosis is not known.MethodsTo explore the mechanism of fibrosis, we created HNF-1β–deficient mIMCD3 renal epithelial cells, used RNA-sequencing analysis to reveal differentially expressed genes in wild-type and HNF-1β–deficient mIMCD3 cells, and performed cell lineage analysis in HNF-1β mutant mice.ResultsThe HNF-1β–deficient cells exhibited properties characteristic of mesenchymal cells such as fibroblasts, including spindle-shaped morphology, loss of contact inhibition, and increased cell migration. These cells also showed upregulation of fibrosis and EMT pathways, including upregulation of Twist2, Snail1, Snail2, and Zeb2, which are key EMT transcription factors. Mechanistically, HNF-1β directly represses Twist2, and ablation of Twist2 partially rescued the fibroblastic phenotype of HNF-1β mutant cells. Kidneys from HNF-1β mutant mice showed increased expression of Twist2 and its downstream target Snai2. Cell lineage analysis indicated that HNF-1β mutant epithelial cells do not transdifferentiate into kidney myofibroblasts. Rather, HNF-1β mutant epithelial cells secrete high levels of TGF-β ligands that activate downstream Smad transcription factors in renal interstitial cells.ConclusionsAblation of HNF-1β in renal epithelial cells leads to the activation of a Twist2-dependent transcriptional network that induces EMT and aberrant TGF-β signaling, resulting in renal fibrosis through a cell-nonautonomous mechanism.
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Bollinger, Lance M., Carol A. Witczak, Joseph A. Houmard, and Jeffrey J. Brault. "SMAD3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner." American Journal of Physiology-Cell Physiology 307, no. 3 (August 1, 2014): C278—C287. http://dx.doi.org/10.1152/ajpcell.00391.2013.
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Muscle-specific RING finger-1 (MuRF-1), a ubiquitin ligase and key regulator of proteasome-dependent protein degradation, is highly expressed during skeletal muscle atrophy. The transcription factor forkhead box O3 (FoxO3) induces MuRF-1 expression, but the direct role of other major atrophy-related transcription factors, such as SMAD3, is largely unknown. The goal of this study was to determine whether SMAD3 individually regulates, or with FoxO3 coordinately regulates, MuRF-1 expression. In cultured myotubes or human embryonic kidney cells, MuRF-1 mRNA content and promoter activity were increased by FoxO3 but not by SMAD3 overexpression. However, FoxO3 and SMAD3 coexpression synergistically increased MuRF-1 mRNA and promoter activity. Mutation of the SMAD-binding element (SBE) in the proximal MuRF-1 promoter or overexpression of a SMAD3 DNA-binding mutant attenuated FoxO3-dependent MuRF-1 promoter activation, showing that SMAD binding to DNA is required for optimal activation of FoxO3-induced transcription of MuRF-1. Using chromatin immunoprecipitation, SMAD3 DNA binding increased FoxO3 abundance and SBE mutation reduced FoxO3 abundance on the MuRF-1 promoter. Furthermore, SMAD3 overexpression dose-dependently increased FoxO3 protein content, and coexpression of FoxO3 and SMAD3 synergistically increased FoxO-dependent gene transcription [assessed with a FoxO response element (FRE)-driven reporter]. Collectively, these results show that SMAD3 regulates transcription of MuRF-1 by increasing FoxO3 binding at a conserved FRE-SBE motif within the proximal promoter region, and by increasing FoxO3 protein content and transcriptional activity. These data are the first to indicate that two major transcription factors regulating protein degradation, FoxO3 and SMAD3, converge to coordinately and directly regulate transcription of MuRF-1.
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Nishiya, Yuri, Kohei Kawaguchi, Kosuke Kudo, Takuya Kawaguchi, Juma Obayashi, Kunihide Tanaka, Kei Ohyama, et al. "The Expression of Transcription Factors in Fetal Lamb Kidney." Journal of Developmental Biology 9, no. 2 (June 19, 2021): 22. http://dx.doi.org/10.3390/jdb9020022.
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(1) Background: Renal development involves frequent expression and loss of transcription factors, resulting in the activation of genes. Wilms’ tumor 1 (WT1), hepatocyte nuclear factor-1-beta (HNF1β), and paired box genes 2 and 8 (Pax2 and Pax8) play an important role in renal development. With this in vivo study, we examined the period and location of expression of these factors in renal development. (2) Methods: Fetal lamb kidneys (50 days from gestation to term) and adult ewe kidneys were evaluated by hematoxylin and eosin staining. Serial sections were subjected to immunohistochemistry for WT1, HNF1β, Pax2, and Pax8. (3) Results: Pax2, Pax8, and HNF1β expression was observed in the ureteric bud and collecting duct epithelial cells. We observed expression of WT1 alone in metanephric mesenchymal cells, glomerular epithelial cells, and interstitial cells in the medullary rays and Pax8 and HNF1β expression in tubular epithelial cells. WT1 was highly expressed in cells more proximal to the medulla in renal vesicles and in C- and S-shaped bodies. Pax2 was expressed in the middle and peripheral regions, and HNF1β in cells in the region in the middle of these. (4) Conclusions: WT1 is involved in nephron development. Pax2, Pax8, and HNF1β are involved in nephron maturation and the formation of peripheral collecting ducts from the Wolffian duct.
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Fuchs, Serge Y., and Ze’ev Ronai. "Ubiquitination and Degradation of ATF2 Are Dimerization Dependent." Molecular and Cellular Biology 19, no. 5 (May 1, 1999): 3289–98. http://dx.doi.org/10.1128/mcb.19.5.3289.
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ABSTRACT Ubiquitination and proteasome-dependent degradation are key determinants of the half-lives of many transcription factors. Homo- or heterodimerization of basic region-leucine zipper (bZIP) transcription factors is required for their transcriptional activities. Here we show that activating transcription factor 2 (ATF2) heterodimerization with specific bZIP proteins is an important determinant of the ubiquitination and proteasome-dependent degradation of ATF2. Depletion of c-Jun as one of the ATF2 heterodimer partners from the targeting proteins decreased the efficiency of ATF2 ubiquitination in vitro, whereas the addition of exogenously purified c-Jun restored it. Similarly, overexpression of c-Jun in 293T human embryo kidney cells increased ATF2 ubiquitination in vivo and reduced its half-life in a dose-dependent manner. Mutations of ATF2 that disrupt its dimerization inhibited ATF2 ubiquitination in vitro and in vivo. Conversely, removal of residues 150 to 248, as in a constitutively active ATF2 spliced form, enhanced ATF2 dimerization and transactivation, which coincided with increased ubiquitination and decreased stability. Our findings indicate the increased sensitivity of transcriptionally active dimers of ATF2 to ubiquitination and proteasome-dependent degradation. Based on these observations, we conclude that increased targeting of a transcriptionally active ATF2 form indicates the mechanism by which the magnitude and the duration of the cellular stress response are regulated.
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Cohen, D. M., and S. R. Gullans. "Urea induces Egr-1 and c-fos expression in renal epithelial cells." American Journal of Physiology-Renal Physiology 264, no. 4 (April 1, 1993): F593—F600. http://dx.doi.org/10.1152/ajprenal.1993.264.4.f593.
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The membrane-permeant solute urea, in concentrations present in the mammalian renal medulla, increased expression at the mRNA level of two immediate-early gene (IEG) transcription factors, Egr-1 and c-fos, in a time- and dose-dependent fashion in confluent growth-suppressed Madin-Darby canine kidney (MDCK) cells. This upregulation occurred in the absence of both cytotoxicity and an inhibition of protein synthesis, two potential nonspecific inducers of IEG expression. These findings were of interest because we have previously shown that hyperosmotic stress induced by the functionally membrane-impermeant solute NaCl increased expression of these IEG, whereas hyperosmotic stress induced by the membrane-permeant solute glycerol failed to do so. The urea-induced increase in Egr-1 mRNA expression was not secondary to enhanced message stability as determined by actinomycin D experiments and is therefore likely a consequence of urea-induced transcriptional activation. Augmented Egr-1 expression in response to urea treatment was also observed in another renal epithelial cell line, LLC-PK1, but not in other cell types examined. Therefore cells of renal epithelial origin may be uniquely capable of responding to hyperosmotic urea with increased expression of IEG transcription factors, and this increase is likely transcriptionally mediated.
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MARCHENKO, George N., Natalia D. MARCHENKO, Jay LENG, and Alex Y. STRONGIN. "Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin." Biochemical Journal 363, no. 2 (April 8, 2002): 253–62. http://dx.doi.org/10.1042/bj3630253.
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A novel matrix metalloproteinase-26 (MMP-26) is known to be specifically expressed in epithelial carcinomas. To facilitate studies of MMP-26 transcriptional regulation, we have cloned and characterized a 1kb 5′-flanking region of the human MMP-26 gene. Altogether, our findings indicate that the MMP-26 promoter has distinctive structural and functional features among MMP genes. An unusual polyadenylation site proximal to the transcription-factor-binding sites protects transcription of the MMP-26 gene from the upstream promoters and represents a part of the stringent transcriptional regulation of the gene. The MMP-26 gene has a consensus TATA-box and one transcriptional start site located 60 and 35 nucleotides upstream of the translational start site, respectively. The MMP-26 promoter was able to drive luciferase expression in human A549 lung carcinoma, HT1080 fibrosarcoma and HEK293 embryonic kidney cells. The basal transcription efficiency of the MMP-26 promoter is relatively low, thereby explaining the minute expression of the gene in most cells and tissues. When compared with other MMP genes, the MMP-26 promoter contains binding sites for a few transcription factors. Sequential deletion and mutation analysis, and electrophoretic mobility-shift assay have identified the T-cell factor-4 (Tcf-4) motif and the activator protein-1 site as the major regulatory elements of the MMP-26 promoter. Since previous studies have established that the Tcf-4 transcription factor is subjected exclusively to regulation through the β-catenin/E(epithelial)-cadherin pathway, this implies the specific expression of MMP-26 in cancer cells of epithelial origin.
