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FAWCETT, Timothy W., Jennifer L. MARTINDALE, Kathryn Z. GUYTON, Tsonwin HAI, and Nikki J. HOLBROOK. "Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)–ATF composite site to regulate Gadd153 expression during the stress response." Biochemical Journal 339, no. 1 (March 25, 1999): 135–41. http://dx.doi.org/10.1042/bj3390135.
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Gadd153, also known as chop, encodes a member of the CCAAT/enhancer-binding protein (C/EBP) transcription factor family and is transcriptionally activated by cellular stress signals. We recently demonstrated that arsenite treatment of rat pheochromocytoma PC12 cells results in the biphasic induction of Gadd153 mRNA expression, controlled in part through binding of C/EBPβ and two uncharacterized protein complexes to the C/EBP–ATF (activating transcription factor) composite site in the Gadd153 promoter. In this report, we identified components of these additional complexes as two ATF/CREB (cAMP-responsive-element-binding protein) transcription factors having differential binding activities dependent upon the time of arsenite exposure. During arsenite treatment of PC12 cells, we observed enhanced binding of ATF4 to the C/EBP–ATF site at 2 h as Gadd153 mRNA levels increased, and enhanced binding of ATF3 complexes at 6 h as Gadd153 expression declined. We further demonstrated that ATF4 activates, while ATF3 represses, Gadd153 promoter activity through the C/EBP–ATF site. ATF3 also repressed ATF4-mediated transactivation and arsenite-induced activation of the Gadd153 promoter. Our results suggest that numerous members of the ATF/CREB family are involved in the cellular stress response, and that regulation of stress-induced biphasic Gadd153 expression in PC12 cells involves the ordered, sequential binding of multiple transcription factor complexes to the C/EBP–ATF composite site.
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Mori, Kazutoshi. "Divest Yourself of a Preconceived Idea: Transcription Factor ATF6 Is Not a Soluble Protein!" Molecular Biology of the Cell 21, no. 9 (May 2010): 1435–38. http://dx.doi.org/10.1091/mbc.e09-07-0600.
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The unfolded protein response (UPR), an evolutionarily conserved transcriptional induction program that is coupled with intracellular signaling from the endoplasmic reticulum (ER) to the nucleus, is activated to cope with ER stress and to maintain the homeostasis of the ER. In 1996, we isolated a basic leucine zipper protein, which had been previously named activating transcription factor (ATF)6, as a candidate transcription factor responsible for the mammalian UPR. Subsequent analysis, however, was confounding. The problem was eventually tracked down to an unusual property of ATF6: rather than being a soluble nuclear protein, as expected for an active transcription factor, ATF6 was instead synthesized as a transmembrane protein embedded in the ER, which was activated by ER stress-induced proteolysis. ATF6 was thus unique: an ER stress sensor/transducer that is involved in all steps of the UPR, from the sensing step in the ER to the transcriptional activation step in the nucleus.
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Keeton, Adam B., Katherine D. Bortoff, J. Lee Franklin, and Joseph L. Messina. "Blockade of Rapid Versus Prolonged Extracellularly Regulated Kinase 1/2 Activation Has Differential Effects on Insulin-Induced Gene Expression." Endocrinology 146, no. 6 (June 1, 2005): 2716–25. http://dx.doi.org/10.1210/en.2004-1662.
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Abstract In the present work, insulin’s regulation of expression of activating transcription factor 3 (ATF-3), the putative transcription factor proline-rich induced protein (Pip)92, and insulin-inducible gene-1 (Insig-1) (an ER resident protein involved in regulation of sterol-responsive element-binding protein 1 activation) have been examined in a liver-derived cell line (rat H4IIE hepatoma cells). We report that: 1) insulin-induced transcription of ATF-3, Pip92, and Insig-1 required MEK-ERK activation; 2) insulin-induced transcription of ATF-3 and Pip92 reached maximum levels within 15 min and was blocked by wortmannin but not LY294002; 3) in contrast, the maximum level of insulin-induced transcription of Insig-1 was delayed and was not blocked by either wortmannin or LY294002; 4) insulin activated ERK1/2 in two distinct phases, a rapid peak and a later plateau; 5) the delayed plateau phase of insulin-induced ERK1/2 activation was partially phosphatidylinositol 3-OH-kinase dependent; and 6) however, the rapid, insulin-induced peak of ERK1/2 activation was blocked by wortmannin but not LY294002.
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Seo, Hye-Young, Yong Deuk Kim, Kyeong-Min Lee, Ae-Kyung Min, Mi-Kyung Kim, Hye-Soon Kim, Kyu-Chang Won, et al. "Endoplasmic Reticulum Stress-Induced Activation of Activating Transcription Factor 6 Decreases Insulin Gene Expression via Up-Regulation of Orphan Nuclear Receptor Small Heterodimer Partner." Endocrinology 149, no. 8 (May 1, 2008): 3832–41. http://dx.doi.org/10.1210/en.2008-0015.
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The highly developed endoplasmic reticulum (ER) structure of pancreatic β-cells is a key factor in β-cell function. Here we examined whether ER stress-induced activation of activating transcription factor (ATF)-6 impairs insulin gene expression via up-regulation of the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), which has been shown to play a role in β-cell dysfunction. We examined whether ER stress decreases insulin gene expression, and this process is mediated by ATF6. A small interfering RNA that targeted SHP was used to determine whether the effect of ATF6 on insulin gene expression is mediated by SHP. We also measured the expression level of ATF6 in pancreatic islets in Otsuka Long Evans Tokushima Fatty rats, a rodent model of type 2 diabetes. High glucose concentration (30 mmol/liter glucose) increased ER stress in INS-1 cells. ER stress induced by tunicamycin, thapsigargin, or dithiotreitol decreased insulin gene transcription. ATF6 inhibited insulin promoter activity, whereas X-box binding protein-1 and ATF4 did not. Adenovirus-mediated overexpression of active form of ATF6 in INS-1 cells impaired insulin gene expression and secretion. ATF6 also down-regulated pancreatic duodenal homeobox factor-1 and RIPE3b1/MafA gene expression and repressed the cooperative action of pancreatic duodenal homeobox factor-1, RIPE3b1/MafA, and β-cell E box transactivator 2 in stimulating insulin transcription. The ATF6-induced suppression of insulin gene expression was associated with up-regulation of SHP gene expression. Finally, we found that expression of ATF6 was increased in the pancreatic islets of diabetic Otsuka Long Evans Tokushima Fatty rats, compared with their lean, nondiabetic counterparts, Long-Evans Tokushima Otsuka rats. Collectively, this study shows that ER stress-induced activation of ATF6 plays an important role in the development of β-cell dysfunction.
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Spinello, Zaira, Luana Abballe, Elena Splendiani, Angela Di Giannatale, Felice Giangaspero, Angela Mastronuzzi, Elisabetta Ferretti, Evelina Miele, and Giuseppina Catanzaro. "MEDB-09. Unraveling the role of unfolded protein response in medulloblastoma cancer stem cells." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i105—i106. http://dx.doi.org/10.1093/neuonc/noac079.384.
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Abstract Medulloblastoma (MB) is the most common malignant childhood brain tumor. The current clinical approach consists of multimodal strategies with debilitating long-term effects and risk of tumor recurrence. Medulloblastoma stem cells (MBSCs) are a fraction of tumor cells with high proliferation potential and the capability to adapt to adverse/restrictive conditions in tumor milieu thus driving the refractoriness to conventional therapies. Recently, high basal levels of Unfolded Protein Response (UPR) molecules have been found in tumors of different tissue-origin and are correlated with poor prognosis and low patient survival. However, little is known about the role of UPR in MB. We investigated the expression and activation of UPR players in MBSCs. Human group 3 MB (G3MB) cell lines, specifically CHLA-01, D283- and D341-Med, were grown in Vitamin A and/or FBS or in stem selective medium (B27™) for 72 h before collection. Cells were fixed, stained with proper primary antibodies and images were acquired by confocal microscopy. The analysis of the transcription factors ATF-4 and CHOP revealed their elevated nuclear expression and co-localization, which resulted to be more marked in G3MB stem-like cells than in the differentiated ones. Also the ATF-6 branch was investigated, in differentiating conditions D283 and D341-Med showed a greater activation of ATF-6, represented by its nuclear localization, in respect to stem cells, while CHLA-01 did not show differences. Conversely XBP1, the transcription factor downstream IRE1 signaling, was not expressed in the three cell lines. Lastly, a Kaplan-Meier analysis on MB patients showed a worse prognosis with a shorter survival rate of patients expressing high ATF4 transcript levels. Our results reveal, even in resting conditions, preferential activation of the PERK branch in G3MB cells grown in stem-like condition suggesting that ATF-4 might be a promising therapeutic and prognostic factor to specifically target the stem compartment in aggressive MB.
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Fu, Lingchen, and Michael S. Kilberg. "Elevated cJUN expression and an ATF/CRE site within the ATF3 promoter contribute to activation of ATF3 transcription by the amino acid response." Physiological Genomics 45, no. 4 (February 15, 2013): 127–37. http://dx.doi.org/10.1152/physiolgenomics.00160.2012.
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Mammalian cells respond to amino acid deprivation through multiple signaling pathways referred to as the amino acid response (AAR). Transcription factors mediate the AAR after their activation by several mechanisms; examples include translational control (activating transcription factor 4, ATF4), phosphorylation (p-cJUN), and transcriptional control (ATF3). ATF4 induces ATF3 transcription through a promoter-localized C/EBP-ATF response element (CARE). The present report characterizes an ATF/CRE site upstream of the CARE that also contributes to AAR-induced ATF3 transcription. ATF4 binds to the ATF/CRE and CARE sequences and both are required for a maximal response to ATF4 induction. ATF3, which antagonizes ATF4 and represses its own gene, also exhibited binding activity to the ATF/CRE and CARE sequences. The AAR resulted in elevated total cJUN and p-cJUN protein levels and both forms exhibited binding activity to the ATF/CRE and CARE ATF3 sequences. Knockdown of AAR-enhanced cJUN expression blocked induction of the ATF3 gene and mutation of either the ATF/CRE or the CARE site prevented the cJUN-dependent increase in ATF3-driven luciferase activity. The results indicate that both increased cJUN and the cis-acting ATF/CRE sequence within the ATF3 promoter contribute to the transcriptional activation of the gene during the AAR.
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Vidičević-Novaković, Sašenka, and Željka Stanojević. "Molecular mechanisms involved in endoplasmic reticulum stress development: What do we know today." Medicinski podmladak 75, no. 2 (2024): 36–42. http://dx.doi.org/10.5937/mp75-44722.
