CHOP-dependent regulation of p21/waf1 during ER stress.
TLDR
It is shown that tunicamycin, an antibiotic promoting ER stress, suppresses the expression of p21, a tumor suppressor that induces cell cycle arrest and inhibits apoptosis and is consistent with a CHOP-dependent role for p21 in the shift from the pro-survival to thePro-apoptotic function of UPR.Abstract:
The transcription factor CHOP/GADD153 is induced during the unfolded protein response (UPR) and is associated to the induction of ER stress-related apoptosis. However, how the transition between the pro-survival and the pro-apoptotic role of ER stress is being orchestrated remains poorly understood. Here we show that tunicamycin, an antibiotic promoting ER stress, suppresses the expression of p21, a tumor suppressor that induces cell cycle arrest and inhibits apoptosis. This suppression of p21 levels was independent of p53 that is the major transcriptional regulator of p21, but could be reproduced by forced expression of CHOP. Consistently with these findings, siRNA-mediated inhibition of p21 levels restored the sensitivity of CHOP-deficient cells to tunicamycin. Our findings are consistent with a CHOP-dependent role for p21 in the shift from the pro-survival to the pro-apoptotic function of UPR.read more
Citations
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The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress.
TL;DR: Advancing molecular insight into the transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER stress may provide answers on how to overcome the limitations of current anti-tumor therapies.
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Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways
Tsui-Fen Chou,Steve J. Brown,Dmitriy Minond,Brian E. Nordin,Kelin Li,Amanda C. Jones,Peter Chase,Patrick Porubsky,Brian M. Stoltz,Frank J. Schoenen,Matthew P. Patricelli,Peter Hodder,Hugh Rosen,Raymond J. Deshaies +13 more
TL;DR: N2,N4-Dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor that blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters.
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Cadmium and cellular signaling cascades: interactions between cell death and survival pathways.
Frank Thévenod,Wing-Kee Lee +1 more
TL;DR: This review critically surveys recent literature to outline major features of death and survival signaling pathways as well as their activation, interactions and cross talk in cells exposed to Cd2+.
Journal ArticleDOI
Distinct Cytoplasmic and Nuclear Functions of the Stress Induced Protein DDIT3/CHOP/GADD153
Alexandra Jauhiainen,Christer Thomsen,Linda Strömbom,Pernilla Grundevik,Carola Andersson,Anna Danielsson,Mattias K Andersson,Olle Nerman,Olle Nerman,Linda Rörkvist,Anders Ståhlberg,Pierre Åman +11 more
TL;DR: Characterization of DDIT3 regulated functions helps understanding its role in stress response and involvement in cancer and degenerative disorders.
Journal ArticleDOI
Safranal induces DNA double-strand breakage and ER-stress-mediated cell death in hepatocellular carcinoma cells.
Ala’a Al-Hrout,Amphun Chaiboonchoe,Basel Khraiwesh,Chandraprabha Murali,Badriya Baig,Raafat El-Awady,Hamadeh Tarazi,Amnah Alzahmi,David R. Nelson,Yaser E. Greish,Wafaa S. Ramadan,Kourosh Salehi-Ashtiani,Amr Amin,Amr Amin +13 more
TL;DR: Gene set enrichment analysis provided consistent findings where UPR is among the top terms of up-regulated genes in response to safranal treatment, indicating proteins involved in ER stress were regulated through safranals treatment to induce UPR in HepG2 cells.
References
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Journal ArticleDOI
WAF1, a potential mediator of p53 tumor suppression
Wafik S. El-Deiry,Takashi Tokino,Victor E. Velculescu,Daniel B. Levy,Ramon Parsons,Jeffrey M. Trent,D Lin,W. Edward Mercer,Kenneth W. Kinzler,Bert Vogelstein +9 more
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
Journal ArticleDOI
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases
TL;DR: In this article, an improved two-hybrid system was employed to isolate human genes encoding Cdk-interacting proteins (Cips) and found that CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2.
Journal ArticleDOI
In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
Lyubomir T. Vassilev,Binh Thanh Vu,Bradford Graves,Daisy Carvajal,Frank John Podlaski,Zoran Filipovic,Norman Kong,Ursula Kammlott,Christine Lukacs,Christian Klein,Nader Fotouhi,Liu Emily Aijun +11 more
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
Journal ArticleDOI
Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response
Anne Bertolotti,Yuhong Zhang,Linda M. Hendershot,Linda M. Hendershot,Heather P. Harding,David Ron +5 more
TL;DR: In this article, the lumenal domains of transmembrane protein kinases (PERK and IRE1) were found to be functionally interchangeable in mediating an ER stress response and that in unstressed cells, both L1 and L2 domains formed a stable complex with the ER chaperone BiP.
Dynamic interaction of BiP and ER stress transducers in the unfolded
TL;DR: It is shown that the lumenal domains of these two proteins are functionally interchangeable in mediating an ER stress response and that, in unstressed cells, both lumenAL domains form a stable complex with the ER chaperone BiP.
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