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Fujitani, Yoshio, Yoshitaka Kajimoto, Tetsuyuki Yasuda, Taka-Aki Matsuoka, Hideaki Kaneto, Yutaka Umayahara, Noriko Fujita, et al. "Identification of a Portable Repression Domain and an E1A-Responsive Activation Domain in Pax4: a Possible Role of Pax4 as a Transcriptional Repressor in the Pancreas." Molecular and Cellular Biology 19, no. 12 (December 1, 1999): 8281–91. http://dx.doi.org/10.1128/mcb.19.12.8281.
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ABSTRACT Pax4 is a paired-domain (PD)-containing transcription factor which plays a crucial role in pancreatic β/δ-cell development. In this study, we characterized the DNA-binding and transactivation properties of mouse Pax4. Repetitive rounds of PCR-based selection led to identification of the optimal DNA-binding sequences for the PD of Pax4. In agreement with the conservation of the optimal binding sequences among the Pax family transcription factors, Pax4 could bind to the potential binding sites for Pax6, another member of the Pax family also involved in endocrine pancreas development. The overexpression of Pax4 in HIT-T15 cells dose dependently inhibited the basal transcriptional activity as well as Pax6-induced activity. Detailed domain mapping analyses using GAL4-Pax4 chimeras revealed that the C-terminal region of Pax4 contains both activation and repression domains. The activation domain was active in the embryonic kidney-derived 293/293T cells and embryonal carcinoma-derived F9 cells, containing adenoviral E1A protein or E1A-like activity, respectively but was inactive or very weakly active in other cells including those of pancreatic β- and α-cell origin. Indeed, the exogenous overexpression of type 13S E1A in heterologous cell types could convert the activation domain to an active one. On the other hand, the repression domain was active regardless of the cell type. When the repression domain was linked to the transactivation domain of a heterologous transcription factor, PDX-1, it could completely abolish the transactivation potential of PDX-1. These observations suggest a primary role of Pax4 as a transcriptional repressor whose function may involve the competitive inhibition of Pax6 function. The identification of the E1A-responsive transactivation domain, however, indicates that the function of Pax4 is subject to posttranslational regulation, providing further support for the complexity of mechanisms that regulate pancreas development.
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Baserga, Mariana, Rajwinderjit Kaur, Merica A. Hale, Allyson Bares, Xing Yu, Christopher W. Callaway, Robert A. McKnight, and Robert H. Lane. "Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11β-hydroxysteroid dehydrogenase type 2 in a sex-specific manner." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, no. 1 (July 2010): R334—R342. http://dx.doi.org/10.1152/ajpregu.00122.2010.
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Intrauterine growth restriction (IUGR) increases the risk of serious adult morbidities such as hypertension. In an IUGR rat model of hypertension, we reported a persistent decrease in kidney 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) mRNA and protein levels from birth through postnatal (P) day 21. This enzyme deficiency can lead to hypertension by limiting renal glucocorticoid deactivation. In the present study, we hypothesized that IUGR affects renal 11β-HSD2 epigenetic determinants of chromatin structure and alters key transcription factor binding to the 11β-HSD2 promoter in association with persistent downregulation of its mRNA expression. To test this hypothesis, we performed bilateral uterine artery ligation on embryonic day 19.5 pregnant rats and harvested kidneys at day 0 (P0) and P21. Key transcription factors that can affect 11β-HSD2 expression include transcriptional enhancers specificity protein 1 (SP1) and NF-κB p65 and transcriptional repressors early growth response factor (Egr-1) and NF-κB p50. Our most important findings were as follows: 1) IUGR significantly decreased SP1 and NF-κB (p65) binding to the 11β-HSD2 promoter in males, while it increased Egr-1 binding in females and NF-κB (p50) binding in males; 2) IUGR increased CpG methylation status, as well as modified the pattern of methylation in several CpG sites of 11β-HSD2 promoter at P0 also in a sex-specific manner; and 3) IUGR decreased trimethylation of H3K36 in exon 5 of 11β-HSD2 at P0 and P21 in both genders. We conclude that IUGR is associated with altered transcriptional repressor/activator binding in connection with increased methylation in the 11β-HSD2 promoter region in a sex-specific manner, possibly leading to decreased transcriptional activity. Furthermore, IUGR decreased trimethylation of H3K36 of the 11β-HSD2 gene in both genders, which is associated with decreased transcriptional elongation. We speculate that alterations in transcription factor binding and chromatin structure play a role in in utero reprogramming.
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Imhof, Axel, Marion Schuierer, Oliver Werner, Markus Moser, Christina Roth, Reinhard Bauer, and Reinhard Buettner. "Transcriptional Regulation of the AP-2α Promoter by BTEB-1 and AP-2rep, a Novel wt-1/egr-Related Zinc Finger Repressor." Molecular and Cellular Biology 19, no. 1 (January 1, 1999): 194–204. http://dx.doi.org/10.1128/mcb.19.1.194.
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ABSTRACT AP-2 transcription factors have been suggested to exert key regulatory functions in vertebrate embryonic development, in tumorigenicity of various cancer cell types, and in controlling cell cycle and apoptotic effector genes. In this study, we investigated transcriptional regulation of the AP-2α gene promoter mediated by an autoregulatory element (referred to as A32) with a core consensus AP-2 binding site at position −336 relative to the mRNA initiation site. AP-2 and multiple different nuclear proteins in HeLa and Neuro2A cell extracts form specific bandshifts with the A32 element. By screening a mouse brain cDNA expression library, we isolated two different cDNAs encoding the transcription factor BTEB-1 and a novel zinc finger protein, AP-2rep. AP-2rep reveals a modular structure with homology to transcription factors of the wt-1/egr-1-family. AP-2rep, BTEB-1, and AP-2 interact in a mutually exclusive manner with overlapping binding sites in the A32 element. Transfection studies revealed that BTEB-1 is a strong activator of AP-2α promoter activity, whereas cotransfected AP-2α resulted in moderate autoactivation of promoter activity. In contrast, AP-2rep confers strong transcriptional repression to the AP-2α gene, and we observed an excellent correlation between induction of AP-2rep mRNA expression and downregulation of AP-2α mRNA during development of the kidney. In summary, we have identified multiple transcription factors and cloned from an expression library a novel zinc finger silencing factor, AP-2rep, mediating positive and negative regulation of AP-2α expression through a set of overlappingcis-regulatory promoter elements.
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Spirina, L. V., I. V. Kondakova, E. A. Usynin, E. M. Slonimskaya, and Z. A. Yurmazov. "IMPACT OF TRANSCRIPTION FACTORS, VEGF AND PROTEASES ON KIDNEY CANCER PROGRESSION." Siberian journal of oncology 17, no. 4 (September 4, 2018): 67–74. http://dx.doi.org/10.21294/1814-4861-2018-17-4-67-74.
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Introduction.The efficacy of anticancer treatment depends on biological factors of tumor.The aimof the study was to determine the activity of proteasomes and calpains and to reveal their association with VEGF, HIF-1α and NF-κΒ expressions in normal, primary and metastatic renal cell carcinoma (RCC) tissues.Methods.Ninety-three patients with renal cell carcinoma were included into the study. The expression levels of transcription factor and VEGF were measured using ELISA kits. The levels of proteasome subunits were measured by Western Blotting. Proteasome and calpain activities were determined using specific fluorogenic substrates.Results.We revealed inactivation of proteolysis in patients with kidney cancer. Disease advance was associated with a significant depression of cellular proteolysis and increase in transcription and growth factor levels in primary kidney cancer tissues. The proteolysis activation was found in metastatic tissues.Conclusions.Our results suggest that NF-κΒ, HIF-1α and VEGF transcription factors and intracellular proteolytic systems are involved in kidney cancer progression.
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Fu, Xiaoyong, Resel Pereira, Carmine De Angelis, Jamunarani Veeraraghavan, Sarmistha Nanda, Lanfang Qin, Maria L. Cataldo, et al. "FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer." Proceedings of the National Academy of Sciences 116, no. 52 (December 11, 2019): 26823–34. http://dx.doi.org/10.1073/pnas.1911584116.
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Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER+) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER+breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER+/HER2−metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with theESR1mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α–dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.
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Higgins, P. J., M. P. Ryan, and A. Ahmed. "Cell-shape-associated transcriptional activation of the p52(PAI-1) gene in rat kidney cells." Biochemical Journal 288, no. 3 (December 15, 1992): 1017–24. http://dx.doi.org/10.1042/bj2881017.
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The microfilament-disrupting agent cytochalasin D (CD) increased (by 10-22-fold) the synthesis de novo and extracellular matrix deposition of plasminogen-activator inhibitor type-1 [p52(PAI-1)] in normal rat kidney (NRK) cells. Transition from a flat to a round phenotype occurred concomitantly with, and may actually precede, p52(PAI-1) induction; both the morphological and p52(PAI-1) responses were dose-dependent. Augmented synthesis became evident between 4 and 5 h of treatment of NRK cells with 100 microM-CD, correlating with a transition from 25 to more than 60% rounded cells. CD-associated increases in p52(PAI-1) mRNA abundance and protein biosynthesis were maximal between 6 and 8 h of continuous CD exposure, declined by 50% thereafter, but remained elevated (by at least 6-21-fold respectively over control values) for 24 h. Changes in p52(PAI-1) mRNA abundance at this 24 h point reflected an approx. 5-fold increase in p52(PAI-1)-gene transcription. These data confirm previous suggestions, based on actinomycin D-sensitivity of the inductive response [Higgins & Ryan (1992) Biochem. J. 284, 433-439], that CD-mediated increases in p52(PAI-1) expression are at least partly due to transcription-level events. Since CD also augments specific cellular responses to growth factors or cytokines, the potential effectiveness of this inducer was evaluated both in the presence and absence of serum growth factors using quiescent NRK cells [a growth state in which p52(PAI-1) is not expressed] as a model system. Induction of p52(PAI-1) synthesis and matrix deposition in CD-stimulated quiescent NRK cells was as efficient under growth-factor-deficient conditions as when CD was added simultaneously with serum. CD alone is thus a complete inducer of p52(PAI-1) expression in NRK cells, an observation that supports the contention that cell shape is an important regulatory element in p52(PAI-1)-gene control.