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Endoplasmic reticulum (ER) is an intracellular organelle involved in protein synthesis and folding. When the balance between cell needs for proteins and ER capacity to fold proteins is disrupted, nonfunctional, unfolded, or misfolded proteins accumulate in ER lumen, leading to endoplasmic reticulum stress (ER stress). One of the ways cell uses to overcome ER stress is unfolded protein response (UPR) activation. UPR is initiated by the activation of three ER transmembrane proteins. These proteins are IRE-1a (inositol requiring enzyme-1a), PERK (protein kinase RNA-like endoplasmic reticulum kinase) and ATF6 (activating transcription factor 6) and they are activated when ER chaperone, GRP78 (glucose-regulates protein 78) releases their intraluminal domains. Activation of these transmembrane sensors starts mechanisms that should restore ER function. If ER function is not restored and balance is not achieved, apoptosis is induced in order to maintain cell homeostasis. Activated IRE-1a leads to XBP-1 (X-box binding protein-1) mRNA splicing and activates MAP kinases and inflam-matory pathways that involve nuclear factor cB (NFcB). Activated ATF 6 (ATF6f) functions as a transcriptional factor and increases gene expression for XBP-1, while PERK activation leads to phosphorylation and inactivation of eukaryotic initiation factor 2 (eIF2a) which further leads to decreased protein synthesis. Additionally, eIF2a phosphorylation leads to selective synthesis of ATF4, a transcriptional factor that in irreversibly damaged cells induces cell death activation by C/EBP homologous protein (CHOP) transcription. It is known that ER stress and UPR have a role in different diseases pathogenesis such as diabetes, inflammation, tumors and neurodegenerative diseases. Knowing signaling pathways of UPR and mechanisms by which UPR is involved in diseases pathogenesis can be very significant in targeted therapeutic approaches development.
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Ross, Heather L., Michael R. Nonnemacher, Tricia H. Hogan, Shane J. Quiterio, Andrew Henderson, John J. McAllister, Fred C. Krebs, and Brian Wigdahl. "Interaction between CCAAT/Enhancer Binding Protein and Cyclic AMP Response Element Binding Protein 1 Regulates Human Immunodeficiency Virus Type 1 Transcription in Cells of the Monocyte/Macrophage Lineage." Journal of Virology 75, no. 4 (February 15, 2001): 1842–56. http://dx.doi.org/10.1128/jvi.75.4.1842-1856.2001.
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ABSTRACT Recent observations have shown two CCAAT/enhancer binding protein (C/EBP) binding sites to be critically important for efficient human immunodeficiency virus type 1 (HIV-1) replication within cells of the monocyte/macrophage lineage, a cell type likely involved in transport of the virus to the brain. Additionally, sequence variation at C/EBP site I, which lies immediately upstream of the distal nuclear factor kappa B site and immediately downstream of a binding site for activating transcription factor (ATF)/cyclic AMP response element binding protein (CREB), has been shown to affect HIV-1 long terminal repeat (LTR) activity. Given that C/EBP proteins have been shown to interact with many other transcription factors including members of the ATF/CREB family, we proceeded to determine whether an adjacent ATF/CREB binding site could affect C/EBP protein binding to C/EBP site I. Electrophoretic mobility shift analyses indicated that selected ATF/CREB site variants assisted in the recruitment of C/EBP proteins to an adjacent, naturally occurring, low-affinity C/EBP site. This biophysical interaction appears to occur via at least two mechanisms. First, low amounts of CREB-1 and C/EBP appear to heterodimerize and bind to a site consisting of a half site from both the ATF/CREB and C/EBP binding sites. In addition, CREB-1 homodimers bind to the ATF/CREB site and recruit C/EBP dimers to their cognate weak binding sites. This interaction is reciprocal, since C/EBP dimer binding to a strong C/EBP site leads to enhanced CREB-1 recruitment to ATF/CREB sites that are weakly bound by CREB. Sequence variation at both C/EBP and ATF/CREB sites affects the molecular interactions involved in mediating both of these mechanisms. Most importantly, sequence variation at the ATF/CREB binding site affected basal LTR activity as well as LTR function following interleukin-6 stimulation, a treatment that leads to increases in C/EBP activation. Thus, HIV-1 LTR ATF/CREB binding site sequence variation may modulate cellular signaling at the viral promoter through the C/EBP pathway.
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Xu, Linhao, Yanli Bi, Yizhou Xu, Yihao Wu, Xiaoxue Du, Yixuan Mou, and Jian Chen. "Suppression of CHOP Reduces Neuronal Apoptosis and Rescues Cognitive Impairment Induced by Intermittent Hypoxia by Inhibiting Bax and Bak Activation." Neural Plasticity 2021 (August 21, 2021): 1–14. http://dx.doi.org/10.1155/2021/4090441.
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Our previous study showed that growth arrest- and DNA damage-inducible gene 153 (GAD153/CHOP) plays an important role in intermittent hypoxia- (IH-) induced apoptosis and impaired synaptic plasticity. This study is aimed at determining which signaling pathway is activated to induce CHOP and the role of this protein in mitochondria-dependent apoptosis induced by IH. In the in vivo study, mice were placed in IH chambers for 8 h daily over a period of 2 weeks; the IH chambers had oxygen (O2) concentrations that oscillated between 10% and 21%, cycling every 90 s. In the in vitro study, PC12 cells were exposed to 21% O2 (normoxia) or 8 IH cycles (25 min at 21% O2 and 35 min at 0.1% O2 for each cycle). After 2 weeks of IH treatment, we observed that the expression levels of phosphorylated protein kinase-like endoplasmic reticulum kinase (p-PERK), activating transcription factor 4 (ATF-4) and phosphorylated eukaryotic initiation factor 2 alpha (p-elf2α), were increased, but the levels of activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1) were not increased. GSK2606414, a specific chemical inhibitor of the PERK pathway, reduced the expression of p-PERK, ATF-4, p-elf2α, and CHOP and rescued ER structure. In addition, Bax and Bak accumulated in the mitochondria after IH treatment, which induced cytochrome c release and initiated apoptosis. These effects were prevented by GSK2606414 and CHOP shRNA. Finally, the impaired long-term potentiation and long-term spatial memory in the IH group were rescued by GSK2606414. Together, the data from the in vitro and in vivo experiments indicate that IH-induced apoptosis and impaired synaptic plasticity were mediated by the PERK-ATF-4-CHOP pathway. Suppressing PERK-ATF-4-CHOP signaling pathway attenuated mitochondria-dependent apoptosis by reducing the expression of Bax and Bak in mitochondria, which may serve as novel adjunct therapeutic strategy for ameliorating obstructive sleep apnea- (OSA-) induced neurocognitive impairment.
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Konsavage, Wesley M., Lianqin Zhang, Yuchieh Wu, and Jeffrey S. Shenberger. "Hyperoxia-induced activation of the integrated stress response in the newborn rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 1 (January 1, 2012): L27—L35. http://dx.doi.org/10.1152/ajplung.00174.2011.
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Diverse environmental stresses stimulate eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, leading to a stress-resistant state characterized by global attenuation of protein synthesis and induction of cytoprotective genes. The signal transduction network culminating in these effects is referred to as the integrated stress response (ISR) or, when initiated by misfolded proteins within the endoplasmic reticulum (ER), the unfolded protein response (UPR). Given that we previously reported that exposure of 4-day-old Sprague-Dawley rats to 95% O2 (Ox) diminishes global pulmonary protein synthesis and increases eIF2α phosphorylation, we conducted the current study to determine whether Ox activates the ISR or UPR. We found that Ox-induced alterations in ER morphology of alveolar type II cells and interstitial fibroblasts were not associated with activation of the UPR sensors PERK or activating transcription factor (ATF) 6 or with X-box binding protein-1 mRNA splicing in whole lung extracts. Exposure to Ox enhanced ATF4 immunoreactivity and nuclear protein content, followed by a 2- and 5-fold increase in ATF3 protein and mRNA expression, respectively. The accumulation of nuclear ATF4 protein coincided with induction of glutamate-cysteine ligase catalytic subunit, an ISR-responsive gene. Immunohistochemistry revealed that changes in ATF3/4 expression were prominent in the alveolus, whereas primary cell culture implicated epithelial and endothelial cells as targets. Finally, induction of ISR intermediates in the intact lung occurred in the absence of the phosphorylation of PKR, JNK, ERK1/2, and p38 MAPK. These findings demonstrate that Ox activates the ISR within the newborn lung and highlight regional and cell-specific alterations in the expression ISR transcription factors that regulate redox balance.
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Hisatsune, Junzo, Eiki Yamasaki, Masaaki Nakayama, Daisuke Shirasaka, Hisao Kurazono, Yohtaro Katagata, Hiroyasu Inoue, et al. "Helicobacter pylori VacA Enhances Prostaglandin E2 Production through Induction of Cyclooxygenase 2 Expression via a p38 Mitogen-Activated Protein Kinase/Activating Transcription Factor 2 Cascade in AZ-521 Cells." Infection and Immunity 75, no. 9 (June 25, 2007): 4472–81. http://dx.doi.org/10.1128/iai.00500-07.
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ABSTRACT Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E2 (PGE2) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-κB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.
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Lu, Dan, Jingchun Chen, and Tsonwin Hai. "The regulation of ATF3 gene expression by mitogen-activated protein kinases." Biochemical Journal 401, no. 2 (December 21, 2006): 559–67. http://dx.doi.org/10.1042/bj20061081.
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ATF3 (activating transcription factor 3) gene encodes a member of the ATF/CREB (cAMP-response-element-binding protein) family of transcription factors. Its expression is induced by a wide range of signals, including stress signals and signals that promote cell proliferation and motility. Thus the ATF3 gene can be characterized as an ‘adaptive response’ gene for the cells to cope with extra- and/or intra-cellular changes. In the present study, we demonstrate that the p38 signalling pathway is involved in the induction of ATF3 by stress signals. Ectopic expression of CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6], a kinase upstream of p38, indicated that activation of the p38 pathway is sufficient to induce the expression of the ATF3 gene. Inhibition of the pathway indicated that the p38 pathway is necessary for various signals to induce ATF3, including anisomycin, IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and H2O2. Analysis of the endogenous ATF3 gene indicates that the regulation is at least in part at the transcription level. Specifically, CREB, a transcription factor known to be phosphorylated by p38, plays a role in this induction. Interestingly, the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase)/SAPK (stress-activated protein kinase) signalling pathways are neither necessary nor sufficient to induce ATF3 in the anisomycin stress paradigm. Furthermore, analysis of caspase 3 activation indicated that knocking down ATF3 reduced the ability of MKK6(CA) to exert its pro-apoptotic effect. Taken together, our results indicate that a major signalling pathway, the p38 pathway, plays a critical role in the induction of ATF3 by stress signals, and that ATF3 is functionally important to mediate the pro-apoptotic effects of p38.
