scholarly journals Dynamic recruitment of transcription factors and epigenetic changes on the ER stress response gene promoters

2006 ◽  
Vol 34 (10) ◽  
pp. 3116-3127 ◽  
Author(s):  
G. Donati
Keyword(s):  
Transcription Factors ◽  
Stress Response ◽  
Er Stress ◽  
Gene Promoters ◽  
Epigenetic Changes ◽  
Response Gene ◽  
Er Stress Response ◽  
Stress Response Gene

Abstract 211: ATF6 and the Adaptive ER Stress Response Enhances Proliferation and Viability in Mouse Cardiac Stem Cells

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Winston T Stauffer ◽  
Shirin Doroudgar ◽  
Haley N Stephens ◽  
Brandi Bailey ◽  
Christopher C Glembotski
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stress Response ◽  
Er Stress ◽  
Ischemic Heart ◽  
Cardiac Stem Cells ◽  
Response Gene ◽  
Er Stress Response ◽  
Chemical Inhibition ◽  
Stress Response Gene

Rationale: Cardiac stem cells (CSCs) are beneficial when administered to infarcted mouse or rat hearts. Though the mechanism of these benefits is unknown, CSC vitality likely plays a major role. Thus, investigating the factors governing CSC survival in the ischemic heart may lead to more effective therapeutic strategies. Our previous studies showed that misfolded proteins accumulate in the sarco/endoplasmic reticulum (SR/ER) of the ischemic heart. The transcription factor, ATF6, is a key component of the adaptive ER stress response because it induces genes that reduce the accumulation of misfolded proteins, improving myocyte survival during ischemic stress. While our lab has shown that, in cardiac myocytes, ATF6 is cardioprotective in the ischemic heart, neither the ER stress response nor ATF6 have been examined in CSCs. We hypothesize that ATF6 and the adaptive ER stress response are critical for optimal survival of CSCs. Objective/Methods: To gauge the relevance of the ER stress response in CSCs, we used MTT assays to compare the viabilities of mouse CSCs to neonatal rat ventricular myocytes (NRVM) subjected to treatments that mimic ischemic ER stress in the heart. We also assessed the effect of inhibiting ATF6 on both the ER stress response and CSC viability by using chemical inhibition of ATF6 activation or siRNA-mediated ATF6 knock down. Results: We found that, compared to NRVM, CSCs exhibited lower levels of adaptive ER stress response gene expression and decreased viability in response to ER stress. Thus, relative to NRVM, the adaptive ER stress response is not fully developed in CSCs. We also found that either chemical inhibition of ATF6 activation or ATF6 knock down decreased adaptive ER stress response gene expression. Strikingly, ATF6 inhibition or knockdown decreased CSC viability and cell number by as much as 70%. Conclusions: Thus, compared to cardiac myocytes, CSCs exhibit a reduced adaptive ER stress response and are more sensitive to ER stress, suggesting that enhancement of the ATF6-mediated adaptive ER stress response in CSCs may be a viable therapeutic approach for enhancing stem cell-mediated myocardial repair.

scholarly journals Induction of Endoplasmic Reticulum-induced Stress Genes in Panc-1 Pancreatic Cancer Cells Is Dependent on Sp Proteins

2005 ◽  
Vol 280 (16) ◽  
pp. 16508-16513 ◽  
Author(s):  
Maen Abdelrahim ◽  
Shengxi Liu ◽  
Stephen Safe
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Transcription Factors ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Gene Promoters ◽  
Er Stress Response ◽  
Pancreatic Cancer Cells ◽  
Pharmacologically Active

Endoplasmic reticulum (ER) stress plays a critical role in multiple diseases, and pharmacologically active drugs can induce cell death through ER stress pathways. Stress-induced genes are activated through assembly of transcription factors on ER stress response elements (ERSEs) in target gene promoters. Gel mobility shift and chromatin immunoprecipitation assays have confirmed interactions of NF-Y and YY1 with the distal motifs of the tripartite ERSE from the glucose-related protein 78 (GRP78) gene promoter. The GC-rich nonanucleotide (N9) sequence, which forms the ER stress response binding factor (ERSF) complex binds TFII-I and ATF6; however, we have now shown that in Panc-1 pancreatic cancer cells, this complex also binds Sp1, Sp3, and Sp4 proteins. Sp proteins are constitutively bound to the ERSE; however, activation of GRP78 protein (or reporter gene) by thapsigargin or tunicamycin is inhibited after cotransfection with small inhibitory RNAs for Sp1, Sp3, and Sp4. This study demonstrates that Sp transcription factors are important for stress-induced responses through their binding to ERSEs.