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Chambers, Brooke E., Eleanor G. Clark, Allison E. Gatz, and Rebecca A. Wingert. "Kctd15 regulates nephron segment development by repressing Tfap2a activity." Development 147, no. 23 (October 7, 2020): dev191973. http://dx.doi.org/10.1242/dev.191973.
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ABSTRACTA functional vertebrate kidney relies on structural units called nephrons, which are epithelial tubules with a sequence of segments each expressing a distinct repertoire of solute transporters. The transcriptiona`l codes driving regional specification, solute transporter program activation and terminal differentiation of segment populations remain poorly understood. Here, we demonstrate that the KCTD15 paralogs kctd15a and kctd15b function in concert to restrict distal early (DE)/thick ascending limb (TAL) segment lineage assignment in the developing zebrafish pronephros by repressing Tfap2a activity. During renal ontogeny, expression of these factors colocalized with tfap2a in distal tubule precursors. kctd15a/b loss primed nephron cells to adopt distal fates by driving slc12a1, kcnj1a.1 and stc1 expression. These phenotypes were the result of Tfap2a hyperactivity, where kctd15a/b-deficient embryos exhibited increased abundance of this transcription factor. Interestingly, tfap2a reciprocally promoted kctd15a and kctd15b transcription, unveiling a circuit of autoregulation operating in nephron progenitors. Concomitant kctd15b knockdown with tfap2a overexpression further expanded the DE population. Our study reveals that a transcription factor-repressor feedback module employs tight regulation of Tfap2a and Kctd15 kinetics to control nephron segment fate choice and differentiation during kidney development.
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Groves, Angela K., Murray A. Cotter, Chitra Subramanian, and Erle S. Robertson. "The Latency-Associated Nuclear Antigen Encoded by Kaposi's Sarcoma-Associated Herpesvirus Activates Two Major Essential Epstein-Barr Virus Latent Promoters." Journal of Virology 75, no. 19 (October 1, 2001): 9446–57. http://dx.doi.org/10.1128/jvi.75.19.9446-9457.2001.
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ABSTRACT The latency-associated nuclear antigen (LANA) encoded by the Kaposi's sarcoma-associated herpesvirus (KSHV) is expressed in the majority of KSHV-infected cells and in cells coinfected with Epstein-Barr virus (EBV). In coinfected body cavity-based lymphomas (BCBLs), EBV latent membrane protein 1 (LMP1), which is essential for B-lymphocyte transformation, is expressed. EBNA2 upregulates the expression of LMP1 and other cellular genes through specific interactions with cellular transcription factors tethering EBNA2 to its responsive promoters. In coinfected BCBL cells, EBNA2 is not detected but LANA, which is constitutively expressed, contains motifs suggestive of potential transcriptional activity. Additionally, recent studies have shown that LANA is capable of activating cellular promoters. Therefore, we investigated whether LANA can affect transcription from two major EBV latent promoters. In this study, we demonstrated that LANA can efficiently transactivate both the LMP1 and C promoters in the human B-cell line BJAB as well as in the human embryonic kidney 293 cell line. Moreover, we demonstrated that specific domains of LANA containing the putative leucine zipper and the glutamic acid-rich region are highly effective in upregulating these viral promoters, while the amino-terminal region (435 amino acids) exhibited little or no transactivation activity in our assays. We also specifically tested truncations of the LMP1 promoter element and showed that the −204 to +40 region had increased levels of activation compared with a larger region, −512 to +40, which contains two recombination signal-binding protein Jκ binding sites. The smaller, −204 to +40 promoter region contains specific binding sites for the Ets family transcription factor PU.1, transcription activating factor/cyclic AMP response element, and Sp1, all of which are known to function as activators of transcription. Our data therefore suggest a potential role for LANA in regulation of the major EBV latent promoters in KSHV- and EBV-coinfected cells. Furthermore, LANA may be able to activate transcription of viral and cellular promoters in the absence of EBNA2, potentially through association with transcription factors bound to their cognate sequences within the −204 to +40 region. This regulation of viral gene expression is critical for persistence of these DNA tumor viruses and most likely involved in mediating the oncogenic process in these coinfected cells.
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Boyle, Scott, and Mark de Caestecker. "Role of transcriptional networks in coordinating early events during kidney development." American Journal of Physiology-Renal Physiology 291, no. 1 (July 2006): F1—F8. http://dx.doi.org/10.1152/ajprenal.00447.2005.
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Many of the signaling pathways that regulate tissue specification and coordinate cellular differentiation during embryogenesis have been identified over the last decade. These pathways are integrated at the transcriptional level, enabling activation of specific developmental programs in a temporally and spatially restricted fashion. Such developmental events are usually thought of in terms of hierarchical relationships, in which the expression of upstream factors leads to the sequential activation of a linear cascade of downstream genes. Whereas these models provide a simplistic approach to understand complex cellular events, genetic and biochemical studies in mice and other model organisms provide ample evidence that many of these factors interact at multiple levels in vivo and emphasize the importance of considering these linear events in context. The purpose of this review is to emphasize the complexity of these regulatory networks during the early phases of mammalian kidney development, outlining some of the limitations and alternative approaches that are being used to explore the complex nature of these networks in vivo. Before describing these networks in detail, we will provide a brief overview of the main structural changes and tissue interactions involved in mammalian kidney development, and go on to describe some of the limitations of our current approaches to evaluate the role of these developmental pathways in vivo.
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Ruan, X. Z., J. F. Moorhead, R. Fernando, D. C. Wheeler, S. H. Powis, and Z. Varghese. "Regulation of lipoprotein trafficking in the kidney: role of inflammatory mediators and transcription factors." Biochemical Society Transactions 32, no. 1 (February 1, 2004): 88–91. http://dx.doi.org/10.1042/bst0320088.
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Inflammation and dyslipidaemia both play important roles in the development of glomerular atherosclerosis in renal diseases. We have demonstrated that inflammatory mediators induced Scr (scavenger receptor) expression and the formation of foam cells, and that AP-1 (activator protein 1)/ets were necessary transcriptional factors for Scr induction in HMCs (human kidney mesangial cells). Most cells are protected from excessive native LDL (low-density lipoprotein) accumulation by tight feedback regulation of the LDLr (LDL receptor). However, we observed that HMCs formed foam cells via the LDLr pathway when incubated with IL-1β (interleukin-1β; 5 ng/ml) and unmodified LDL (200 μg/ml), suggesting that inflammatory mediators may disrupt the cholesterol-mediated feedback regulation. This feedback involves cholesterol-mediated down-regulation of LDLr controlled by SCAP [SREBP (sterol responsive element-binding protein) cleavage-activating protein]. We have also demonstrated that both tumour necrosis factor α and IL-1β increased nuclear SREBP-1 levels by increasing SCAP mRNA expression, even in the presence of a high concentration of LDL. Since intracellular lipid content is governed by both influx and efflux mechanisms, we set out to examine the impact of inflammatory cytokines on cholesterol efflux, a process mediated by the protein ABCA1 (ATP binding cassette A1). IL-1β inhibited [3H]cholesterol efflux from HMCs by inhibition of the peroxisome-proliferator-activated receptor/LXR (liver X receptor)/ABCA1 pathway. Taken together, our results suggest that inflammatory mediators increase lipid accumulation in HMCs not only by promoting increased lipoprotein uptake by Scr and LDLr, but also by inhibiting ABCA1-mediated cholesterol efflux to high-density lipoprotein.
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Zhou, Xiaoming, Hong Wang, Nancy L. Koles, Aihong Zhang, and Naomi E. Aronson. "Leishmania infantum-chagasi activates SHP-1 and reduces NFAT5/TonEBP activity in the mouse kidney inner medulla." American Journal of Physiology-Renal Physiology 307, no. 5 (September 1, 2014): F516—F524. http://dx.doi.org/10.1152/ajprenal.00006.2014.
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Visceral leishmaniasis patients have been reported to have a urine concentration defect. Concentration of urine by the renal inner medulla is essentially dependent on a transcription factor, NFAT5/TonEBP, because it activates expression of osmoprotective genes betaine/glycine transporter 1 (BGT1) and sodium/myo-inositol transporter (SMIT), and water channel aquaporin-2, all of which are imperative for concentrating urine. Leishmania parasites evade macrophage immune defenses by activating protein tyrosine phosphatases, among which SHP-1 is critical. We previously demonstrated that SHP-1 inhibits tonicity-dependent activation of NFAT5/TonEBP in HEK293 cells through screening a genome-wide small interfering (si) RNA library against phosphatases (Zhou X, Gallazzini M, Burg MB, Ferraris JD. Proc Natl Acad Sci USA 107: 7072–7077, 2010). We sought to examine whether Leishmania can activate SHP-1 and inhibit NFAT5/TonEBP activity in the renal inner medulla in a murine model of visceral leishmaniasis by injection of female BALB/c mice with a single intravenous dose of 5 × 105 L. chagasi metacyclic promastigotes. We found that SHP-1 is expressed in the kidney inner medulla. L. chagasi activates SHP-1 with an increase in stimulatory phosphorylation of SHP-1-Y536 in the region. L. chagasi reduces expression of NFAT5/TonEBP mRNA and protein as well as expression of its targeted genes: BGT1, SMIT, and aquaporin-2. The culture supernatant from L. chagasi metacyclic promastigotes increases SHP-1 protein abundance and potently inhibits NFAT5 transcriptional activity in mIMCD3 cells. However, L. chagasi in our animal model has no significant effect on urinary concentration. We conclude that L. chagasi, most likely through its secreted virulence factors, activates SHP-1 and reduces NFAT5/TonEBP gene expression, which leads to reduced NFAT5/TonEBP transcriptional activity in the kidney inner medulla.