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Balague, Olga, Luis Colomo, Armando Lopez-Guillermo, Elias Campo, and Antonio Martinez. "Activation of the Endoplasmic Reticulum (ER) Unfolded Protein Response (UPR) in Aggressive B-Cell Lymphomas." Blood 108, no. 11 (November 1, 2006): 2038. http://dx.doi.org/10.1182/blood.v108.11.2038.2038.
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Abstract BACKGROUND The UPR is a prosurvival pathway activated in cells under ER stress induced by the accumulation of unfolded proteins. UPR activation in B cells normally occurs during the differentiation to antibody secreting plasma cells and requires XBP1activation. XBP-1 is a member of the TREB family of transcription factors that exists in the endoplasmic reticulum (ER) as a 33kDa protein, and in the nucleus as an active 50kDa transcription factor. The UPR stimulates two different ER proteins, ATF-6 and Ire-1, to increase XBP-1 transcription and XBP-1 mRNA splicing resulting in the accumulation of the active 50kDa nuclear protein. Moreover XBP1 is a target of proteosome inhibitors and is related to the aggressive behaviour of some carcinomas. The role of the activation of XBP-1 in lymphomas is still unknown. DESIGN: Reactive lymphoid tissues and 25 neoplastic human B-cell lines representing different stages of B-cell development were studied for XBP-1 expression by western blot and XBP-1, PAX-5, Blimp-1/prdm1, MUM-1/IRF-4 and ICSBP1/IRF-8 by immunohistochemistry. XBP-1 activation was assessed in 225 B-cell lymphomas from the archives of the laboratory of pathology by western blot, RT-PCR and immunohistochemistry . To further evaluate whether XBP-1 activation was related to the plasmacytic program or to ER stress signals we analyzed the cell lines by Western blot for XBP-1 and ATF-6 expression. RESULTS We characterize XBP-1 expression in reactive lymphoid tissues, 25 human cell lines and 225 B-cell tumors. In nearly all tonsillar lymphoid cells XBP-1 was detected as a cytoplasmic protein with a paranuclear dot pattern. Nuclear positivity was observed only in scattered centrocytes in the light zone of the germinal centers and in plasma cells, always coexpressed with plasma cell related transcription factors as MUM-1/IRF-4 and Blimp1/prdm1. Active p50XBP-1 was found in 24/25 cell lines by western blot regardless ATF-6 expression and confirmed by immunohistochemistry . Moreover p50XBP1 was found in 27/31(87%) plasmacytomas, 36/64(56%) DLBCL-ABC and in 3/10(30%) DLBCL-GCB and 22/43(51%) plasmablastic lymphomas. Intriguingly, p50XBP1 was detected also in 2/11(18%)BL and 4/25(16%)MCL with blastic features. CONCLUSIONS.XBP-1 is activated in a subset of follicular centre cells committed to plasma cell differentiation and in plasma cells.UPR prosurvival pathways in the neoplastic cell lines are activated independently of the extent of the ATF-6 activation.p50XBP1 is mostly activated in aggressive B-cell lymphomas regardless to the plasmacytic differentiation of the tumours. Thus, p50XBP-1 may be a new molecular target in the treatment of aggressive B-cell malignancies.
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Le, Vu Thuy Khanh, Mirko Trilling, Albert Zimmermann, and Hartmut Hengel. "Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome." Journal of General Virology 89, no. 5 (May 1, 2008): 1131–41. http://dx.doi.org/10.1099/vir.0.83538-0.
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We have investigated beta interferon (IFN-β) and IFN-α4 gene expression and activation of related transcription factors in mouse cytomegalovirus (MCMV)-infected fibroblasts. mRNA analysis demonstrated an initial phase of IFN gene induction upon MCMV infection, which was followed by a sustained MCMV-mediated simultaneous downregulation of IFN-β and IFN-α4 gene expression. The induction of IFN transcription resulted from the activation of the components of the IFN-β enhanceosome, i.e. IFN regulatory factor (IRF) 3, nuclear factor (NF)-κB, activating transcription factor (ATF)-2 and c-Jun. Activation of the transcription factors occurred rapidly and in a sequential order upon infection, but only lasted a while. As a consequence, IFN-α/β gene expression became undetectable 6 h post-infection and throughout the MCMV replication cycle. This effect is based on an active interference since restimulation of IFN gene induction by further external stimuli (e.g. Sendai virus infection) was completely abolished. This inhibition required MCMV gene expression and was not observed in cells infected with UV-inactivated MCMV virions. The efficiency of inhibition is achieved by a concerted blockade of IκBα degradation and a lack of nuclear accumulation of IRF3 and ATF-2/c-Jun. Using an MCMV mutant lacking pM27, a signal transducer and activator of transcription (STAT) 2-specific inhibitor of Jak/STAT signalling, we found that the initial phase of IFN induction and the subsequent inhibition does not depend on the positive-IFN feedback loop. Our findings indicate that the MCMV-mediated downregulation of IFN transcription in fibroblasts relies on a large arsenal of inhibitory mechanisms targeting each pathway that contributes to the multiprotein enhanceosome complex.
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Lund, Caren V., Mikhail Popkov, Laurent Magnenat, and Carlos F. Barbas. "Zinc Finger Transcription Factors Designed for Bispecific Coregulation of ErbB2 and ErbB3 Receptors: Insights into ErbB Receptor Biology." Molecular and Cellular Biology 25, no. 20 (October 15, 2005): 9082–91. http://dx.doi.org/10.1128/mcb.25.20.9082-9091.2005.
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ABSTRACT Signaling through the ErbB family of tyrosine kinase receptors in normal and cancer-derived cell lines contributes to cell growth and differentiation. In this work, we altered the levels of ErbB2 and ErbB3 receptors, individually and in combination, by using 6-finger and 12-finger synthetic zinc finger protein artificial transcription factors (ATFs) in an epidermoid squamous cell carcinoma line, A431. We successfully designed 12-finger ATFs capable of coregulating ErbB3 and ICAM-1 or ErbB2 and ErbB3. With ATFs, the effects of changes in ErbB2 and ErbB3 receptor levels were evaluated by using cell proliferation, cell migration, and cell signaling assays. Cell proliferation was increased when ErbB2 and ErbB3 were both overexpressed. Cell migration on collagen was decreased when ErbB2 was down-regulated, yet migration on laminin was significantly increased with ErbB3 overexpression. ErbB2 and ErbB3 overexpression also stimulated the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Our ATF approach has elucidated differences in ErbB receptor-mediated proliferation, migration, and intracellular signaling that cannot be explained merely by the presence or absence of particular ErbB receptors and emphasizes the dynamic nature of the ErbB signaling system. The transcription factor approach developed here provides a gene-economical route to the regulation of multiple genes and may be important for complex gene therapies.
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Bantignies, F., R. Rousset, C. Desbois, and P. Jalinot. "Genetic characterization of transactivation of the human T-cell leukemia virus type 1 promoter: Binding of Tax to Tax-responsive element 1 is mediated by the cyclic AMP-responsive members of the CREB/ATF family of transcription factors." Molecular and Cellular Biology 16, no. 5 (May 1996): 2174–82. http://dx.doi.org/10.1128/mcb.16.5.2174.
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To achieve a better understanding of the mechanism of transactivation by Tax of human T-cell leukemia virus type 1 Tax-responsive element 1 (TRE-1), we developed a genetic approach with Saccharomyces cerevisiae. We constructed a yeast reporter strain containing the lacZ gene under the control of the CYC1 promoter associated with three copies of TRE-1. Expression of either the cyclic AMP response element-binding protein (CREB) or CREB fused to the GAL4 activation domain (GAD) in this strain did not modify the expression of the reporter gene. Tax alone was also inactive. However, expression of the reporter gene was induced by coexpression of Tax and CREB. This effect was stronger with the GAD-CREB fusion protein. Analysis of different CREB mutants with this genetic system indicated that the C-terminal 92 amino acid residues, which include the basic domain and the leucine zipper, are necessary and sufficient to mediate transactivation by Tax. To identify cellular proteins binding to TRE-1 in a Tax-dependent manner, this strain was also used to screen a library of human cDNAs fused to GAD. Of five positive clones isolated from 0.75 x 10(6) yeast colonies, four were members of the CREB/activating transcription factor (ATF) family: CREB, two isoforms of the cyclic AMP-responsive element modulator (CREM), and ATF-1. Interestingly, these three proteins can be phosphorylated by protein kinase A and thus form a particular subgroup within the CREB/ATF family. Expression of ATF-2 in S. cerevisiae did not activate TRE-1 in the presence of Tax. This shows that in a eukaryotic nucleus, Tax specifically interacts with the basic domain-leucine zipper region of ATF-1, CREB, and CREM. The fifth clone identified in this screening corresponded to the Ku autoantigen p70 subunit. When fused to GAD, the C-terminal region of Ku was able to activate transcription via TRE-1 but this activation was not dependent on Tax.
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Elmazoglu, Zubeyir, Volkan Ergin, Ergin Sahin, Handan Kayhan, and Cimen Karasu. "Oleuropein and rutin protect against 6-OHDA-induced neurotoxicity in PC12 cells through modulation of mitochondrial function and unfolded protein response." Interdisciplinary Toxicology 10, no. 4 (December 20, 2017): 129–41. http://dx.doi.org/10.1515/intox-2017-0019.
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Abstract Parkinson’s disease (PD) is a highly prevalent neurodegenerative disorder, often associated with oxidative stress-induced transcriptional changes in dopaminergic neurons. Phenolic antioxidants, oleuropein (OLE) and rutin (RUT) have attracted a great interest due to their potential to counteract oxidative protein aggregation and toxicity. This study aimed at examining the effects of OLE and RUT against 6-OHDA-induced stress response in rat pheochromocytoma cells. When differentiated PC12 cells were exposed to oxidative stress composer 6-OHDA (100 μM, 8 h), a decreased mitochondrial membrane potential (ΔΨm) was observed along with a significant loss of cell viability and apoptotic nuclear changes. Exposure to 6-OHDA resulted in unfolded protein response (UPR) in differentiated PC12 cells as evidenced by an increased level of endoplasmic reticulum (ER)-localized transmembrane signal transducer IRE1α, adaptive response proteins ATF-4 and proapoptotic transcription factor CHOP. OLE or RUT pretreatment (24 h) at low doses (1-50 μM) protected the differentiated PC12 cells from 6-OHDA-induced cytotoxicity as assessed by increased viability, improved ΔΨm and inhibited apoptosis, whereas relatively high doses of OLE or RUT (>50 μM) inhibited cell growth and proliferation, indicating a typical hormetic effect. In hormetic doses, OLE and RUT up-regulated 6-OHDA-induced increase in IRE1α, ATF-4 and inhibited CHOP, PERK, BIP and PDI. 6-OHDA-activated XBP1 splicing was also inhibited by OLE or RUT. The presented results suggest that neuroprotection against 6-OHDA-induced oxidative toxicity may be attributable to neurohormetic effects of OLE or RUT at low doses through regulating mitochondrial functions, controlling persistent protein misfolding, activating and/or amplificating the adaptive response-related signaling pathways, leading to UPR prosurvival output.