scholarly journals Transcriptional regulation of mouse mesencephalic astrocyte-derived neurotrophic factor in Neuro2a cells

2013 ◽  
Vol 18 (3) ◽  
Author(s):  
Kentaro Oh-Hashi ◽  
Yoko Hirata ◽  
Kazutoshi Kiuchi
Keyword(s):  
Transcription Factors ◽  
Stress Response ◽  
Er Stress ◽  
Neurotrophic Factor ◽  
Promoter Activity ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Er Stress Response ◽  
Neuro2a Cells ◽  
Flanking Region

AbstractMesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel type of trophic factor. Recent studies indicate that the MANF gene is induced in response to endoplasmic reticulum (ER) stress through ER stress response element II (ERSE-II) in its 5′-flanking region. In this study, we evaluated the roles of six ER stress response transcription factors in the regulation of the promoter activities of the mouse MANF gene via ERSE-II using various types of mutant MANF luciferase reporter constructs. Treatment with thapsigargin (Tg) induced MANF mRNA generation in parallel with the elevation of ATF6α, sXBP and Luman mRNA levels in Neuro2a cells. Of the six transcription factors, ATF6β most strongly increased the MANF promoter activity via ERSE-II, while the effects of ATF6β and sXBP1 were moderate. However, overexpression of Luman or OASIS did not enhance ERSE-II-dependent MANF promoter activity in Neuro2a cells. To evaluate the relationships between transcription factors in the regulation of ERSE-II-dependent MANF promoter activity, we transfected two effective transcription factor constructs chosen from ATF6α, ATF6β, uXBP1 and sXBP1 into Neuro2a cells with the MANF reporter construct. The MANF promoter activity induced by co-transfection of ATF6α with ATF6β was significantly lower than that induced by ATF6α alone, while other combinations did not show any effect on the ERSE-II-dependent MANF promoter activity in Neuro2a cells. Our study is the first to show the efficiency of ER stress-related transcription factors for ERSE-II in activating the transcription of the mouse MANF gene in Neuro2a cells.

scholarly journals Endoplasmic Reticulum Stress-Induced Formation of Transcription Factor Complex ERSF Including NF-Y (CBF) and Activating Transcription Factors 6α and 6β That Activates the Mammalian Unfolded Protein Response

2001 ◽  
Vol 21 (4) ◽  
pp. 1239-1248 ◽  
Author(s):  
Hiderou Yoshida ◽  
Tetsuya Okada ◽  
Kyosuke Haze ◽  
Hideki Yanagi ◽  
Takashi Yura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factors ◽  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Consensus Sequence ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Protein Response ◽  
Transcriptional Induction

ABSTRACT The levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) are controlled by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element (ERSE), the consensus sequence of which is CCAAT-N9-CCACG. We recently proposed that ER stress response factor (ERSF) binding to ERSE is a heterologous protein complex consisting of the constitutive component NF-Y (CBF) binding to CCAAT and an inducible component binding to CCACG and identified the basic leucine zipper-type transcription factors ATF6α and ATF6β as inducible components of ERSF. ATF6α and ATF6β produced by ER stress-induced proteolysis bind to CCACG only when CCAAT is bound to NF-Y, a heterotrimer consisting of NF-YA, NF-YB, and NF-YC. Interestingly, the NF-Y and ATF6 binding sites must be separated by a spacer of 9 bp. We describe here the basis for this strict requirement by demonstrating that both ATF6α and ATF6β physically interact with NF-Y trimer via direct binding to the NF-YC subunit. ATF6α and ATF6β bind to the ERSE as a homo- or heterodimer. Furthermore, we showed that ERSF including NF-Y and ATF6α and/or β and capable of binding to ERSE is indeed formed when the cellular UPR is activated. We concluded that ATF6 homo- or heterodimers recognize and bind directly to both the DNA and adjacent protein NF-Y and that this complex formation process is essential for transcriptional induction of ER chaperones.

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