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Auwardt, R. B., S. J. Mudge, C. G. Chen, and D. A. Power. "Regulation of nuclear factor kappaB by corticosteroids in rat mesangial cells." Journal of the American Society of Nephrology 9, no. 9 (September 1998): 1620–28. http://dx.doi.org/10.1681/asn.v991620.
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Nuclear factor kappaB (NF-kappaB) is one of the most important proinflammatory transcription factors. The anti-inflammatory activity of steroids in leukocytes is partly due to inhibition of signaling by NF-kappaB, but it is not known whether steroids inhibit NF-kappaB in kidney cells. Since the mesangial cell is important in several kidney diseases, especially mesangial proliferative glomerulonephritis, the aims of this study were: (1) to define the mechanism of NF-kappaB activation in rat glomerular mesangial cells; and (2) to determine whether steroids inhibit activation of NF-kappaB in these cells. Electrophoretic mobility shift assays (EMSA) showed that interleukin-1beta and tumor necrosis factor-alpha activated NF-kappaB from 15 min to 48 h after stimulation. Supershift EMSA demonstrated that p65 and p50 were the predominant subunits involved. Degradation of the inhibitory subunit IkappaB-alpha was first observed 15 min after stimulation by Western blot, was maximal at 15 to 30 min (>90% by densitometry), and had returned to near normal levels at 90 min. In contrast, IkappaB-beta was maximally degraded at 60 to 120 min and was still reduced at 48 h (<50% of the untreated level). Although treatment of mesangial cells with dexamethasone increased IkappaB-alpha mRNA by 1.92x and protein by 1.45x over controls, pretreatment did not inhibit degradation of IkappaB-alpha or -beta in response to stimulation, or prevent the increase in NF-kappaB binding activity shown by EMSA. However, dexamethasone significantly inhibited the increase in monocyte chemoattractant protein-1 mRNA seen after stimulation with interleukin 1beta, although this was not complete. It did not reduce transcription of an NF-kappaB reporter. In comparison, the pyrrolidine derivative of dithiocarnamate (PDTC), a known inhibitor of NF-kappaB, prevented the increase in NF-kappaB binding activity and significantly reduced transcription of the NF-kappaB reporter. These studies suggest that steroids can partially inhibit transcriptional activation by NF-kappaB in mesangial cells but not through an increase in IkappaB-alpha protein alone. Their effect must occur at the promoter and may be restricted to some NF-kappaB-responsive genes. Therapies that block NF-kappaB more effectively than steroids in mesangial cells, therefore, may be useful in the treatment of mesangial proliferative glomerulonephritis.
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Zhu, Denghui, Rong Huang, Peipei Fu, Liangming Chen, Lifei Luo, Pengfei Chu, Libo He, et al. "Investigating the Role of BATF3 in Grass Carp (Ctenopharyngodon idella) Immune Modulation: A Fundamental Functional Analysis." International Journal of Molecular Sciences 20, no. 7 (April 4, 2019): 1687. http://dx.doi.org/10.3390/ijms20071687.
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Basic leucine zipper transcription factor ATF-like (BATF)-3, belonging to activator protein 1 (AP-1) superfamily transcription factors, is essential for homeostatic development of CD8α+ classical dendritic cells activating CD8 T-cell responses to intracellular pathogens. In this study, the characteristics and cDNA cloning of the CiBATF3 molecule were described in grass carp (Ctenopharyngodon idella). CiBATF3 had abundant expression in immune-related organizations, including liver, spleen and gill, and grass carp reovirus (GCRV) infection had significantly changed its expression level. After Ctenopharyngodon idella kidney (CIK) cells were challenged with pathogen-associated molecular patterns (PAMPs), polyinosinic:polycytidylic acid (poly(I:C)) stimulation induced higher mRNA levels of CiBATF3 than that of lipopolysaccharide (LPS). Subcellular localization showed that CiBATF3-GFP was entirely distributed throughout cells and nuclear translocation of CiBATF3 was found after poly(I:C) treatment. Additionally, the interaction between CiBATF3 and interleukin 10 (IL-10) was proven by bimolecular fluorescence complementation (BiFC) system. The small interfering RNA (siRNA)-mediated CiBATF3 silencing showed that the mRNA of CiBATF3 and its downstream genes were down-regulated in vitro and in vivo. CiBATF3 played a negative regulatory role in the transcriptional activities of AP-1 and NF-κB reporter gene. In summary, the results may provide valuable information on fundamental functional mechanisms of CiBATF3.
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Sailaja, Badi Sri, Rohit Aita, Shane Maledatu, David Ribnicky, Michael P. Verzi, and Ilya Raskin. "Moringa isothiocyanate-1 regulates Nrf2 and NF-κB pathway in response to LPS-driven sepsis and inflammation." PLOS ONE 16, no. 4 (April 1, 2021): e0248691. http://dx.doi.org/10.1371/journal.pone.0248691.
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This study aims to document the dual mode of pharmacological action of moringa isothiocyanate-1 (MIC-1) derived from seeds of Moringa oleifera Lam. Oral administration of chemically stable MIC-1 (80 mg/kg) significantly reduced the expression of inflammatory markers (Tnf-α, Ifn-α, IL-1β, IL-6) in the liver, kidney, spleen, and colon and decreased spleen weight in the lipopolysaccharide (LPS)-induced sepsis / acute inflammation model in mice. Transcriptomic analysis of the effect of MIC-1 on the liver and in the LPS-induced RAW264.7 murine macrophage showed that MIC-1 decreases inflammation via inflammation, immunity, and oxidative stress pathways. These results are supported by the immunocytochemical observations that MIC-1 increased the nuclear accumulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor and decreased the nuclear accumulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the LPS-induced macrophages. Transcriptional activation of antioxidant genes by MIC-1 translated into a reduction of reactive oxygen species (ROS) in the cytoplasm, decrease of mitochondrial superoxide content, and restoration of the mitochondrial membrane potential in the LPS-induced macrophages. Our data indicate that MIC-1 affects inflammation and oxidative stress, two key processes involved in the etiology of many chronic diseases. These effects involve upstream regulation of two key transcriptional factors regulating responses to these processes at a gene expression level.
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Gu, Daqian, Dandong Fang, Mingming Zhang, Jingwen Guo, Hongmei Ren, Xinyue Li, Ziyue Zhang, et al. "Gastrin, via activation of PPARα, protects the kidney against hypertensive injury." Clinical Science 135, no. 2 (January 2021): 409–27. http://dx.doi.org/10.1042/cs20201340.
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Abstract Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.
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Maldonado, Nicolás, Melina Villalba, Fernanda Fredericksen, Gardenia Payne, and Victor Hugo Olavarria. "Cytopathic BVDV-1 Induces Type I Interferon Expression through IRF-1 and IRF-7 Transcriptional Factors in MDBK Cells." Proceedings 50, no. 1 (June 17, 2020): 82. http://dx.doi.org/10.3390/proceedings2020050082.
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Bovine viral diarrhea virus (BVDV-1) is responsible for the Bovine Viral Diarrhea/Mucosal Disease complex, endemic pathology of cattle, as well as for heavy losses for the livestock and dairy industry in the world. Several investigations have shown that BVDV-1 is capable of altering the host animal's immune system, but there is little information available on the molecular and cellular mechanisms involved. The production of interferon (IFN-a/b) is considered a potent and rapid response of the innate immune system against the presence of a virus. In the case of BVDV-1, the antecedents that show whether IFN-b expression is triggered during an infection in bovine models are contradictory, and the transcription factors that regulate the expression of this key cytokine to trigger antiviral status have not been established. To investigate the effects of BVDV-1 on the activation of the immune response, Madin–Dardy bovine kidney (MDBK) cells were infected with the cytopathic biotype cpBVDV-1, and the expression of IFN-b, interferon regulatory factors (IRF) and immunity markers was analyzed. Additionally, a transient silencing of the IRF-7 factor was performed. The results obtained show that BVDV-1 is capable of inducing the production of IFN-b, IRF-1, and IRF-7 in a manner similar to polycytidylic acid, evaluated transcript, and protein level. The use of pharmacological inhibitors against IRF-1 and IRF-7 decreases the production of IFN-b, a phenomenon observed by mainly interfering with the activation pathway of IRF-7. These results propose that in an infection with cpBVDV-1, the activation of the IRF-7 factor is required and indispensable for the regulation of the transcription of the IFN-b gene in an in vitro model of infection.
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Sanchez, Amber P., JingHong Zhao, Young You, Anne-Emilie Declèves, Maggie Diamond-Stanic, and Kumar Sharma. "Role of the USF1 transcription factor in diabetic kidney disease." American Journal of Physiology-Renal Physiology 301, no. 2 (August 2011): F271—F279. http://dx.doi.org/10.1152/ajprenal.00221.2011.