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Pan, Yuan-Xiang, Hong Chen, Michelle M. Thiaville, and Michael S. Kilberg. "Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitation." Biochemical Journal 401, no. 1 (December 11, 2006): 299–307. http://dx.doi.org/10.1042/bj20061261.
Full textAbstract:
Expression of ATF3 (activating transcription factor 3) is induced by a variety of environmental stress conditions, including nutrient limitation. In the present study, we demonstrate that the increase in ATF3 mRNA content following amino acid limitation of human HepG2 hepatoma cells is dependent on transcriptional activation of the ATF3 gene, through a highly co-ordinated amino acid-responsive programme of transcription factor synthesis and action. Studies using transient over-expression and knockout fibroblasts showed that several ATF and C/EBP (CCAAT/enhancer-binding protein) family members contribute to ATF3 regulation. Promoter analysis showed that a C/EBP-ATF composite site at −23 to −15 bp relative to the transcription start site of the ATF3 gene functions as an AARE (amino acid response element). Chromatin immunoprecipitation demonstrated that amino acid limitation increased ATF4, ATF3, and C/EBPβ binding to the ATF3 promoter, but the kinetics of each was markedly different. Immediately following histidine removal, there was a rapid increase in histone H3 acetylation prior to an enhancement in ATF4 binding and in histone H4 acetylation. These latter changes closely paralleled the initial increase in RNA pol II (RNA polymerase II) binding to the promoter and in the transcription rate from the ATF3 gene. The increase in ATF3 and C/EBPβ binding was considerably slower and more closely correlated with a decline in transcription rate. A comparison of the recruitment patterns between ATF and C/EBP transcription factors and RNA polymerase II at the AARE of several amino acid-responsive genes revealed that a highly co-ordinated response programme controls the transcriptional activation of these genes following amino acid limitation.
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OKADA, Tetsuya, Hiderou YOSHIDA, Rieko AKAZAWA, Manabu NEGISHI, and Kazutoshi MORI. "Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response." Biochemical Journal 366, no. 2 (September 1, 2002): 585–94. http://dx.doi.org/10.1042/bj20020391.
Full textAbstract:
In response to accumulation of unfolded proteins in the endoplasmic reticulum (ER), a homoeostatic response, termed the unfolded protein response (UPR), is activated in all eukaryotic cells. The UPR involves only transcriptional regulation in yeast, and approx. 6% of all yeast genes, encoding not only proteins to augment the folding capacity in the ER, but also proteins working at various stages of secretion, are induced by ER stress [Travers, Patil, Wodicka, Lockhart, Weissman and Walter (2000) Cell (Cambridge, Mass.) 101, 249–258]. In the present study, we conducted microarray analysis of HeLa cells, although our analysis covered only a small fraction of the human genome. A great majority of human ER stress-inducible genes (approx. 1% of 1800 genes examined) were classified into two groups. One group consisted of genes encoding ER-resident molecular chaperones and folding enzymes, and these genes were directly regulated by the ER-membrane-bound transcription factor activating transcription factor (ATF) 6. The ER-membrane-bound protein kinase double-stranded RNA-activated protein kinase-like ER kinase (PERK)-mediated signalling pathway appeared to be responsible for induction of the remaining genes, which are not involved in secretion, but may be important after cellular recovery from ER stress. In higher eukaryotes, the PERK-mediated translational-attenuation system is known to operate in concert with the transcriptional-induction system. Thus we propose that mammalian cells have evolved a strategy to cope with ER stress different from that of yeast cells.
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Lopez, Alex B., Chuanping Wang, Charlie C. Huang, Ibrahim Yaman, Yi Li, Kaushik Chakravarty, Peter F. Johnson, et al. "A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvation." Biochemical Journal 402, no. 1 (January 25, 2007): 163–73. http://dx.doi.org/10.1042/bj20060941.
Full textAbstract:
The adaptive response to amino acid limitation in mammalian cells inhibits global protein synthesis and promotes the expression of proteins that protect cells from stress. The arginine/lysine transporter, cat-1, is induced during amino acid starvation by transcriptional and post-transcriptional mechanisms. It is shown in the present study that the transient induction of cat-1 transcription is regulated by the stress response pathway that involves phosphorylation of the translation initiation factor, eIF2 (eukaryotic initiation factor-2). This phosphorylation induces expression of the bZIP (basic leucine zipper protein) transcription factors C/EBP (CCAAT/enhancer-binding protein)-β and ATF (activating transcription factor) 4, which in turn induces ATF3. Transfection experiments in control and mutant cells, and chromatin immunoprecipitations showed that ATF4 activates, whereas ATF3 represses cat-1 transcription, via an AARE (amino acid response element), TGATGAAAC, in the first exon of the cat-1 gene, which functions both in the endogenous and in a heterologous promoter. ATF4 and C/EBPβ activated transcription when expressed in transfected cells and they bound as heterodimers to the AARE in vitro. The induction of transcription by ATF4 was inhibited by ATF3, which also bound to the AARE as a heterodimer with C/EBPβ. These results suggest that the transient increase in cat-1 transcription is due to transcriptional activation caused by ATF4 followed by transcriptional repression by ATF3 via a feedback mechanism.
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Hsieh, Tusty-Jiuan, Pierre Fustier, Shao-Ling Zhang, Janos G. Filep, Shiow-Shih Tang, Julie R. Ingelfinger, I. George Fantus, Pavel Hamet, and John S. D. Chan. "High Glucose Stimulates Angiotensinogen Gene Expression and Cell Hypertrophy via Activation of the Hexosamine Biosynthesis Pathway in Rat Kidney Proximal Tubular Cells." Endocrinology 144, no. 10 (October 1, 2003): 4338–49. http://dx.doi.org/10.1210/en.2003-0220.
Full textAbstract:
The present study investigated whether activation of the hexosamine biosynthesis pathway might mediate at least in part the high glucose effect on angiotensinogen (ANG) gene expression and immortalized renal proximal tubular cell (IRPTC) hypertrophy. IRPTC were cultured in monolayer. ANG, renin, and β-actin mRNA expression were determined by specific RT-PCR assays. Phosphorylation of p38 MAPK, activating transcription factor-2 (ATF-2), and cAMP-responsive element-binding protein (CREB) was determined by Western blot analysis. Cell hypertrophy was assessed by flow cytometry, intracellular p27kip1 protein levels, and [3H]leucine incorporation into proteins. Glucosamine stimulated ANG and renin mRNA expression and enhanced p38 MAPK, ATF-2, and CREB phosphorylation in normal glucose (5 mm) medium. Azaserine and 6-diazo-5-oxo-l-norleucine (inhibitors of glutamine: fructose-6-phosphate amino transferase enzyme) blocked the stimulatory effect of high glucose, but not that of glucosamine, on ANG gene expression in IRPTCs. SB 203580 (a specific p38 MAPK inhibitor) attenuated glucosamine action on ANG gene expression as well as p38 MAPK and ATF-2 phosphorylation, but not that of CREB. GF 109203X and calphostin C (inhibitors of protein kinase C) blocked the effect of glucosamine on ANG gene expression and CREB phosphorylation, but had no impact on p38 MAPK and ATF-2 phosphorylation. Finally, both glucosamine and high glucose induced IRPTC hypertrophy. The hypertrophic effect of glucosamine was blocked in the presence of GF 109203X, but not azaserine and SB 203580. In contrast, the hypertrophic effect of high glucose was blocked in the presence of azaserine and GF 109203X, but not SB203580. Our studies demonstrate that the stimulatory effect of high glucose on ANG gene expression and IRPTC hypertrophy may be mediated at least in part via activation of hexosamine biosynthesis pathway signaling.
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Schindler, Maria, Sünje Fischer, René Thieme, Bernd Fischer, and Anne Navarrete Santos. "cAMP-Responsive Element Binding Protein: A Vital Link in Embryonic Hormonal Adaptation." Endocrinology 154, no. 6 (April 8, 2013): 2208–21. http://dx.doi.org/10.1210/en.2012-2096.
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Abstract The transcription factor cAMP responsive element-binding protein (CREB) and activating transcription factors (ATFs) are downstream components of the insulin/IGF cascade, playing crucial roles in maintaining cell viability and embryo survival. One of the CREB target genes is adiponectin, which acts synergistically with insulin. We have studied the CREB-ATF-adiponectin network in rabbit preimplantation development in vivo and in vitro. From the blastocyst stage onwards, CREB and ATF1, ATF3, and ATF4 are present with increasing expression for CREB, ATF1, and ATF3 during gastrulation and with a dominant expression in the embryoblast (EB). In vitro stimulation with insulin and IGF-I reduced CREB and ATF1 transcripts by approximately 50%, whereas CREB phosphorylation was increased. Activation of CREB was accompanied by subsequent reduction in adiponectin and adiponectin receptor (adipoR)1 expression. Under in vivo conditions of diabetes type 1, maternal adiponectin levels were up-regulated in serum and endometrium. Embryonic CREB expression was altered in a cell lineage-specific pattern. Although in EB cells CREB localization did not change, it was translocated from the nucleus into the cytosol in trophoblast (TB) cells. In TB, adiponectin expression was increased (diabetic 427.8 ± 59.3 pg/mL vs normoinsulinaemic 143.9 ± 26.5 pg/mL), whereas it was no longer measureable in the EB. Analysis of embryonic adipoRs showed an increased expression of adipoR1 and no changes in adipoR2 transcription. We conclude that the transcription factors CREB and ATFs vitally participate in embryo-maternal cross talk before implantation in a cell lineage-specific manner. Embryonic CREB/ATFs act as insulin/IGF sensors. Lack of insulin is compensated by a CREB-mediated adiponectin expression, which may maintain glucose uptake in blastocysts grown in diabetic mothers.
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Kim, Sungjin, Yun-Jeong Song, Darryl A. Higuchi, Hyunseok P. Kang, Jennifer R. Pratt, Liping Yang, Caron M. Hong, et al. "Arrested natural killer cell development associated with transgene insertion into the Atf2 locus." Blood 107, no. 3 (February 1, 2006): 1024–30. http://dx.doi.org/10.1182/blood-2005-04-1493.
