Serum levels of RBP4 and adipose tissue levels of PTP1B are increased in obese men resident in northeast Scotland without associated changes in ER stress response genes

103 Background: ER stress, triggered by the disruption of intracellular protein homeostasis, promotes the activation of a highly conserved adaptive program called unfolded protein response (UPR). UPR signaling has been reported to contribute to tumor initiation and progression, as well as microenvironment remodeling and chemoresistance in multiple cancer types, including CRC. Several studies point to a direct role of the UPR in tumor angiogenesis and an interaction with EGFR signaling. We therefore hypothesized that genetic variants in ER stress response genes may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 17 functional SNPs in 8 core genes of the ER stress response pathway ( IRE1, PERK, ATF6, XBP1, CHOP, GRP78, GADD34, ATF4) was analyzed on a total of 560 pts enrolled in two independent randomized first-line trials: MAVERICC (FOLFIRI/bevacizumab, [bev] n = 163; FOLFOX6/bev, n = 161), and FIRE-3 (FOLFIRI/bev, n = 107; FOLFIRI/cetuximab [cet], n = 129). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. The association between SNPs and clinical outcomes was evaluated using Cox regression and log-rank tests. The SNP*treatment interaction was assessed in both trials. Results: IRE1 rs16947383 any T allele variant was associated with shorter progression free survival (PFS) and overall survival (OS) compared to the C/C genotype in pts treated with FOLFIRI/bev in the MAVERICC trial both in uni- and multivariate analysis: 10.5 vs 14.1 months for PFS, adjusted hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.12-2.99, adjusted P-value = 0.02; 23.8 vs 38.4 months for OS, adjusted HR 2.12, 95%CI 1.1-4.09, adjusted P-value = 0.02. The association with OS was validated in the FIRE-3 FOLFIRI/bev arm where any T allele carriers showed significantly shorter OS compared to the C/C genotype in both uni- and multivariate analysis: 21.1 vs 44.2 months, adjusted HR 2.06, 95%CI 1.01-4.18, adjusted P-value = 0.05. This effect was not observed in MAVERICC FOLFOX6 and FIRE-3 cet cohorts. A significant interaction was found between IRE1 rs16947383 and treatment on OS in both trials: P = 0.04 in MAVERICC (FOLFIRI vs FOLFOX6), and P = 0.03 in FIRE-3 (bev vs cet). In the MAVERICC FOLFOX6/bev arm, XBP1 rs2239815 and PERK rs6731022 SNPs were associated with shorter PFS and OS, while GADD34 rs610308 with longer OS, in multivariable analysis ( P < 0.05). Conclusions: Our results provide evidence that germline polymorphisms in ER stress response genes may have a predictive value in mCRC pts receiving first-line bev-based treatment and contribute to modulate anti-VEGF efficacy.

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Abstract 467: ATF6B and ATF6A Play Complimentary Roles in Mediating Adaptive and Maladaptive Signaling in Cardiac Myocytes

Circulation Research ◽

10.1161/res.121.suppl_1.467 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Shivsmriti Koul ◽

Jung-kang Jin ◽

Clifford M Hogan ◽

Christopher C Glembotski

Keyword(s):