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The predominant transcription factors regulating key genes in diabetic kidney disease have not been established. The transcription factor upstream stimulatory factor 1 (USF1) is an important regulator of glucose-mediated transforming growth factor (TGF)-β1 expression in mesangial cells; however, its role in the development of diabetic kidney disease has not been evaluated. In the present study, wild-type (WT; USF1 +/+), heterozygous (USF1 +/−), and homozygous (USF1 −/−) knockout mice were intercrossed with Akita mice (Ins2/Akita) to induce type 1 diabetes. Mice were studied up to 36 wk of age. The degree of hyperglycemia and kidney hypertrophy were similar in all groups of diabetic mice; however, the USF1 −/− diabetic mice had significantly less albuminuria and mesangial matrix expansion than the WT diabetic mice. TGF-β1 and renin gene expression and protein were substantially increased in the WT diabetic mice but not in USF1 −/− diabetic mice. The underlying pathway by which USF1 is regulated by high glucose was investigated in mesangial cell culture. High glucose inhibited AMP-activated protein kinase (AMPK) activity and increased USF1 nuclear translocation. Activation of AMPK with AICAR stimulated AMPK activity and reduced nuclear accumulation of USF1. We thus conclude that USF1 is a critical transcription factor regulating diabetic kidney disease and plays a critical role in albuminuria, mesangial matrix accumulation, and TGF-β1 and renin stimulation in diabetic kidney disease. AMPK activity may play a key role in high glucose-induced regulation of USF1.
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Tomc, Jana, and Nataša Debeljak. "Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis." International Journal of Molecular Sciences 22, no. 13 (June 30, 2021): 7074. http://dx.doi.org/10.3390/ijms22137074.
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Erythropoiesis is regulated by several factors, including the oxygen-sensing pathway as the main regulator of erythropoietin (EPO) synthesis in the kidney. The release of EPO from the kidney and its binding to the EPO receptor (EPOR) on erythrocyte progenitor cells in the bone marrow results in increased erythropoiesis. Any imbalance in these homeostatic mechanisms can lead to dysregulated erythropoiesis and hematological disorders. For example, mutations in genes encoding key players of oxygen-sensing pathway and regulation of EPO production (HIF-EPO pathway), namely VHL, EGLN, EPAS1 and EPO, are well known causative factors that contribute to the development of erythrocytosis. We aimed to investigate additional molecular mechanisms involved in the HIF-EPO pathway that correlate with erythropoiesis. To this end, we conducted an extensive literature search and used several in silico tools. We identified genes encoding transcription factors and proteins that control transcriptional activation or repression; genes encoding kinases, deacetylases, methyltransferases, conjugating enzymes, protein ligases, and proteases involved in post-translational modifications; and genes encoding nuclear transport receptors that regulate nuclear transport. All these genes may modulate the stability or activity of HIF2α and its partners in the HIF-EPO pathway, thus affecting EPO synthesis. The theoretical information we provide in this work can be a valuable tool for a better understanding of one of the most important regulatory pathways in the process of erythropoiesis. This knowledge is necessary to discover the causative factors that may contribute to the development of hematological diseases and improve current diagnostic and treatment solutions in this regard.
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Suzuki, Hideaki, Oleg N. Denisenko, Yu Suzuki, Daniel S. Schullery, and Karol Bomsztyk. "Inducible transcriptional activity of bcn-1 element from laminin γ1-chain gene promoter in renal and nonrenal cells." American Journal of Physiology-Renal Physiology 275, no. 4 (October 1, 1998): F518—F526. http://dx.doi.org/10.1152/ajprenal.1998.275.4.f518.
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Laminin is a major component of the extracellular matrix whose expression is regulated by growth factors. The laminin γ1-chain promoter contains a newly identified transcriptional element denoted bcn-1 that is both active and inducible in mesangial cells. In this study, we explored activation of the bcn-1 element in other renal and nonrenal cells. Treatment of rat glomerular epithelial cells (GEC) with phorbol 12-myristate 13-acetate (PMA) increased activity of the bcn-1 transcriptional element, within the context of the native laminin γ1-chain promoter or when cloned upstream of a heterologous promoter. Treatment of GEC with PMA induced nuclear DNA-binding activity, BCN-1, which was recognized by the bcn-1 motif in a gel shift assay. These results provide evidence that the bcn-1 motif and its cognate BCN-1 factor(s) may regulate transcription of the laminin γ1-chain in GEC. The bcn-1 element and its cognate BCN-1 DNA-binding activity were also inducible in monkey kidney COS-7 and in human T cell Jurkat lines. SDS-PAGE of in situ ultraviolet cross-linked nucleoproteins from GEC, COS, and Jurkat cells revealed one major 110–115 kDa adduct in all three cell lines. These results demonstrate that the bcn-1 element is active in renal and nonrenal cells from different mammalian species where the same protein contributes to the inducible BCN-1 DNA-binding activity.
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Whyte, Dilys A., Congyi Li, R. Brent Thomson, Stacey L. Nix, Reza Zanjani, Sharon L. Karp, Peter S. Aronson, and Peter Igarashi. "Ksp-cadherin gene promoter. I. Characterization and renal epithelial cell-specific activity." American Journal of Physiology-Renal Physiology 277, no. 4 (October 1, 1999): F587—F598. http://dx.doi.org/10.1152/ajprenal.1999.277.4.f587.
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Kidney-specific cadherin (Ksp-cadherin, cadherin 16) is a novel, kidney-specific member of the cadherin superfamily that is expressed exclusively in the basolateral membrane of renal tubular epithelial cells. To characterize the Ksp-cadherin gene promoter, a λ bacteriophage clone containing 3.7 kb of the proximal 5′ flanking region of the mouse Ksp-cadherin gene was isolated. The transcription initiation site was mapped by RNase protection assays and 5′ rapid amplification of cDNA ends, and a 709-bp intron was identified within the 5′ untranslated region. The proximal 5′ flanking region was “TATA-less” but contained other consensus promoter elements including an initiator (Inr), GC boxes, and a CAAT box. Potential binding sites were identified for transcription factors that are involved in tissue-specific gene expression including activator protein-2 (AP-2), hepatocyte nuclear factor-3 (HNF-3), basic helix-loop-helix (bHLH) proteins, CCAAT/enhancer-binding protein (C/EBP), and GATA factors. Transfection of luciferase reporter plasmids containing 2.6 kb of the 5′ flanking region markedly increased luciferase activity in renal epithelial cells (MDCK and mIMCD-3) but not in mesenchymal cells (NIH 3T3 and MMR1). Deletion analysis identified an 82-bp region from −31 to −113 that was essential for promoter activity in transfected renal epithelial cells. Electrophoretic mobility-shift assays showed that mIMCD-3 cells contain nuclear proteins that bind to this region of the promoter. Mutational analysis showed that sequences within the HNF-3 consensus site and CAAT box were involved in protein binding and promoter activity. We conclude that the proximal 5′ flanking region of the mouse Ksp-cadherin gene contains an orientation-dependent promoter that is kidney epithelial cell specific. The region of the promoter from −113 to −31 is required for transcriptional activity and contains binding sites for nuclear proteins that are specifically expressed in renal epithelial cells.
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Martinka, Scott, and Leslie A. Bruggeman. "Persistent NF-κB activation in renal epithelial cells in a mouse model of HIV-associated nephropathy." American Journal of Physiology-Renal Physiology 290, no. 3 (March 2006): F657—F665. http://dx.doi.org/10.1152/ajprenal.00208.2005.
Full textAbstract:
Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is caused, in part, by direct infection of kidney epithelial cells by HIV-1. In the spectrum of pathogenic host-virus interactions, abnormal activation or suppression of host transcription factors is common. NF-κB is a necessary host transcription factor for HIV-1 gene expression, and it has been shown that NF-κB activity is dysregulated in many naturally infected cell types. We show here that renal glomerular epithelial cells (podocytes) expressing the HIV-1 genome, similar to infected immune cells, also have a dysregulated and persistent activation of NF-κB. Although podocytes produce p50, p52, RelA, RelB, and c-Rel, electrophoretic mobility shift assays and immunocytochemistry showed a predominant nuclear accumulation of p50/RelA-containing NF-κB dimers in HIV-1-expressing podocytes compared with normal. In addition, the expression level of a transfected NF-κB reporter plasmid was significantly higher in HIVAN podocytes. The mechanism of NF-κB activation involved increased phosphorylation of IκBα, resulting in an enhanced turnover of the IκBα protein. There was no evidence for regulation by IκBβ or the alternate pathway of NF-κB activation. Altered activation of this key host transcription factor likely plays a role in the well-described cellular phenotypic changes observed in HIVAN, such as proliferation. Studies with inhibitors of proliferation and NF-κB suggest that NF-κB activation may contribute to the proliferative mechanism in HIVAN. In addition, because NF-κB regulates many aspects of inflammation, this dysregulation may also contribute to disease severity and progression through regulation of proinflammatory processes in the kidney microenvironment.
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Simonson, M. S. "Anti-AP-1 activity of all-trans retinoic acid in glomerular mesangial cells." American Journal of Physiology-Renal Physiology 267, no. 5 (November 1, 1994): F805—F815. http://dx.doi.org/10.1152/ajprenal.1994.267.5.f805.