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AbstractNatural killer (NK) cell development in the bone marrow is not fully understood. Following lineage commitment, these cells appear to advance through a series of developmental stages that are beginning to be characterized. We previously reported a selective deficiency of NK cells in a C57BL/6 mouse with a transgenic construct consisting of the cDNA for the Ly49A major histocompatibility complex (MHC) class 1–specific inhibitory receptor driven by the granzyme A gene. This mouse has few NK cells in peripheral tissues with relative preservation of other immune cells, including T and B cells. Herein we demonstrate that these mice have an accumulation of NK cells with an immature phenotype in the bone marrow, consistent with a block at a previously proposed stage in normal NK-cell development. The phenotype is associated with transgenic insertion into Atf2, the gene for the basic leucine zipper (bZIP) transcription factor family member ATF-2. Although analysis of Atf2-null NK cells shows no defect, the transgenic mice express abnormal truncated Atf2 transcripts that may mediate a repressor effect because ATF2 can heterodimerize with other bZIP molecules. The defect is cell intrinsic, suggesting that certain bZIP molecules play significant roles in NK-cell development.
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Gonnella, Roberta, Maria Saveria Gilardini Montani, Luisa Guttieri, Maria Anele Romeo, Roberta Santarelli, and Mara Cirone. "IRE1 Alpha/XBP1 Axis Sustains Primary Effusion Lymphoma Cell Survival by Promoting Cytokine Release and STAT3 Activation." Biomedicines 9, no. 2 (January 27, 2021): 118. http://dx.doi.org/10.3390/biomedicines9020118.
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Primary Effusion Lymphoma (PEL) is a highly aggressive B cell lymphoma associated with Kaposi’s Sarcoma-associated Herpesvirus (KSHV). It is characterized by a high level of basal Endoplasmic Reticulum (ER) stress, Unfolded Protein Response (UPR) activation and constitutive phosphorylation of oncogenic pathways such as the Signal Transducer and activator of Transcription (STAT3). In this study, we found that the inositol requiring kinase (IRE) 1alpha/X-box binding protein (XBP1) axis of UPR plays a key role in the survival of PEL cells, while double stranded RNA-activated protein kinase-like ER kinase (PERK) and activating transcription factor (ATF) 6 slightly influence it, in correlation with the capacity of the IRE1alpha/XBP1 axis to induce the release of interleukin (IL)-6, IL-10 and Vascular-Endothelial Growth Factor (VEGF). Moreover, we found that IRE1alpha/XBP1 inhibition reduced STAT3 Tyr705 phosphorylation and induced a pro-survival autophagy in PEL cells. In conclusion, this study suggests that targeting the IRE1alpha/XBP1 axis represents a promising strategy against PEL cells and that the cytotoxic effect of this treatment may be potentiated by autophagy inhibition.
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Seo, Eun-Hye, Liyun Piao, Eun-Hwa Cho, Seung-Wan Hong, and Seong-Hyop Kim. "The Effect of Ketamine on Endoplasmic Reticulum Stress in Rats with Neuropathic Pain." International Journal of Molecular Sciences 24, no. 6 (March 10, 2023): 5336. http://dx.doi.org/10.3390/ijms24065336.
Full textAbstract:
This study aimed to investigate the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on endoplasmic reticulum (ER) stress in rats with neuropathic pain (NP). NP was induced in rats through ligation and transection of the sciatic nerve. After confirmation of NP, the animals were randomly divided into ketamine and control groups. The ketamine group was administered 50 mg/kg of ketamine at 15, 18, and 21 days after surgery. The expression of NMDA receptor subtype 2B (NR2B) and ER stress markers in the spinal cord (L5) was evaluated. The ipsilateral side of the surgery in the ketamine group was less sensitive to mechanical and cold stimulations. The expression of NR2B on the ipsilateral side was significantly lower in the ketamine group than in the control group (18.93 ± 1.40% vs. 31.08 ± 0.74%, p < 0.05). All markers for ER stress on the ipsilateral side of the surgery in both groups had higher expression than those on the contralateral side. The expression of activating transcription factor-6 (ATF-6) on the ipsilateral side was significantly lower in the ketamine group than in the control group (p < 0.05). Systemic administration of ketamine inhibited the expression of NMDA receptors and improved NP symptoms. Among the markers of ER stress, the therapeutic effect of ketamine is associated with the inhibition of ATF-6 expression.
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Cai, Yong, Chun Zhang, Tigre Nawa, Teijiro Aso, Makiko Tanaka, Satoru Oshiro, Hidenori Ichijo, and Shigetaka Kitajima. "Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of c-Jun NH2-terminal kinase and promoter response element." Blood 96, no. 6 (September 15, 2000): 2140–48. http://dx.doi.org/10.1182/blood.v96.6.2140.
Full textAbstract:
Abstract Activating transcription factor (ATF) 3 is a member of ATF/cyclic adenosine monophosphate (cAMP)–responsive element binding protein (ATF/CREB) family of transcription factors and functions as a stress-inducible transcriptional repressor. To understand the stress-induced gene regulation by homocysteine, we investigated activation of the ATF3 gene in human endothelial cells. Homocysteine caused a rapid induction of ATF3 at the transcriptional level. This induction was preceded by a rapid and sustained activation of c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK), and dominant negative mitogen-activated protein kinase kinase 4 and 7 abolished these effects. The effect of homocysteine appeared to be specific, because cysteine or homocystine had no appreciable effect, but it was mimicked by dithiothreitol and β-mercaptoethanol as well as tunicamycin. The homocysteine effect was not inhibited by an active oxygen scavenger. Deletion analysis of the 5′ flanking sequence of the ATF3 gene promoter revealed that one of the major elements responsible for the induction by homocysteine is an ATF/cAMP responsive element (CRE) located at −92 to −85 relative to the transcriptional start site. Gel shift, immunoprecipitation, and cotransfection assays demonstrated that a complex (or complexes) containing ATF2, c-Jun, and ATF3 increased binding to the ATF/CRE site in the homocysteine-treated cells and activated the ATF3 gene expression, while ATF3 appeared to repress its own promoter. These data together suggested a novel pathway by which homocysteine causes the activation of JNK/SAPK and subsequent ATF3 expression through its reductive stress. Activation of JNK/SAPK and ATF3 expression in response to homocysteine may have a functional role in homocysteinemia-associated endothelial dysfunction.
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Cai, Yong, Chun Zhang, Tigre Nawa, Teijiro Aso, Makiko Tanaka, Satoru Oshiro, Hidenori Ichijo, and Shigetaka Kitajima. "Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of c-Jun NH2-terminal kinase and promoter response element." Blood 96, no. 6 (September 15, 2000): 2140–48. http://dx.doi.org/10.1182/blood.v96.6.2140.h8002140_2140_2148.
Full textAbstract:
Activating transcription factor (ATF) 3 is a member of ATF/cyclic adenosine monophosphate (cAMP)–responsive element binding protein (ATF/CREB) family of transcription factors and functions as a stress-inducible transcriptional repressor. To understand the stress-induced gene regulation by homocysteine, we investigated activation of the ATF3 gene in human endothelial cells. Homocysteine caused a rapid induction of ATF3 at the transcriptional level. This induction was preceded by a rapid and sustained activation of c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK), and dominant negative mitogen-activated protein kinase kinase 4 and 7 abolished these effects. The effect of homocysteine appeared to be specific, because cysteine or homocystine had no appreciable effect, but it was mimicked by dithiothreitol and β-mercaptoethanol as well as tunicamycin. The homocysteine effect was not inhibited by an active oxygen scavenger. Deletion analysis of the 5′ flanking sequence of the ATF3 gene promoter revealed that one of the major elements responsible for the induction by homocysteine is an ATF/cAMP responsive element (CRE) located at −92 to −85 relative to the transcriptional start site. Gel shift, immunoprecipitation, and cotransfection assays demonstrated that a complex (or complexes) containing ATF2, c-Jun, and ATF3 increased binding to the ATF/CRE site in the homocysteine-treated cells and activated the ATF3 gene expression, while ATF3 appeared to repress its own promoter. These data together suggested a novel pathway by which homocysteine causes the activation of JNK/SAPK and subsequent ATF3 expression through its reductive stress. Activation of JNK/SAPK and ATF3 expression in response to homocysteine may have a functional role in homocysteinemia-associated endothelial dysfunction.
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Du, Bei, Jia-Lin Zheng, Liang-Yu Huang, Hong Zhang, Qiong Wang, Ya-Ru Hong, Xiao-min Zhang, Xiao-Rong Li, and Li-Jie Dong. "Protective Effect and Mechanism of Bone Morphogenetic Protein-4 on Apoptosis of Human Lens Epithelium Cells under Oxidative Stress." BioMed Research International 2021 (January 29, 2021): 1–10. http://dx.doi.org/10.1155/2021/8109134.
Full textAbstract:
Bone morphogenetic proteins (BMPs), a member of the transforming growth factor β (TGF-β) superfamily, are abundant in human ocular tissues and play an important role in lens development. Targeted deletion of BMP-4 in mice results in failure of lens placode formation. Following lens maturation, the formation of senile cataracts is demonstrably associated with free radical-related oxidative stress. Previous studies reported that BMPs play an antiapoptotic role in cells under oxidative stress, and the BMP-4 signal is important in inflammation regulation and homeostasis. BMP-4 evidently suppressed the apoptosis of human lens epithelial cells (HLECS) under oxidative stress induced by H2O2. This protective antiapoptotic effect is partly due to a decrease in caspase-3 activity and reactive oxygen species (ROS) level. Furthermore, the expression of activating transcription factor- (ATF-) 6 and Krüppel-like factor- (KLF-) 6 increased under oxidative stress and decreased after BMP-4 treatment.
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Mulloy, J. C., T. Kislyakova, A. Cereseto, L. Casareto, A. LoMonico, J. Fullen, M. V. Lorenzi, et al. "Human T-Cell Lymphotropic/Leukemia Virus Type 1 Tax Abrogates p53-Induced Cell Cycle Arrest and Apoptosis through Its CREB/ATF Functional Domain." Journal of Virology 72, no. 11 (November 1, 1998): 8852–60. http://dx.doi.org/10.1128/jvi.72.11.8852-8860.1998.