Cell Death ◽

Heart Disease ◽

Stress Response ◽

Ischemic Heart Disease ◽

Er Stress ◽

Ischemic Heart ◽

Neonatal Rat ◽

Loss Of Function ◽

Er Stress Response ◽

Stress Response Genes

Rationale: ATF6α and ATF6β are endoplasmic reticulum (ER) transmembrane proteins that sense the accumulation of toxic misfolded proteins in the ER of cardiomyocytes, which can be brought about by ER stresses as ischemia. Upon ER stress, ATF6α is proteolytically cleaved into a transcription factor that binds to ER stress response elements (ERSEs) and increases expression of cardioprotective genes that restore ER protein folding. If ER proteostasis is not restored, maladaptive signaling is initiated. ATF6β is also proteolytically cleaved during ER stress, binds to the same ERSEs as ATF6α, but does not induce transcription. Hence it is clear from the above studies done in cancer cells that there are some marked similarities and differences between ATF6α and ATF6β. However, the relative roles of ATF6α and ATF6β have not been studied in the heart, where they might work in concert to mediate the dynamic switch from adaptive to maladaptive gene programing during myocardial pathology. Methods: We used neonatal rat ventricular myocytes (NRVMs) to explore the effects of ATF6α or ATF6β loss-of-function in cells treated with the ER stressor, thapsigargin (TG), which mimics ischemic heart disease. Results: In NRVM treated with TG, knockdown of ATF6β resulted in much more pronounced cell death in isolated myocytes than knockdown of ATF6α. Consistent with this finding, transcriptome analyses showed that compared to knocking down ATF6α, knockdown of ATF6β upregulated much more maladaptive, cell death-inducing genes and downregulated more cardioprotective genes. Surprisingly, knockdown of either ATF6α or ATF6β downregulated some common adaptive ER stress response genes, such as GRP78 and Derlin while also upregulating common maladaptive ER stress response genes, such as CHOP, Bcl2, Bax. Conclusion: These data indicate that both ATF6α and ATF6 β are needed for optimal viability of NRVM subjected to ER stress. There is a common, as well as differential gene regulation program controlled by these two isoforms of ATF6. Importantly, this study demonstrates a novel mechanism by which these two isoforms of ATF6 interact to govern the progression from adaptive to maladaptive ER stress signaling during chronic misfolding of ER proteins that occurs in ischemic heart disease.

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Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells

Oncogene ◽

10.1038/sj.onc.1205992 ◽

2002 ◽

Vol 21 (57) ◽

pp. 8749-8758 ◽

Cited By ~ 93

Author(s):

Takehiko Segawa ◽

Martin E Nau ◽

Linda L Xu ◽

Rao N Chilukuri ◽

Mazen Makarem ◽

...

Keyword(s):

Prostate Cancer ◽

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Cancer Cells ◽

Prostate Cancer Cells ◽

Induced Expression ◽

Er Stress Response ◽

Stress Response Genes

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Elongin functions as a loading factor for Mediator at ATF6α-regulated ER stress response genes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2108751118 ◽

2021 ◽

Vol 118 (39) ◽

pp. e2108751118

Author(s):

Yanfeng He ◽

Shigeo Sato ◽

Chieri Tomomori-Sato ◽

Shiyuan Chen ◽

Zach H. Goode ◽

...

Keyword(s):

Transcription Factor ◽

Stress Response ◽

Er Stress ◽

Rna Polymerase Ii ◽

Transcription Activation ◽

Bzip Transcription Factor ◽

Er Stress Response ◽

Stress Response Genes ◽

Biochemical Studies ◽

Rna Polymerase Ii Transcription

The bZIP transcription factor ATF6α is a master regulator of endoplasmic reticulum (ER) stress response genes. In this report, we identify the multifunctional RNA polymerase II transcription factor Elongin as a cofactor for ATF6α-dependent transcription activation. Biochemical studies reveal that Elongin functions at least in part by facilitating ATF6α-dependent loading of Mediator at the promoters and enhancers of ER stress response genes. Depletion of Elongin from cells leads to impaired transcription of ER stress response genes and to defects in the recruitment of Mediator and its CDK8 kinase subunit. Taken together, these findings bring to light a role for Elongin as a loading factor for Mediator during the ER stress response.

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Faculty Opinions recommendation of Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4958956.4891054 ◽

2010 ◽

Author(s):

Ji-Zeng Du ◽

Yang Zhao ◽

Xue-Qun Chen

Keyword(s):

Stress Response ◽

Er Stress ◽

Response Regulators ◽

Er Stress Response

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Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in Mice

Cellular and Molecular Gastroenterology and Hepatology ◽

10.1016/j.jcmgh.2020.11.006 ◽

2020 ◽

Author(s):

John P. Kennelly ◽

Stephanie Carlin ◽

Tingting Ju ◽

Jelske N. van der Veen ◽

Randal C. Nelson ◽

...