Full textAbstract:
Functional antagonism between retinoic acid (RA) receptors and activator protein-1 (AP-1) transcription factors might regulate expression of genes involved in the response to injury in the kidney. We designed experiments to analyze the mechanisms by which RA inhibits AP-1-directed transcriptional responses in glomerular mesangial cells. RA inhibited serum-stimulated mesangial cell proliferation as assessed by measurements of [3H]thymidine uptake and cell number. In transient transfection assays with a chloramphenicol acetyltransferase reporter, RA completely blocked transcription directed by an AP-1 cis-element in cells stimulated by serum. AP-1 DNA binding was analyzed in electrophoretic gel mobility shift assays using nuclear extracts from control or RA-pretreated cells stimulated with serum. RA did not abolish AP-1 DNA binding activity under the conditions of this assay. The apparent equilibrium dissociation constant, maximal density of binding, and association rate for the AP-1-DNA interaction were similar in serum-stimulated cells or RA-pretreated cells stimulated with serum. RA repressed serum-stimulated induction of the immediate early genes c-fos and c-jun, whose protein products dimerize to form AP-1. Repression was relatively selective for c-fos/c-jun; induction of other immediate early transcription factors (junB, c-myc, and egr-1) was not downregulated by RA. That repression of c-fos by RA might contribute to anti-AP-1 activity was suggested by experiments with an antisense c-fos expression vector, which demonstrated that c-fos induction was required for serum-stimulated AP-1 activity. Together, these data demonstrate that RA antagonizes AP-1-directed transcription without inhibiting AP-1 DNA-binding in mesangial cells. Selective repression of c-fos and c-jun might contribute to the anti-AP-1 activity of RA.
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Heylbroeck, Christophe, Siddharth Balachandran, Marc J. Servant, Carmela DeLuca, Glen N. Barber, Rongtuan Lin, and John Hiscott. "The IRF-3 Transcription Factor Mediates Sendai Virus-Induced Apoptosis." Journal of Virology 74, no. 8 (April 15, 2000): 3781–92. http://dx.doi.org/10.1128/jvi.74.8.3781-3792.2000.
Full textAbstract:
ABSTRACT Virus infection of target cells can result in different biological outcomes: lytic infection, cellular transformation, or cell death by apoptosis. Cells respond to virus infection by the activation of specific transcription factors involved in cytokine gene regulation and cell growth control. The ubiquitously expressed interferon regulatory factor 3 (IRF-3) transcription factor is directly activated following virus infection through posttranslational modification. Phosphorylation of specific C-terminal serine residues results in IRF-3 dimerization, nuclear translocation, and activation of DNA-binding and transactivation potential. Once activated, IRF-3 transcriptionally up regulates alpha/beta interferon genes, the chemokine RANTES, and potentially other genes that inhibit viral infection. We previously generated constitutively active [IRF-3(5D)] and dominant negative (IRF-3 ΔN) forms of IRF-3 that control target gene expression. In an effort to characterize the growth regulatory properties of IRF-3, we observed that IRF-3 is a mediator of paramyxovirus-induced apoptosis. Expression of the constitutively active form of IRF-3 is toxic, preventing the establishment of stably transfected cells. By using a tetracycline-inducible system, we show that induction of IRF-3(5D) alone is sufficient to induce apoptosis in human embryonic kidney 293 and human Jurkat T cells as measured by DNA laddering, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay, and analysis of DNA content by flow cytometry. Wild-type IRF-3 expression augments paramyxovirus-induced apoptosis, while expression of IRF-3 ΔN blocks virus-induced apoptosis. In addition, we demonstrate an important role of caspases 8, 9, and 3 in IRF-3-induced apoptosis. These results suggest that IRF-3, in addition to potently activating cytokine genes, regulates apoptotic signalling following virus infection.
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Xu, Yi-Huan, Xiao-Ying Tan, Yi-Chuang Xu, Tao Zhao, Li-Han Zhang, and Zhi Luo. "Novel insights for SREBP-1 as a key transcription factor in regulating lipogenesis in a freshwater teleost, grass carp Ctenopharyngodon idella." British Journal of Nutrition 122, no. 11 (August 9, 2019): 1201–11. http://dx.doi.org/10.1017/s0007114519001934.
Full textAbstract:
AbstractDisturbances in lipid metabolism are at the core of several health issues facing modern society, including fatty liver and obesity. The sterol regulatory element-binding protein 1 (SREBP-1) is one important transcription factor regulating lipid metabolism, but the relevant mechanism still remains unknown. The present study determined the transcriptional regulation of SREBP-1 and its target genes (including acetyl-CoA carboxylase α (accα), fatty acid synthase (fas) and stearoyl-CoA desaturase 1 (scd1)) in a freshwater teleost, grass carp Ctenopharyngodon idella. We cloned and characterised the 1988 bp, 2043 bp, 1632 bp and 1889 bp sequences of srebp-1, accα, scd1 and fas promoters, respectively. A cluster of putative binding sites of transcription factors, such as specific protein, yin yang 1, nuclear factor Y, sterol response elements (SRE) and enhancer box (E-box) element, were predicted on their promoter regions. Overexpression of nSREBP-1 reduced srebp-1 promoter activity, increased scd1 and fas promoter activity but did not influence accα promoter activity. The site-mutation and electrophoretic mobility shift assay analysis indicated that srebp-1, fas and scd1 promoters, but not accα promoter, possessed SRE. In Ctenopharyngodon idella kidney (CIK) cells of grass carp, nSREBP-1 overexpression significantly reduced srebp-1 mRNA expression and up-regulated miR-29 mRNA expression. The 3′UTR of srebp-1 possessed the potential miR-29 binding site and miR-29 up-regulated the luciferase activity of srebp-1 3′UTR and srebp-1 mRNA expression, implying a self-activating loop of SREBP-1 and miR-29 in grass carp. Based on the above-mentioned results, we found two novel transcriptional mechanisms for SREBP-1 in grass carp: (1) the auto-regulation sited on the SREBP-1 promoter regions was suppressive and (2) there was a self-activating loop of SREBP-1 and miR-29.
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Cereghini, S., M. O. Ott, S. Power, and M. Maury. "Expression patterns of vHNF1 and HNF1 homeoproteins in early postimplantation embryos suggest distinct and sequential developmental roles." Development 116, no. 3 (November 1, 1992): 783–97. http://dx.doi.org/10.1242/dev.116.3.783.
Full textAbstract:
The homeoproteins HNF1 (LFB1/HNF1-A) and vHNF1 (LFB3/HNF1 beta) interact with an essential control element of a group of liver-specific genes. During development, these putative target genes are initially expressed in the visceral endoderm of the yolk sac and subsequently in fetal liver. To assess the possible involvement of HNF1 and/or vHNF1 as transcriptional regulators in the early steps of visceral endoderm differentiation, we have analyzed the expression pattern of both factors both in vitro during differentiation of murine F9 embryonal carcinoma cells and in vivo during early postimplantation mouse development. We show here that differentiation of F9 cells into either visceral or parietal endoderm is accompanied by a sharp induction in vHNF1 mRNA and protein. By contrast, only low levels of aberrantly sized HNF1 transcripts, but not DNA-binding protein, are found in F9 cells and its differentiated derivatives. At 6–7.5 days of gestation, high levels of vHNF1 mRNA are present in the visceral extraembryonic endoderm, which co-localize with transcripts of the transthyretin gene. HNF1 transcripts are first detected in the yolk sac roughly two embryonic days later, after the developmental onset of transcription of target genes. As development proceeds, discrepancies are observed between the level of transcripts of both vHNF1 and HNF1 and their respective nuclear binding proteins, notably in the yolk sac and embryonic kidney. In addition, we show that two alternative spliced isoforms of vHNF1 mRNA, vHNF-A and vHNF1-B, are expressed in both embryonic and adult tissues. Taken together, these data suggest that vHNF1 participates as a regulatory factor in the initial transcriptional activation of the target genes in the visceral endoderm of the yolk sac, whereas the later appearance of HNF1 could be required for maintenance of their expression. Our results also provide evidence of a posttranscriptional level of control of vHNF1 and HNF1 gene expression during development, in addition to the spatial restriction in transcription.
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Frede, Stilla, Patricia Freitag, Luise Geuting, Rebecca Konietzny, and Joachim Fandrey. "Oxygen-regulated expression of the erythropoietin gene in the human renal cell line REPC." Blood 117, no. 18 (May 5, 2011): 4905–14. http://dx.doi.org/10.1182/blood-2010-07-298083.
Full textAbstract:
Abstract Erythropoietin (EPO), the key hormone in red blood cell renewal, is mainly produced in the adult kidney. Anemia and hypoxia substantially enhance EPO expression to increase erythropoiesis. Investigations of the cellular physiology of renal EPO production have been hampered by the lack of an adequate human cell line. In the present study, we present the human kidney cell line REPC (for renal Epo–producing cells), established from an explanted human kidney exhibiting EPO gene expression and release of the EPO protein in an oxygen-dependent manner. Hypoxic induction of EPO mRNA showed the typical transient increase and peak in expression after 36 hours under continuous conditions of hypoxia. Bioactive EPO protein accumulated in the culture supernatant. The induction of EPO gene expression in REPCs critically depended on the activation of hypoxia-inducible transcription factors (HIFs). SiRNA treatment revealed that the expression of EPO was largely dependent on the activation of the transcription factor complex HIF-2. In addition, hepatic nuclear factor 4α was shown to be critically involved in hypoxia-induced renal EPO expression. Using the human kidney cell line REPC, we provide for the first time a powerful tool with which to study the cellular and molecular regulation of renal EPO production.
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Barone, Sharon, Kamyar Zahedi, Marybeth Brooks, Elizabeth P. Henske, Yirong Yang, Erik Zhang, John J. Bissler, Jane J. Yu, and Manoocher Soleimani. "Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex." Proceedings of the National Academy of Sciences 118, no. 6 (February 3, 2021): e2020190118. http://dx.doi.org/10.1073/pnas.2020190118.