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ABSTRACT Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) transforms human T cells in vitro, and Tax, a potent transactivator of viral and cellular genes, plays a key role in cell immortalization. Tax activity is mediated by interaction with cellular transcription factors including members of the CREB/ATF family, the NF-κB/c-Rel family, serum response factor, and the coactivators CREB binding protein-p300. Although p53 is usually not mutated in HTLV-1-infected T cells, its half-life is increased and its function is impaired. Here we report that transient coexpression of p53 and Tax results in the suppression of p53 transcriptional activity. Expression of Tax abrogates p53-induced G1 arrest in the Calu-6 cell line and prevents the apoptosis induced by overexpressing p53 in the HeLa/Tat cell line. The Tax mutants M22 and G148V, which selectively activate the CREB/ATF pathway, exert these same biological effects on p53 function. In contrast, the NF-κB-active Tax mutant M47 has no effect on p53 activity in any of these systems. Consistent with the negative effect of Tax on p53, no activity on a p53-responsive promoter was observed upon transfection of HTLV-1-infected T-cell lines. The p53 protein is expressed at high levels in the nucleus, and nuclear extracts of HTLV-1-infected T cells bind constitutively to a DNA oligonucleotide containing the p53 response element, indicating that Tax does not interfere with p53 binding to DNA. Tax is able to suppress the transactivation function of p53 in three different cell lines, and this suppression required Tax-mediated activation of the CREB/ATF, but not the NF-κB/c-Rel, pathway. Tax and the active Tax mutants were able to abrogate the G1 arrest and apoptosis induced by p53, and this effect does not correlate with an altered localization of nuclear p53 or with the disruption of p53-DNA complexes. The suppression of p53 activity by Tax could be important in T-cell immortalization induced by HTLV-1.
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Zhang, Peng, Luhao Liu, Xingqiang Lai, Rongxin Chen, Yuhe Guo, JunjieMa, Wenhao Chen, and Zheng Chen. "Ablation of Basic Leucine Zipper Transcription Factor ATF-Like Potentiates Estradiol to Induce Atopic Dermatitis." Oxidative Medicine and Cellular Longevity 2022 (September 16, 2022): 1–11. http://dx.doi.org/10.1155/2022/7024669.
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Background. Atopic dermatitis (AD) is an inflammatory and immune skin disorder. Basic leucine zipper transcription factor ATF-like (BATF) plays a key role in regulating the differentiation and functions of lymphocytes. However, the mechanism underlying the transcriptional regulation of BATF on AD is still not well understood. Methods. BATF knockout (BATF–/–) and C57BL/6(B6) mice were used for the development of spontaneous dermatitis. 17β-Estradiol was injected intraperitoneally to induce AD. The lesioned tail skin of the mice was stained with hematoxylin and eosin to analyze the pathological characteristics. Impaired skin barrier function was assessed by measuring the transepidermal water loss (TEWL). The skin epithelial barrier indicators and cytokine mRNA levels were quantified by real-time quantitative PCR. The total serum immunoglobulin E (IgE) levels were measured by enzyme-linked immunosorbent assay (ELISA). T lymphocytes were analyzed using flow cytometry. Results. Ablation of BATF led to the spontaneous development of AD only in female mice and not in male mice. BATF deletion led to elevated serum levels of IgE and increased infiltration of eosinophils, neutrophils, and lymphocytes and promoted cytokine production including IL-4, IL-22, IL-1β, IFN-γ, and TNF-α in the lesioned tail skin of the mice. The mRNA expression levels of filaggrin and loricrin significantly decreased, while S100A8 and S100A9 increased in female BATF–/– mice. BATF-deficient female mice were found to increase proliferation and IL-5 production by skin-infiltrating CD4+ T cells which implies Th2 activation. Moreover, AD was successfully induced only in the estradiol-treated BATF-deficient male mice and not in WT male mice. Estradiol enhanced the allergic and immunological responses to dermatitis primarily by triggering Th2-type immune responses via enhanced serum IgE and inflammatory cytokine levels in the male BATF–/– mice. Conclusion. The study concluded that BATF potentiates estradiol to induce mouse atopic dermatitis via potentiating inflammatory cytokine releases and Th2-type immune responses and may have important clinical implications for patients with AD.
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Zhao, Jihua, and Yao Yang. "Vanillic acid alleviates lipopolysaccharides-induced endoplasmic reticulum stress and inflammation in human lung fibroblasts by `inhibiting MAPK and NF-κB pathways." Quality Assurance and Safety of Crops & Foods 14, no. 1 (January 21, 2022): 55–63. http://dx.doi.org/10.15586/qas.v14i1.1018.
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Persistent endoplasmic reticulum stress promotes aberrant inflammation and induces cell death, and inflammation is implicated in the pathogenesis of pneumonia. Vanillic acid exerts pharmacological activities, such as anti-inflammatory, antimicrobial, and antioxidant effects. However, the role of vanillic acid in pneumonia has not been elucidated yet. Human lung fibroblasts (WI-38 and MRC-5) were incubated with different concentrations of lipopolysaccharides to mimic the cell model of pneumonia. Lipopolysaccharides-treated lung fibroblasts were then incubated with different concentrations of vanillic acid. Cell viability and apoptosis were detected by MTT assay and flow cytometry, respectively. Quantitative real-time polymerase chain reaction and enzyme-linked-immunosorbent serologic assay were used to measure the levels of inflammatory factors. Western blot assay was used to detect endoplasmic reticulum stress and downstream pathway. Lipopolysaccharides induced decrease of cell viability in WI-38 and MRC-5 whereas vanillic acid increased cell viability of lipopolysaccharides-treated lung fibroblasts. Lipopolysaccharides-induced increase of cell apoptosis in lung fibroblasts was suppressed by vanillic acid through up-regulation of BCL2, and down-regulation of BCL2 associated X (BAX) and cleaved caspase-3. Vanillic acid reduced levels of tumor necrosis factor-α (TNF-α), Interleukin 6 (IL-6), and IL-1β in lipopolysaccharides-treated lung fibroblasts. Protein expression of glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP-1), activating transcription factor-6 (ATF-6), ATF-4, and C/EBP homologous protein (CHOP) in lung fibroblasts were up-regulated by lipopolysaccharides while reduced by vanillic acid. Vanillic acid attenuated lipopolysaccharides-induced decrease of IκBα and increase of p-IκBα, p-p65, p-ERK, and p-JNK in fibroblasts. Vanillic acid exerted anti-inflammatory effect against lipopolysaccharides-induced human lung fibroblasts by inhibiting mitogen-activated protein kinase and nuclear factor kappa B pathways.
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Wang, Xisheng, Peter F. Barnes, James C. Townsend, Yoon-tae Chung, Homayoun Shams, and Buka Samten. "ESAT-6 inhibits IFN-γ secretion by Mycobacterium tuberculosis responsive-human T cells (129.12)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 129.12. http://dx.doi.org/10.4049/jimmunol.182.supp.129.12.
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Abstract Early secreted antigenic target of 6 kD (ESAT-6) of Mycobacterium tuberculosis (M. tb) is a potent antigen with vaccine potential, but is also a virulence factor. We studied the effect of recombinant His-tagged ESAT-6 on IFN-γ secretion by human primary T cells, using the 10 kD culture filtrate protein (CFP10) as a control. ESAT-6 but not CFP10 started to inhibit IFN-γ secretion by M-tb stimulated PBMC at 1.6 μM and this reached 90% inhibition, compared to that with CFP10 (12.5 + 5.4 vs. 1.3 + 1.2 ng/ml) at 3.3 μM (20 μg/ml). Dimerization of ESAT-6 with CFP10 did not affect inhibition. ESAT-6 inhibited IFN-γ production of α-CD3/CD28 mAb-stimulated T cells by 89% (14.5 + 1.8 vs. 1.6 + 0.4 ng/ml), and proliferation, as measured by CFSE assay. Depleting ESAT-6 with a nickel resin abrogated the inhibition. The inhibitory effect of ESAT-6 was not due to T cell toxicity or apoptosis, as measured by MTT assay and Annexin V staining. ESAT-6 inhibited expression of M. tb-induced IFN-γ mRNA (> 90%) and the transcription factors, ATF-2 and c-Jun, which regulate IFN-γ transcription. ESAT-6 bound to T cells and inhibited expression of CD69 and CD25, without affecting proximal TCR signaling, ZAP70 activation. We conclude that high concentrations of ESAT-6 inhibit T cell responses to M. tb by affecting signaling pathways downstream of ZAP70, and may be a mechanism by which M. tb inhibits effective immunity. (NIH AI063514)
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Badr, Gamal, Nancy K. Ramadan, Hanem S. Abdel-Tawab, Samia F. Ahmed, and Mohamed H. Mahmoud. "Camel whey protein protects lymphocytes from apoptosis via the PI3K–AKT, NF-κB, ATF-3, and HSP-70 signaling pathways in heat-stressed male mice." Biochemistry and Cell Biology 96, no. 4 (August 2018): 407–16. http://dx.doi.org/10.1139/bcb-2017-0217.
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Heat stress (HS) is an environmental factor that depresses the immune systems that mediate dysfunctional immune cells. Camel whey protein (CWP) can scavenge free radicals and enhance immunity. This study investigated the impact of dietary supplementation with CWP on immune dysfunction induced by exposure to HS. Male mice (n = 45) were distributed among 3 groups: control group; HS group; and HS mice that were orally administered CWP (HS + CWP group). The HS group exhibited elevated levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor-α) as well as a significant reduction in the IL-2 and IL-4 levels. Exposure to HS resulted in impaired phosphorylation of AKT and IκB-α (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha); increased expression of activating transcription factor 3 (ATF-3) and 70 kDa heat shock proteins (HSP70); and aberrant distribution of CD3+ T cells and CD20+ B cells in the thymus and spleen. Interestingly, HS mice treated with CWP presented significantly restored levels of reactive oxygen species and pro-inflammatory cytokines near the levels observed in the control mice. Furthermore, supplementation of HS mice with CWP enhanced the phosphorylation of AKT and IκB-α; attenuated the expression of ATF-3, HSP70, and HSP90; and improved T and B cell distributions in the thymus and spleen. Our findings reveal a potential immunomodulatory effect of CWP in attenuating immune dysfunction induced by exposure to thermal stress.
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Badr, Gamal, Leila H. Sayed, Hossam El-Din M. Omar, Ali M. Abd El-Rahim, Emad A. Ahmed, and Mohamed H. Mahmoud. "Camel Whey Protein Protects B and T Cells from Apoptosis by Suppressing Activating Transcription Factor-3 (ATF-3)-Mediated Oxidative Stress and Enhancing Phosphorylation of AKT and IκB-α in Type I Diabetic Mice." Cellular Physiology and Biochemistry 41, no. 1 (2017): 41–54. http://dx.doi.org/10.1159/000455935.
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Background: Diabetes mellitus (DM) is associated with severe immune system complications. Camel whey protein (CWP) decreases free radicals (ROS) and modulates immune functions, but its effect on DM-impaired immune systems has not been studied. We investigated the impact of CWP on the immune system in a Type 1 diabetes mouse model. Methods: Three experimental groups were used: (1) non-diabetic control; (2) diabetic; and (3) CWP-treated diabetic mice. Results: Induction of diabetes by streptozotocin was associated with reduction of body weight and insulin level, increase in glucose level and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and reduction in IL-2 and IL-4 levels. Upregulated ATF-3 expression was followed by a marked elevation in ROS levels. Lymphocytes from diabetic mice exhibited increased apoptosis through decreased phosphorylation of AKT and IκB-α, increased infiltration of T cells in the spleen and thymus, and decreased B cell numbers in the spleen. Supplementation with CWP decreased the levels of proinflammatory cytokines, ROS, and ATF-3 expression, and increased the levels of IL-4. Treatment with CWP decreased apoptosis by enhancing the phosphorylation of AKT and IκB-α as well as T-cell and B-cell distribution in the spleen and thymus. Conclusions: Our findings suggest the beneficial effects of CWP supplementation during diabetes on decreasing and orchestrating the redox status and subsequently rescuing the immune cells from exhaustion.
