scholarly journals UBC9 Regulates the Stability of XBP1, a Key Transcription Factor Controlling the ER Stress Response

2013 ◽  
pp. 67-79 ◽  
Author(s):  
Aya Uemura ◽  
Mai Taniguchi ◽  
Yusaku Matsuo ◽  
Masaya Oku ◽  
Sadao Wakabayashi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Er Stress ◽  
Er Stress Response ◽  
The Stability

Facilitation of Osteoblast Differentiation by ATF-4 Accumulation through Proteasome Inhibition.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1823-1823
Author(s):  
Shingen Nakamura ◽  
Masahiro Abe ◽  
Qu Cui ◽  
Ayako Nakano ◽  
Asuka Oda ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Cell Growth ◽  
Bone Formation ◽  
Er Stress ◽  
Proteasome Inhibition ◽  
Bone Lesions ◽  
Protein Levels ◽  
Er Stress Response ◽  
Bortezomib Treatment

Abstract Abstract 1823 Poster Board I-849 The proteasome inhibitor bortezomib, a novel anti-myeloma (MM) agent, has recently drawn considerable attention to its anabolic actions on bone formation in patients with MM. Bortezomib was reported to enhance the activity of Runx2/cbfa1, an essential transcription factor for osteoblast (OB) induction, in mesenchymal stem cells to induce OB differentiation. However, because over-expression of Runx2 unexpectedly suppresses terminal OB differentiation or mineralization, there may be critical factors involved in OB differentiation in concert with Runx2 to achieve terminal OB differentiation in the treatment with bortezomib. Proteasome inhibition accumulates a variety of proteins and induces ER stress or unfolded protein response. Among proteins induced by ER stress, activating transcription factor-4 (ATF-4) plays a critical role in OB differentiation. ATF-4 is expressed in osteoprogenitors and preOBs following Runx2, and acts in concert with Runx2 to facilitate terminal maturation of OBs. However, it is unknown whether a change in ATF-4 protein levels plays any role in OB differentiation induced by proteasome inhibition. In the present study, we therefore explored the role of ATF-4 in OB differentiation by proteasome inhibition in Runx2-expressing immature OB lineage cells. Bortezomib dose-dependently increased ATF-4 protein levels in primary bone marrow stromal cells and ST-2 stromal and MC3T3-E1 preosteoblastic cell lines at concentrations higher than 10 nM as early as 3 hours. Because serum bortezomib levels reach around 100 nM (Cmax) with T1/2 of 3 hours after iv injection at therapeutic doses, bortezomib treatment in MM patients is expected to enhance ATF-4 protein levels in OB lineage cells. Interestingly, bortezomib treatment did not change mRNA levels of ATF-4 as well as βTrCP1, E3 ligase for ATF-4. Because translation of ATF-4 mRNA is triggered by ER stress response, it is plausible that the ATF-4 accumulation by bortezomib is mediated by the suppression of proteasomal degradation with subsequent induction of ER stress response. MM cell-derived factors and TGF-β released from bone by enhanced bone resorption suppress OB differentiation in MM bone lesions. Treatment with bortezomib was able to accumulate ATF-4 in the presence of MM conditioned media (CM) or TGF-β to the levels similar to those without MM CM nor TGF-β. Furthermore, bortezomib enhanced promotor activity of osteocalcin, a marker of mature OBs, as well as BMP-2-induced mineralized nodule formation in MC3T3-E1 cells, and these effects of bortezomib were suppressed by ATF-4 siRNA. These results demonstrate that bortezomib treatment accumulate ATF-4, and suggest that the effect of bortezomib on OB differentiation is mediated via an accumulation of ATF-4 protein in OB lineage cells. We have previously demonstrated that OB differentiation is suppressed in MM bone lesions, and that differentiated OBs suppress MM cell growth and survival. Thus, resumption of bone formation by bortezomib may further suppress MM cell growth in concert with its direct anti-MM actions. Disclosures No relevant conflicts of interest to declare.

Abstract 257: Endogenous Activating Transcription Factor 6 Preserves Heart Structure and Function in a Mouse Model of Myocardial Infarction-induced Heart Failure

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Winston T Stauffer ◽  
Khalid Azizi ◽  
Erik A Blackwood ◽  
Randal J Kaufman ◽  
Christopher C Glembotski
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Transcription Factor ◽  
Stress Response ◽  
Er Stress ◽  
Heart Function ◽  
Structure And Function ◽  
Er Stress Response ◽  
Activating Transcription Factor ◽  
And Function

Rationale: The ER stress response is activated by the accumulation of misfolded, toxic proteins in the endoplasmic reticulum (ER), and upregulates proteins that restore ER protein-folding capacity. The ER-transmembrane protein, activating transcription factor 6 (ATF6) senses ER stress and responds by transcriptionally inducing many of these genes and is thus a key component of the adaptive ER stress response. We previously showed that in the heart, ischemia activates ATF6. Furthermore, transgenic mouse hearts expressing a conditionally activated form of ATF6, and subjected to ex vivo ischemia/reperfusion, exhibited preserved heart function and smaller infarcts. Our lab also showed that by serving as a novel inducer of a global anti-oxidant gene program, endogenous ATF6 limits cardiac damage caused by reactive oxygen species during reperfusion. However, the effect of endogenous ATF6 in the failing heart is not known. Given that acute ischemia caused by occlusion of the coronary arteries is the cause of myocardial infarction (MI), we hypothesized that endogenous ATF6 limits infarct size and preserves heart function during MI. Additionally, since deleterious cardiac remodeling and heart failure can be long-term consequences of MI, we hypothesized that ATF6 can mitigate these effects. Objective/Methods: To examine the role of endogenous ATF6 in heart failure, in vivo, we used a mouse model of MI-induced heart failure in mice with a global deletion of the ATF6 gene (ATF6 KO). Infarct size was measured by TTC staining and heart function was observed via longitudinal echocardiogram. Results: We found that following infarction, ATF6 KO mouse hearts had larger infarcts compared to control. Thus, ischemic cardiac tissue in the peri-infarct region requires ATF6 to limit cardiac myocyte death. Interestingly, ejection fraction following MI decreased more over 13 weeks in ATF6 KO mice relative to control. While control and ATF6 KO mouse hearts hypertrophied to a similar degree, KO mice showed greater cardiac dilation. Conclusions: Together these findings show for the first time that endogenous ATF6 acts to preserve heart structure and function in an MI model of heart failure, suggesting that ATF6 may be a viable therapeutic target for treatment of this disease.

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

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.

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

Biomaterials ◽  
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

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

Biomolecules ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document