Full textAbstract:
Tuberous sclerosis complex (TSC) is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung, and brain. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomata) and cysts, which eventually leads to kidney failure. The factors promoting cyst formation and tumor growth in TSC are incompletely understood. Here, we report that mice with principal cell-specific inactivation of Tsc1 develop numerous cortical cysts, which are overwhelmingly composed of hyperproliferating A-intercalated (A-IC) cells. RNA sequencing and confirmatory expression studies demonstrated robust expression of Forkhead Transcription Factor 1 (Foxi1) and its downstream targets, apical H+-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in cyst epithelia in Tsc1 knockout (KO) mice but not in Pkd1 mutant mice. In addition, the electrogenic 2Cl−/H+ exchanger (CLC-5) is significantly up-regulated and shows remarkable colocalization with H+-ATPase on the apical membrane of cyst epithelia in Tsc1 KO mice. Deletion of Foxi1, which is vital to intercalated cells viability and H+-ATPase expression, completely abrogated the cyst burden in Tsc1 KO mice, as indicated by MRI images and histological analysis in kidneys of Foxi1/Tsc1 double-knockout (dKO) mice. Deletion of CAII, which is critical to H+-ATPase activation, caused significant reduction in cyst burden and increased life expectancy in CAII/Tsc1 dKO mice vs. Tsc1 KO mice. We propose that intercalated cells and their acid/base/electrolyte transport machinery (H+-ATPase/CAII/CLC-5) are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against cyst generation and/or enlargement in TSC.
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Holewa, B., D. Zapp, T. Drewes, S. Senkel, and G. U. Ryffel. "HNF4beta, a new gene of the HNF4 family with distinct activation and expression profiles in oogenesis and embryogenesis of Xenopus laevis." Molecular and Cellular Biology 17, no. 2 (February 1997): 687–94. http://dx.doi.org/10.1128/mcb.17.2.687.
Full textAbstract:
The transcription factor hepatocyte nuclear factor 4 (HNF4) is an orphan member of the nuclear receptor superfamily expressed in mammals in liver, kidney, and the digestive tract. Recently, we isolated the Xenopus homolog of mammalian HNF4 and revealed that it is not only a tissue-specific transcription factor but also a maternal component of the Xenopus egg and distributed within an animal-to-vegetal gradient. We speculate that this gradient cooperates with the vegetally localized embryonic induction factor activin A to activate expression of HNF1alpha, a tissue-specific transcription factor with an expression pattern overlapping that of HNF4. We have now identified a second Xenopus HNF4 gene, which is more distantly related to mammalian HNF4 than the previously isolated gene. This new gene was named HNF4beta to distinguish it from the known HNF4 gene, which is now called HNF4alpha. By reverse transcription-PCR, we detected within the 5' untranslated region of HNF4beta two splice variants (HNF4beta2 and HNF4beta3) with additional exons, which seem to affect RNA stability. HNF4beta is a functional transcription factor acting sequence specifically on HNF4 binding sites known for HNF4alpha, but it seems to have a lower DNA binding activity and is a weaker transactivator than the alpha isoform. Furthermore, the two factors differ with respect to tissue distribution in adult frogs: whereas HNF4alpha is expressed in liver and kidney, HNF4beta is expressed in addition in stomach, intestine, lung, ovary, and testis. Both factors are maternal proteins and present at constant levels throughout embryogenesis. However, using reverse transcription-PCR, we found the RNA levels to change substantially: whereas HNF4alpha is expressed early during oogenesis and is absent in the egg, HNF4beta is first detected in the latest stage of oogenesis, and transcripts are present in the egg and early cleavage stages. Furthermore, zygotic HNF4alpha transcripts appear in early gastrula and accumulate during further embryogenesis, whereas HNF4beta mRNA transiently appears during gastrulation before it accumulates again at the tail bud stage. All of these distinct characteristics of the newly identified HNF4 protein imply that the alpha and beta isoform have different functions in development and in adult tissues.
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Evans, M. J., and R. C. Scarpulla. "Both upstream and intron sequence elements are required for elevated expression of the rat somatic cytochrome c gene in COS-1 cells." Molecular and Cellular Biology 8, no. 1 (January 1988): 35–41. http://dx.doi.org/10.1128/mcb.8.1.35.
Full textAbstract:
To investigate the transcriptional control of nuclear-encoded respiratory genes in mammals, we have performed a deletional analysis of cis-acting regulatory sequences in the rat somatic cytochrome c gene. Three major regions are required for maximal expression of the transfected gene in kidney cell lines CV-1 and COS-1. One of these, region III (+71 to +115 from the transcription initiation site), is an unusual intragenic controlling element found in the 5' end of the first intron, while the other two, region I (-191 to -165) and region II (-139 to -84), define the upstream promoter. Region II contains two consensus CCAAT boxes and mediates a constitutive level of expression in both cell lines. In contrast, regions I and III are both required for the increased promoter activity observed in COS-1 cells compared with promoter activity observed in CV-1 cells, and the regions function individually as competitors with the full promoter for trans-acting factors or complexes. Region III contains a perfect octanucleotide homology with region I in addition to a consensus Sp1-transcription-factor-binding site. Promoter stimulation in COS-1 cells can be duplicated in CV-1 cells by cotransfecting with a T-antigen-producing vector, but purified T antigen does not bind anywhere in the cytochrome c promoter. A control promoter from the mouse metallothionein I gene is similarly activated in T-antigen-producing cells only in the presence of zinc, which activates its upstream regulatory sites. We conclude that T antigen stimulates these cellular promoters through the activation or induction of cellular factors or complexes that mediate their effects through promoter-specific regulatory elements. Cytochrome c promoter regions activated in this system may play a physiological role in controlling gene expression.
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Evans, M. J., and R. C. Scarpulla. "Both upstream and intron sequence elements are required for elevated expression of the rat somatic cytochrome c gene in COS-1 cells." Molecular and Cellular Biology 8, no. 1 (January 1988): 35–41. http://dx.doi.org/10.1128/mcb.8.1.35-41.1988.
Full textAbstract:
To investigate the transcriptional control of nuclear-encoded respiratory genes in mammals, we have performed a deletional analysis of cis-acting regulatory sequences in the rat somatic cytochrome c gene. Three major regions are required for maximal expression of the transfected gene in kidney cell lines CV-1 and COS-1. One of these, region III (+71 to +115 from the transcription initiation site), is an unusual intragenic controlling element found in the 5' end of the first intron, while the other two, region I (-191 to -165) and region II (-139 to -84), define the upstream promoter. Region II contains two consensus CCAAT boxes and mediates a constitutive level of expression in both cell lines. In contrast, regions I and III are both required for the increased promoter activity observed in COS-1 cells compared with promoter activity observed in CV-1 cells, and the regions function individually as competitors with the full promoter for trans-acting factors or complexes. Region III contains a perfect octanucleotide homology with region I in addition to a consensus Sp1-transcription-factor-binding site. Promoter stimulation in COS-1 cells can be duplicated in CV-1 cells by cotransfecting with a T-antigen-producing vector, but purified T antigen does not bind anywhere in the cytochrome c promoter. A control promoter from the mouse metallothionein I gene is similarly activated in T-antigen-producing cells only in the presence of zinc, which activates its upstream regulatory sites. We conclude that T antigen stimulates these cellular promoters through the activation or induction of cellular factors or complexes that mediate their effects through promoter-specific regulatory elements. Cytochrome c promoter regions activated in this system may play a physiological role in controlling gene expression.
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Ritz-Laser, Beate, Aline Mamin, Thierry Brun, Isabelle Avril, Valérie M. Schwitzgebel, and Jacques Philippe. "The Zinc Finger-Containing Transcription Factor Gata-4 Is Expressed in the Developing Endocrine Pancreas and Activates Glucagon Gene Expression." Molecular Endocrinology 19, no. 3 (March 1, 2005): 759–70. http://dx.doi.org/10.1210/me.2004-0051.
Full textAbstract:
Abstract Gene inactivation studies have shown that members of the Gata family of transcription factors are critical for endoderm development throughout evolution. We show here that Gata-4 and/or Gata-6 are not only expressed in the adult exocrine pancreas but also in glucagonoma and insulinoma cell lines, whereas Gata-5 is restricted to the exocrine pancreas. During pancreas development, Gata-4 is expressed already at embryonic d 10.5 and colocalizes with early glucagon+ cells at embryonic d 12.5. Gata-4 was able to transactivate the glucagon gene both in heterologous BHK-21 (nonislet Syrian baby hamster kidney) and in glucagon-producing InR1G9 cells. Using gel-mobility shift assays, we identified a complex formed with nuclear extracts from InR1G9 cells on the G5 control element (−140 to −169) of the glucagon gene promoter as Gata-4. Mutation of the GATA binding site on G5 abrogated the transcriptional activation mediated by Gata-4 and reduced basal glucagon gene promoter activity in glucagon-producing cells by 55%. Furthermore, Gata-4 acted more than additively with Forkhead box A (hepatic nuclear factor-3) to trans-activate the glucagon gene promoter. We conclude that, besides its role in endoderm differentiation, Gata-4 might be implicated in the regulation of glucagon gene expression in the fetal pancreas and that Gata activity itself may be modulated by interactions with different cofactors.
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Shen, Ching-Hung, and Janet Stavnezer. "Interaction of Stat6 and NF-κB: Direct Association and Synergistic Activation of Interleukin-4-Induced Transcription." Molecular and Cellular Biology 18, no. 6 (June 1, 1998): 3395–404. http://dx.doi.org/10.1128/mcb.18.6.3395.