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Rhoads, J. M., R. A. Argenzio, W. Chen, R. A. Rippe, J. K. Westwick, A. D. Cox, H. M. Berschneider, and D. A. Brenner. "L-glutamine stimulates intestinal cell proliferation and activates mitogen-activated protein kinases." American Journal of Physiology-Gastrointestinal and Liver Physiology 272, no. 5 (May 1, 1997): G943—G953. http://dx.doi.org/10.1152/ajpgi.1997.272.5.g943.
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We studied the mechanisms by which L-glutamine (Gln), a major fuel for enterocytes, signals proliferation in intestinal epithelial cell lines. Gln was additive to epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) in stimulating DNA synthesis, as assessed by [3H]thymidine incorporation. Extracellular signal-regulated kinases (ERKs) p42mapk and p44mapk and Jun nuclear kinases (JNKs) phosphorylate and activate nuclear transcription factors. Proteins of the c-Jun, ATF-2, and c-Fos families aggregate to form DNA-binding homodimers or heterodimers called activating protein 1 (AP-1). In vitro assays and functional assays of phosphorylation demonstrated that Gln activates both ERKs and JNKs, resulting in a fourfold increase in AP-1-dependent gene transcription. Gln was required for EGF signaling through ERKs. Maximal stimulation of proliferation required approximately 2.5 mM Gln. c-Jun mRNA levels responded to Gln in "Gln-starved" porcine IPEC-J2 cells and in rat IEC-6 cells. Although Gln metabolism is required for the proliferative response, several Gln by-products did not stimulate [3H]thymidine incorporation, with the exception of arginine. Gln may be a unique nutrient for enterocytes, capable of dual signaling and augmenting the effects of growth factors that govern cellular proliferation and repair.
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Rhee, Jinseol, Seo-Hee Park, Seul-Ki Kim, Jin-Hong Kim, Chul-Won Ha, Churl-Hong Chun, and Jang-Soo Chun. "Inhibition of BATF/JUN transcriptional activity protects against osteoarthritic cartilage destruction." Annals of the Rheumatic Diseases 76, no. 2 (May 4, 2016): 427–34. http://dx.doi.org/10.1136/annrheumdis-2015-208953.
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ObjectiveThe basic leucine zipper transcription factor, ATF-like (BATF), a member of the Activator protein-1 family, promotes transcriptional activation or repression, depending on the interacting partners (JUN-B or C-JUN). Here, we investigated whether the BATF/JUN complex exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of osteoarthritis (OA).MethodsPrimary cultured mouse chondrocytes were treated with proinflammatory cytokines (interleukin-1β, IL-6 or tumour necrosis factor-α) or infected with adenoviruses carrying the Batf gene (Ad-Batf). Expression of BATF and JUN was examined in human and mouse experimental OA cartilage samples. Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of Ad-Batf. The chromatin immunoprecipitation assay was used to examine the binding of BATF and JUN to the promoter regions of candidate genes.ResultsOverexpression of BATF, which forms a heterodimeric complex with JUN-B and C-JUN, induced upregulation of matrix-degrading enzymes and downregulation of cartilage matrix molecules in chondrocytes. BATF expression in mouse joint tissues promoted OA cartilage destruction, and conversely, knockout of Batf in mice suppressed experimental OA. Pharmacological inhibition of BATF/JUN transcriptional activity reduced the expression of matrix-degrading enzymes and protected against experimental OA in mice.ConclusionsBATF/JUN-B and BATF/C-JUN complexes play important roles in OA cartilage destruction through regulating anabolic and catabolic gene expression in chondrocytes. Our findings collectively support the utility of BATF as a therapeutic target for OA.
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Gozdecka, Malgorzata, and Wolfgang Breitwieser. "The roles of ATF2 (activating transcription factor 2) in tumorigenesis." Biochemical Society Transactions 40, no. 1 (January 19, 2012): 230–34. http://dx.doi.org/10.1042/bst20110630.
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MAPK (mitogen-activated protein kinase) pathways are among the most frequently deregulated signalling events in cancer. Among the critical targets of MAPK activities are members of the AP-1 (activator protein 1) transcription factor, a dimeric complex consisting of Jun, Fos, Maf and ATF (activating transcription factor) family DNA-binding proteins. Depending on the cellular context, the composition of the dimeric complexes determines the regulation of growth, survival or apoptosis. JNK (c-Jun N-terminal kinase), p38 and a number of Jun and Fos family proteins have been analysed for their involvement in oncogenic transformation and tumour formation. These data are also emerging for the ATF components of the AP-1 factor. The aim of the present review is to provide an overview of the functions of two ATF family proteins, ATF2 and ATF7, in mammalian development and their potential functions in tumour formation.
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Aceves, Miriam, Jose Granados, Ana C. Leandro, Juan Peralta, David C. Glahn, Sarah Williams-Blangero, Joanne E. Curran, John Blangero, and Satish Kumar. "Role of Neurocellular Endoplasmic Reticulum Stress Response in Alzheimer’s Disease and Related Dementias Risk." Genes 15, no. 5 (April 28, 2024): 569. http://dx.doi.org/10.3390/genes15050569.
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Currently, more than 55 million people around the world suffer from dementia, and Alzheimer’s Disease and Related Dementias (ADRD) accounts for nearly 60–70% of all those cases. The spread of Alzheimer’s Disease (AD) pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of ADRD’s causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in the induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that the NSCs’ ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR-corrected p-value ≤ 0.05 and fold change absolute ≥ 2.0) differentially expressed (DE). The pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE1), were significantly activated and cooperatively regulated the NSCs’ transcriptional response to ER stress. Our results show that IRE1/X-box binding protein 1 (XBP1) mediated transcriptional regulation of the E2F transcription factor 1 (E2F1) gene, and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in ER stress-challenged NSCs. The ER stress-challenged NSCs also showed the activation of C/EBP homologous protein (CHOP)-mediated apoptosis and the dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that the ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.
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Pham, Duy, Daniel J. Silberger, Kim Nguyen, Min Gao, Robin D. Hatton, and Casey Todd Weaver. "Batf Stabilizes the Th17 Cell Developmental Program through Impairment of Stat5-dependent Recruitment of Ets1-Runx1 Complexes." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 56.05. http://dx.doi.org/10.4049/jimmunol.208.supp.56.05.
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Abstract The emergence of alternative CD4 T cell fates is controlled by transcriptional networks activated downstream of TCR and cytokine signaling inputs. Th17 cells develop from antigen-activated naive CD4 T cells in the presence of IL-6 and TGF-b. An important facet of the Th17 cell program is its intrinsic instability; early development of Th17 cells shares overlapping features with that of Treg cells and Th17 cells are prone to transdifferentiation into Th1-like cells. The basic leucine zipper transcription factor ATF-like (Batf) contributes to the transcriptional programming of multiple effector T cells but is indispensable for Th17 cell development. Although Batf is required for development of Th17 cells, its mechanisms of action to underpin the Th17 program are incompletely understood. Here, we find that in addition to activating core genes of the Th17 program, Batf also acts to restrict expression of genes of the Treg and Th1 programs through its actions to restrain IL-2-induced Stat5 activation, thereby limiting Stat5-dependent recruitment of Ets1-Runx1 factors to Th1 and Treg cell-specific gene loci. Accordingly, Batf acts both to pioneer regulatory elements in Th17-specific genes and limit assembly of a Stat5-Ets1-Runx1 enhanceosome that appears to be required for optimal expression of Th1 and Treg cell-specific genes. Our findings define a new role for Batf in T cell differentiation and unveil an important role for Stat5-Ets1-Runx1 interactions in transcriptional networks that define alternative T cell developmental fates. Supported by NIH R01 DK115172 and T32 AI007051-37
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Sita, Giulia, Agnese Graziosi, Camilla Corrieri, Luca Ghelli, Sabrina Angelini, Pietro Cortelli, Patrizia Hrelia, and Fabiana Morroni. "The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for Predictors." International Journal of Molecular Sciences 24, no. 22 (November 11, 2023): 16200. http://dx.doi.org/10.3390/ijms242216200.
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Alzheimer’s disease (AD) represents the most frequent type of dementia worldwide, and aging is the most important risk factor for the sporadic form of the pathology. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the accumulation of the β-amyloid (Aβ) protein and the phosphorylated Tau protein. Increasing protein misfolding activates a specific cellular response known as Unfolded Protein Response (UPR), which orchestrates the recovery of ER function. The aim of the present study was to investigate the role of UPR in a murine model of AD induced by intracerebroventricular (i.c.v.) injection of Aβ1–42 oligomers at 3 or 18 months. The oligomer injection in aged animals induced memory impairment, oxidative stress, and the depletion of glutathione reserve. Furthermore, the RNA sequencing and the bioinformatic analysis performed showed the enrichment of several pathways involved in neurodegeneration and protein regulations. The analysis highlighted the significant dysregulation of the protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF-6). In turn, ER stress affected the PI3K/Akt/Gsk3β and MAPK/ERK pathways, highlighting Mapkapk5 as a potential marker, whose regulation could lead to the definition of new pharmacological and neuroprotective strategies to counteract AD.
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Jiang, Hao-Yuan, Sheree A. Wek, Barbara C. McGrath, Dan Lu, Tsonwin Hai, Heather P. Harding, Xiaozhong Wang, David Ron, Douglas R. Cavener, and Ronald C. Wek. "Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response." Molecular and Cellular Biology 24, no. 3 (February 1, 2004): 1365–77. http://dx.doi.org/10.1128/mcb.24.3.1365-1377.2004.
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ABSTRACT In response to environmental stress, cells induce a program of gene expression designed to remedy cellular damage or, alternatively, induce apoptosis. In this report, we explore the role of a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) in coordinating stress gene responses. We find that expression of activating transcription factor 3 (ATF3), a member of the ATF/CREB subfamily of basic-region leucine zipper (bZIP) proteins, is induced in response to endoplasmic reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively. Increased expression of ATF3 protein occurs early in response to stress by a mechanism requiring the related bZIP transcriptional regulator ATF4. ATF3 contributes to induction of the CHOP transcriptional factor in response to amino acid starvation, and loss of ATF3 function significantly lowers stress-induced expression of GADD34, an eIF2 protein phosphatase regulatory subunit implicated in feedback control of the eIF2 kinase stress response. Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases. Given that ATF3 is induced by a very large number of environmental insults, this study supports involvement of eIF2 kinases in the coordination of gene expression in response to a more diverse set of stress conditions than previously proposed.