Keyword(s):

Stress Response ◽

Er Stress ◽

Goblet Cell ◽

Er Stress Response

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Targeted regulation of lymphocytic ER stress response with an overall immunosuppression to alleviate allograft rejection

Biomaterials ◽

10.1016/j.biomaterials.2021.120757 ◽

2021 ◽

pp. 120757

Author(s):

Yingying Shi ◽

Yichao Lu ◽

Chunqi Zhu ◽

Zhenyu Luo ◽

Xiang Li ◽

...

Keyword(s):

Stress Response ◽

Er Stress ◽

Allograft Rejection ◽

Er Stress Response

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Highly Specialized Ubiquitin-Like Modifications: Shedding Light into the UFM1 Enigma

Biomolecules ◽

10.3390/biom11020255 ◽

2021 ◽

Vol 11 (2) ◽

pp. 255

Author(s):

Katharina F. Witting ◽

Monique P.C. Mulder

Keyword(s):

Dna Repair ◽

Stress Response ◽

Embryonic Development ◽

Er Stress ◽

Unmet Needs ◽

Biological Function ◽

Post Translational Modification ◽

Er Stress Response ◽

Cellular Events ◽

Complex Signaling

Post-translational modification with Ubiquitin-like proteins represents a complex signaling language regulating virtually every cellular process. Among these post-translational modifiers is Ubiquitin-fold modifier (UFM1), which is covalently attached to its substrates through the orchestrated action of a dedicated enzymatic cascade. Originally identified to be involved embryonic development, its biological function remains enigmatic. Recent research reveals that UFM1 regulates a variety of cellular events ranging from DNA repair to autophagy and ER stress response implicating its involvement in a variety of diseases. Given the contribution of UFM1 to numerous pathologies, the enzymes of the UFM1 cascade represent attractive targets for pharmacological inhibition. Here we discuss the current understanding of this cryptic post-translational modification especially its contribution to disease as well as expand on the unmet needs of developing chemical and biochemical tools to dissect its role.

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Abstract 292: The Role of the ATF6 Branch of the ER Stress Response in the Endocrine Heart

Circulation Research ◽

10.1161/res.119.suppl_1.292 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Erik A Blackwood ◽

Christopher C Glembotski

Keyword(s):

Stress Response ◽

Er Stress ◽

Knockout Mice ◽

Ex Vivo ◽

Proteolytic Cleavage ◽

Isolated Perfused Heart ◽

Wild Type ◽

Atrial Myocytes ◽

Perfused Heart ◽

Er Stress Response

Rationale: Atrial natriuretic peptide (ANP) is stored in the heart in large dense core granules of atrial myocytes as a biologically inactive precursor, pro-ANP. Hemodynamic stress and atrial stretch stimulate coordinate secretion and proteolytic cleavage of pro-ANP to its bioactive form, ANP, which promotes renal salt excretion and vasodilation, which, together contribute to decreasing blood pressure. While the ATF6 branch of the ER stress response has been studied in ventricular tissue mouse models of myocardial ischemia and pathological hypertrophy, roles for ATF6 and ER stress on the endocrine function of atrial myocytes have not been studied. Objective/Methods: To address this gap in our knowledge, we knocked down ATF6 in primary cultured neonatal rat atrial myocytes (NRAMs) using a chemical inhibitor of the proteolytic cleavage site enabling ATF6 activation and siRNA and measured ANP expression and secretion basally and in response to alpha- adrenergic agonist stimulation using phenylephrine. We also compared the ANP secretion from wild- type mice and ATF6 knockout mice in an ex vivo Langendorff model of the isolated perfused heart. Results: ATF6 knockdown in NRAMs significantly impaired basal and phenylephrine-stimulated ANP secretion. ATF6 knockout mice displayed lower levels of ANP in atrial tissue at baseline as well as after phenylephrine treatment. Similarly, in the ex vivo isolated perfused heart model, less ANP was detected in effluent of ATF6 knockout hearts compared to wild-type hearts. Conclusions: The ATF6 branch of the ER stress response is necessary for efficient co-secretional processing of pro-ANP to ANP and for agonist-stimulated ANP secretion from atrial myocytes. As ANP is secreted in a regulated manner in response to a stimulus and pro-ANP is synthesized and packaged through the classical secretory pathway, we posit that ATF6 is required for adequate expression, folding, trafficking, processing and secretion of biologically active ANP from the endocrine heart.

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