Full textAbstract:
ABSTRACT Signal transducer and activator of transcription 6 (Stat6) and NF-κB are widely distributed transcription factors which are induced by different stimuli and bind to distinct DNA sequence motifs. Interleukin-4 (IL-4), which activates Stat6, synergizes with activators of NF-κB to induce IL-4-responsive genes, but the molecular mechanism of this synergy is poorly understood. Using glutathioneS-transferase pulldown assays and coimmunoprecipitation techniques, we find that NF-κB and tyrosine-phosphorylated Stat6 can directly bind each other in vitro and in vivo. An IL-4-inducible reporter gene containing both cognate binding sites in the promoter is synergistically activated in the presence of IL-4 when Stat6 and NF-κB proteins are coexpressed in human embryonic kidney 293 (HEK 293) cells. The same IL-4-inducible reporter gene is also synergistically activated by the endogenous Stat6 and NF-κB proteins in IL-4-stimulated I.29μ B lymphoma cells. Furthermore, Stat6 and NF-κB bind cooperatively to a DNA probe containing both sites, and the presence of a complex formed by their cooperative binding correlates with the synergistic activation of the promoter by Stat6 and NF-κB. We conclude that the direct interaction between Stat6 and NF-κB may provide a basis for synergistic activation of transcription by IL-4 and activators of NF-κB.
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Inaba, T., L. H. Shapiro, T. Funabiki, A. E. Sinclair, B. G. Jones, R. A. Ashmun, and A. T. Look. "DNA-binding specificity and trans-activating potential of the leukemia-associated E2A-hepatic leukemia factor fusion protein." Molecular and Cellular Biology 14, no. 5 (May 1994): 3403–13. http://dx.doi.org/10.1128/mcb.14.5.3403.
Full textAbstract:
Hybrid transcription factors, resulting from gene fusions in the wake of chromosomal translocations, have been implicated in leukemogenesis, but their precise contributions to oncogenic conversion remain unclear. The E2A-HLF fusion gene, formed by a t(17;19)(q22;p13) in childhood pro-B-cell acute lymphoid leukemia, encodes a hybrid protein that contains the trans-activation domain of E2A (E12/E47) linked to the bZIP DNA-binding and dimerization domain of hepatic leukemia factor (HLF). Here we report that both HLF and E2A-HLF bind to a 10-bp consensus sequence, 5'-GTTACGTAAT-3', with a core dyad-symmetric motif characteristic of the bZIP scissors-grip model of DNA binding. A probe containing this sequence bound chimeric E2A-HLF proteins in nuclear extracts of a leukemic cell line (UOC-B1) containing the t(17;19), as demonstrated by complexes supershifted with antibodies specific for amino-terminal epitopes of E2A or carboxyl-terminal eptiopes of HLF. E2A-HLF functioned as a potent trans activator of reporter gene expression from a plasmid that contained the consensus DNA-binding sequence. Interestingly, wild-type HLF was restricted in its capacity to act as a trans activator, functioning in human fetal kidney cells but not HepG2 hepatocarcinoma cells or NIH 3T3 mouse fibroblasts. The ability of the E2A-HLF hybrid protein to bind DNA in a sequence-specific manner and trans activate the expression of artificial reporter genes suggests that it could subvert transcriptional programs that normally control the growth, differentiation, and survival of lymphoid progenitor cells.
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Inaba, T., L. H. Shapiro, T. Funabiki, A. E. Sinclair, B. G. Jones, R. A. Ashmun, and A. T. Look. "DNA-binding specificity and trans-activating potential of the leukemia-associated E2A-hepatic leukemia factor fusion protein." Molecular and Cellular Biology 14, no. 5 (May 1994): 3403–13. http://dx.doi.org/10.1128/mcb.14.5.3403-3413.1994.
Full textAbstract:
Hybrid transcription factors, resulting from gene fusions in the wake of chromosomal translocations, have been implicated in leukemogenesis, but their precise contributions to oncogenic conversion remain unclear. The E2A-HLF fusion gene, formed by a t(17;19)(q22;p13) in childhood pro-B-cell acute lymphoid leukemia, encodes a hybrid protein that contains the trans-activation domain of E2A (E12/E47) linked to the bZIP DNA-binding and dimerization domain of hepatic leukemia factor (HLF). Here we report that both HLF and E2A-HLF bind to a 10-bp consensus sequence, 5'-GTTACGTAAT-3', with a core dyad-symmetric motif characteristic of the bZIP scissors-grip model of DNA binding. A probe containing this sequence bound chimeric E2A-HLF proteins in nuclear extracts of a leukemic cell line (UOC-B1) containing the t(17;19), as demonstrated by complexes supershifted with antibodies specific for amino-terminal epitopes of E2A or carboxyl-terminal eptiopes of HLF. E2A-HLF functioned as a potent trans activator of reporter gene expression from a plasmid that contained the consensus DNA-binding sequence. Interestingly, wild-type HLF was restricted in its capacity to act as a trans activator, functioning in human fetal kidney cells but not HepG2 hepatocarcinoma cells or NIH 3T3 mouse fibroblasts. The ability of the E2A-HLF hybrid protein to bind DNA in a sequence-specific manner and trans activate the expression of artificial reporter genes suggests that it could subvert transcriptional programs that normally control the growth, differentiation, and survival of lymphoid progenitor cells.
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Yang, Z., L. Gu, P. H. Romeo, D. Bories, H. Motohashi, M. Yamamoto, and J. D. Engel. "Human GATA-3 trans-activation, DNA-binding, and nuclear localization activities are organized into distinct structural domains." Molecular and Cellular Biology 14, no. 3 (March 1994): 2201–12. http://dx.doi.org/10.1128/mcb.14.3.2201.
Full textAbstract:
GATA-3 is a zinc finger transcription factor which is expressed in a highly restricted and strongly conserved tissue distribution pattern in vertebrate organisms, specifically, in a subset of hematopoietic cells, in cells within the central and peripheral nervous systems, in the kidney, and in placental trophoblasts. Tissue-specific cellular genes regulated by GATA-3 have been identified in T lymphocytes and the placenta, while GATA-3-regulated genes in the nervous system and kidney have not yet been defined. We prepared monoclonal antibodies with which we could dissect the biochemical and functional properties of human GATA-3. The results of these experiments show some anticipated phenotypes, for example, the definition of discrete domains required for specific DNA-binding site recognition (amino acids 303 to 348) and trans activation (amino acids 30 to 74). The signaling sequence for nuclear localization of human GATA-3 is a property conferred by sequences within and surrounding the amino finger (amino acids 249 to 311) of the protein, thereby assigning a function to this domain and thus explaining the curious observation that this zinc finger is dispensable for DNA binding by the GATA family of transcription factors.
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Yang, Z., L. Gu, P. H. Romeo, D. Bories, H. Motohashi, M. Yamamoto, and J. D. Engel. "Human GATA-3 trans-activation, DNA-binding, and nuclear localization activities are organized into distinct structural domains." Molecular and Cellular Biology 14, no. 3 (March 1994): 2201–12. http://dx.doi.org/10.1128/mcb.14.3.2201-2212.1994.
Full textAbstract:
GATA-3 is a zinc finger transcription factor which is expressed in a highly restricted and strongly conserved tissue distribution pattern in vertebrate organisms, specifically, in a subset of hematopoietic cells, in cells within the central and peripheral nervous systems, in the kidney, and in placental trophoblasts. Tissue-specific cellular genes regulated by GATA-3 have been identified in T lymphocytes and the placenta, while GATA-3-regulated genes in the nervous system and kidney have not yet been defined. We prepared monoclonal antibodies with which we could dissect the biochemical and functional properties of human GATA-3. The results of these experiments show some anticipated phenotypes, for example, the definition of discrete domains required for specific DNA-binding site recognition (amino acids 303 to 348) and trans activation (amino acids 30 to 74). The signaling sequence for nuclear localization of human GATA-3 is a property conferred by sequences within and surrounding the amino finger (amino acids 249 to 311) of the protein, thereby assigning a function to this domain and thus explaining the curious observation that this zinc finger is dispensable for DNA binding by the GATA family of transcription factors.
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Smirnova, K. V., S. V. Diduk, and V. E. Gurtsevitch. "Functional analysis of epstein-barr virus latent membrane proteins (LMP1) in patients with limphoproliferative disorders." Biomeditsinskaya Khimiya 57, no. 1 (January 2011): 114–26. http://dx.doi.org/10.18097/pbmc20115701114.
Full textAbstract:
Latent membrane protein1 (LMP1) encoded by the LMP1 gene of the Epstein-Barr virus (EBV) is a transmembrane protein, which can activate a number of cellular signal cascades and transcriptional factors leading to cell transformation. In the present study the sequencing of full-length LMP1 variants isolated from Russian patients with Hodgkin's lymphoma (HL), non-Hodgkin's lymphomaе (NHL) and infectious mononucleosis (IM) has been carried out. The phylogenetic analysis of obtained sequences revealed dominance of the LMP1 variants belonging to proteins of low-divergent group LMP1-B95.8b characterized by minimal set of mutations. Investigation of biological properties in the Russian representatives of this group revealed that expression of studied LMP1 variants in embryonic kidney 293 cells was accompanied by insignificant increase in transcriptional factor NF-κB activation and had minor influence on activation of transcriptional factor AP-1. It was also detected that all investigated low-divergent LMP1 variants expressed in Rat-1 cells induced activation of inducible NO-synthase (iNOS) and intracellular production of nitric oxide (NO). At the same time the level of NO accumulation was lower than that induced by the low-transforming prototype variant LMP1-B95.8. The data obtained indicate that the LMP1 variants, which are the most common among Russian patients with EBV-associated lymphoproliferative diseases, are characterized by minimum number of mutations and rather low ability to activate basic cellular signaling pathways regardless the nature of pathological process, benign (IM) or malignant (HL, NHL). It is suggested that in addition to the modest activation of NF-κB and iNOS induction by LMP1 other factors are involved in the cell transformation process.