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Denechaud, Pierre-Damien, Albert Giralt, Francois Pattou, Caroilne Bonner, Jean-Sébastien Annicotte, and Lluis Fajas. "Le facteur de transcription E2F1 contrôle la néoglucogenèse hépatique et participe au développement de l’hyperglycémie." Diabetes & Metabolism 43, no. 2 (March 2017): A24. http://dx.doi.org/10.1016/s1262-3636(17)30172-6.
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Gade, Padamja, Uday B. Machaani, and Dhan V. Kalvakolanu. "CS11-7. IFN-autophagy and tumor suppression: a novel IFN-γ induced signaling cascade involving Activated transcription factor-6 (ATF-6) that collaborates with C/EBP-beta and promotes tumor suppression." Cytokine 56, no. 1 (October 2011): 61. http://dx.doi.org/10.1016/j.cyto.2011.07.375.
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Petrovic, Isidora, Natasa Kovacevic-Grujicic, Jelena Popovic, A. Krstic, Milena Milivojevic, and Milena Stevanovic. "Members of the CREB/ATF and AP1 family of transcription factors are involved in the regulation of SOX18 gene expression." Archives of Biological Sciences 63, no. 3 (2011): 517–25. http://dx.doi.org/10.2298/abs1103517p.
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The SOX18 transcription factor plays an important role in endothelial cell specification, angiogenesis and atherogenesis. By profiling transcription factor interactions (TranSignal TM TF Protein Array) we identified several transcription factors implicated in angiogenesis that have the ability to bind to the SOX18 optimal promoter region in vitro. In this report we focused our attention on distinct transcription factors identified by the array as belonging to AP-1 and CREB/ATF protein families. In particular, we analyzed the effects of CREB, JunB, c-Jun and ATF3 on SOX18 gene expression. Functional analysis revealed that CREB acts as a repressor, while JunB, c-Jun and ATF3 act as activators of SOX18 promoter activity. Our findings indicate that a transcriptional network that includes CREB, JunB, c-Jun and ATF3 could be involved in angiogenesis-related transcriptional regulation of the SOX18 gene.
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Mahmoud, Mohamed H., Gamal Badr, and Nashwa A. El Shinnawy. "Camel whey protein improves lymphocyte function and protects against diabetes in the offspring of diabetic mouse dams." International Journal of Immunopathology and Pharmacology 29, no. 4 (September 30, 2016): 632–46. http://dx.doi.org/10.1177/0394632016671729.
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The prevalence of health problems in the offspring of pregnant diabetic mothers has recently been verified. Therefore, the present study was designed to investigate the influence of dietary camel whey protein (CWP), administered as a supplement to streptozotocin (STZ)-induced diabetic pregnant mice, on the efficiency of the immune system of the offspring. Three groups of female mice (n = 10) were used: non-diabetic control mice, diabetic mice, and diabetic mice orally administered CWP during the pregnancy and lactation periods. We then tested the immune response of B and T cells in adult male offspring (n = 15 in each group) by using flow cytometry, western blotting, and ELISAs. Our data demonstrated that the offspring of diabetic dams exhibited several postpartum complications, such as significant aberrant overexpression of activating transcription factor-3 (ATF-3), significant elevation of the plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and reactive oxygen species (ROS), marked decreases in the plasma levels of IL-2 and IL-7, significant inhibition of CCL21- and CXCL12-mediated chemotaxis of B- and T-lymphocytes, and a marked decrease in the proliferative capacity of antigen-stimulated B- and T-lymphocytes. Interestingly, administration of CWP to diabetic dams substantially restored the expression of ATF-3 and the levels of ROS, pro-inflammatory cytokines, IL-2, and IL-7 in the offspring. Furthermore, the chemotaxis of B- and T-lymphocytes toward CCL21 and CXCL12 and the proliferative capacities of these lymphocytes were restored in the male offspring of diabetic mice administered CWP. Our data provide evidence of a protective role of CWP in decreasing the tendency of the offspring of diabetic mothers to develop diabetes and related complications.
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Navas-Madroñal, Miquel, Cristina Rodriguez, Modar Kassan, Joan Fité, José R. Escudero, Laia Cañes, José Martínez-González, Mercedes Camacho, and María Galán. "Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm." Clinical Science 133, no. 13 (July 2019): 1421–38. http://dx.doi.org/10.1042/cs20190399.
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Abstract Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of cardiovascular diseases (CVDs), although their contribution to AAA development is uncertain. Therefore, we aimed to determine their implication in AAA and investigated the profile of oxysterols in plasma, specifically 7-ketocholesterol (7-KC), as an ER stress inducer. In the present study, we determined aortic ER stress activation in a large cohort of AAA patients compared with healthy donors. Higher gene expression of activating transcription factor (ATF) 6 (ATF6), IRE-1, X-binding protein 1 (XBP-1), C/EBP-homologous protein (CHOP), CRELD2 and suppressor/enhancer of Lin-12-like (SEL1L) and greater protein levels of active ATF6, active XBP1 and of the pro-apoptotic protein CHOP were detected in human aneurysmatic samples. This was accompanied by an exacerbated apoptosis, higher reactive oxygen species (ROS) production and by a reduction in mitochondrial biogenesis in the vascular wall of AAA. The quantification of oxysterols, performed by liquid chromatography-(atmospheric pressure chemical ionization (APCI))-mass spectrometry, showed that levels of 7-KC were significantly higher while those of 7α-hydroxycholesterol (HC), 24-HC and 27-HC were lower in AAA patients compared with healthy donors. Interestingly, the levels of 7-KC correlate with the expression of ER stress markers. Our results evidence an induction of ER stress in the vascular wall of AAA patients associated with an increase in circulating 7-KC levels and a reduction in mitochondrial biogenesis suggesting their implication in the pathophysiology of this disease.
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Lim, Chunghun, Hekwang Sohn, Yousang Gwack, and Joonho Choe. "Latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity." Journal of General Virology 81, no. 11 (November 1, 2000): 2645–52. http://dx.doi.org/10.1099/0022-1317-81-11-2645.
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Latency-associated nuclear antigen (LANA), encoded by ORF 73 of Kaposi’s sarcoma-associated herpesvirus (KSHV; human herpesvirus-8), may play an important role in the persistence of the viral episome by tethering it to host chromosomes during mitosis. It also has been suggested from its amino acid sequence features that LANA may have transcription-regulatory activity. Here, it is reported that LANA interacts with activating transcription factor (ATF) 4/cAMP response element-binding protein (CREB) 2, a member of the ATF/CREB family of transcription factors, and represses the transcriptional activation activity of ATF4/CREB2. Repression by LANA is independent of the DNA-binding ability of ATF4/CREB2, since LANA also represses transactivation of ATF4/CREB2 fused to the GAL4 DNA-binding domain and does not affect the DNA-binding ability of ATF4/CREB2 in an electrophoretic mobility shift assay. The putative leucine zipper domain of LANA is required for binding to the relatively conserved basic region/leucine zipper domain (bZIP) of ATF4/CREB2, suggesting that the interaction may involve leucine zipper dimerization.
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STEINMÜLLER, Lars, Giuseppe CIBELLI, Jonathan R. MOLL, Charles VINSON, and Gerald THIEL. "Regulation and composition of activator protein 1 (AP-1) transcription factors controlling collagenase and c-Jun promoter activities." Biochemical Journal 360, no. 3 (December 10, 2001): 599–607. http://dx.doi.org/10.1042/bj3600599.
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The activator protein 1 (AP-1) transcription factor is composed of heterodimers of the Fos/activating transcription factor (ATF) and Jun subfamilies of basic-region leucine-zipper (B-ZIP) proteins. In order to determine the identities of individual B-ZIP proteins in various AP-1 complexes we tested the effect of dominant-negative mutants to the B-ZIP proteins c-Fos, ATF2, ATF4 and CCAAT-enhancer-binding protein (C/EBP) on the activities of the collagenase and c-Jun promoters. These dominant-negative mutants inhibit DNA binding of wild-type B-ZIP proteins in a leucine-zipper-dependent fashion. Transcription of a collagenase promoter/reporter gene was induced in HepG2 hepatoma cells by expression of c-Fos and c-Jun, administration of PMA (‘TPA’) or by expression of a truncated form of MEK (mitogen-activated/extracellular-signal-regulated kinase kinase) kinase-1, MEKK1Δ. In all cases, the dominant-negative mutants A-Fos and A-ATF2 decreased collagenase promoter activity. However, A-ATF4 and A-C/EBP had no effect. A-Fos and A-ATF2 also reduced MEKK1Δ-induced stimulation of the c-Jun promoter. In contrast, constitutive c-Jun promoter activity was blocked solely by A-ATF2, strongly suggesting that ATF2 and/or an ATF2-dimerizing protein are of major importance for c-Jun transcription in unstimulated cells. These results demonstrate that AP-1 transcription factors of different compositions control c-jun gene transcription in resting or stimulated cells.
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Stutzmann, F., M. Ghoussaini, C. Couturier, V. Vatin, L. Corset, C. Lecoeur, B. Balkau, et al. "O21 Des mutations du facteur de transcription hypothalamique SIM1 sont responsables d’obésité sévère monogénique de l’enfant." Diabetes & Metabolism 35 (March 2009): A6. http://dx.doi.org/10.1016/s1262-3636(09)71713-6.
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Ebert, Scott M., Steven A. Bullard, Nathan Basisty, George R. Marcotte, Zachary P. Skopec, Jason M. Dierdorff, Asma Al-Zougbi, et al. "Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ." Journal of Biological Chemistry 295, no. 9 (January 17, 2020): 2787–803. http://dx.doi.org/10.1074/jbc.ra119.012095.
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Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP transcription factors are obligate dimers, and because ATF4 is unable to form highly-stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by forming a heterodimer with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo. Interestingly, we found that ATF4 forms at least five distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. Furthermore, one of these heterodimers, composed of ATF4 and CCAAT enhancer-binding protein β (C/EBPβ), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4–C/EBPβ heterodimer interacts with a previously unrecognized and evolutionarily conserved ATF–C/EBP composite site in exon 4 of the Gadd45a gene. This three-way interaction between ATF4, C/EBPβ, and the ATF–C/EBP composite site activates the Gadd45a gene, which encodes a critical mediator of muscle atrophy. Together, these results identify a biochemical mechanism by which ATF4 induces skeletal muscle atrophy, providing molecular-level insights into the etiology of skeletal muscle atrophy.