CHOP-dependent Regulation of p21/waf1 During ER Stress

Mihailidou, Chrysovalantou; Papazian, Irene; Papavassiliou, Athanasios G.; Kiaris, Hippokratis

doi:10.1159/000315096

Cited by 59 publications

(60 citation statements)

References 20 publications

(28 reference statements)

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“…2B, lane 8). CHOP induces apoptosis in part by downregulating p21 (36). Consistent with this finding, we also observed a decrease of p21 protein level in cells that were depleted of p97 or overexpressed the ATPase-inactive mutant (Fig.…”

Section: Resultssupporting

confidence: 89%

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

Chou

Brown²,

Minond³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

289

350

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A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen. N 2 ,N 4 -dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor. DBeQ 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, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy.apoptosis | autophagy | unfolded protein response T he AAA (ATPase associated with diverse cellular activities) ATPase p97 is conserved across all eukaryotes and is essential for life in budding yeast (1) and mice (2). p97 was first linked to the ubiquitin-proteasome system (UPS) through its role in the turnover of ubiquitin−β-galactosidase fusion proteins via the "ubiquitin fusion degradation" (UFD) pathway (3). Since then, p97 has been shown to play a critical role in the degradation of misfolded membrane and secretory proteins (4) and has also been linked to a broad array of cellular processes, including Golgi membrane reassembly (5), membrane transport (6), regulation of myofibril assembly (7), cell division (8), formation of protein aggregates (9), and autophagosome maturation (10, 11). The broad range of cellular functions for p97 is thought to derive from its ability to unfold proteins or disassemble protein complexes, but the detailed mechanism of how p97 works and is linked to specific cellular processes remains largely unknown.The structure of p97 comprises three domains: an N-terminal domain that recruits adaptors/substrate specificity factors, followed by two ATPase domains, D1 and D2 (12, 13). p97 monomers assemble to form a homohexamer that is thought to provide a platform for transduction of chemical activity into mechanical force that is applied to substrate proteins. The D1 domain mediates hexamerization (14) and has very low ATPase activity (15). Most of the ATPase activity is contributed by the D2 domain, which is thought to underlie p97's function as a mechanochemical transducer (16).The mechanochemical activity of p97 is linked to substrate proteins by an array of 13 UBX (ubiquitin regulatory X) domain adapters that bind the N-terminal domain of p97 (17), as well as the non-UBX domain adaptors Ufd1 and Npl4 (18). The functions and mechanisms of action of these different p97-adaptor complexes remain poorly u...

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Section: Resultssupporting

confidence: 89%

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

Chou

Brown²,

Minond³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

289

350

View full text Add to dashboard Cite

show abstract

“…Is it a novel independent pro-apoptotic pathway, or a previously uncharacterised pleotropic downstream effect of the ATF4-CHOP axis? As it was suggested previously by the same group, the second hypothesis sounds more plausible as p21 expression seems to be governed by CHOP (Mihailidou et al 2010). This was demonstrated by the absence of p21 downregulation in the tunicamycin-induced CHOP KO mice and also by the drop in p21 mRNA and protein levels in the CHOP-transfected lung cancer cells.…”

mentioning

confidence: 60%

Targeting unfolded protein response in cancer and diabetes

Mkrtchian

2015

Endocrine-Related Cancer

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The maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is tightly regulated by the unfolded protein response (UPR), a signal transduction pathway maintaining ER protein folding homeostasis. However, certain ER states are incompatible with cell survival and therefore the UPR may choose to eliminate severely disrupted cells by apoptosis. This is accomplished primarily through the activation of the transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP). In the April 2015 issue of Endocrine-Related Cancer, researchers from the universities of South Carolina and Athens (Greece) suggested a novel mechanism of CHOP-mediated apoptosis connected with the suppression of a prominent cell cycle regulator with anti-apoptotic activity, p21. These findings and suggested clinical applications, such as potentiation of cancer chemotherapy and a novel therapeutic approach for type 2 diabetes, are discussed in the context of UPR.

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“…Consistent with this notion, during its earlier stages the UPR is pro-survival while at subsequent stages it becomes pro-apoptotic (Ron & Walter 2011). Results of previous studies at our laboratory indicated that an inverse correlation between the activation of the UPR and the expression of P21 exists (Mihailidou et al 2010). P21 is a cell-cycle regulator with strong anti-apoptotic activity produced by both cellautonomous and non-cell-autonomous mechanisms (Blagosklonny 2002, Roninson 2002, Weiss 2003, Trimis et al 2008.…”

Section: Introductionmentioning

confidence: 94%

Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress

Mihailidou¹,

Chatzistamou²,

Papavassiliou³

et al. 2015

Endocrine-Related Cancer

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Tunicamycin (TUN), an inhibitor of protein glycosylation and therefore a potent stimulator of endoplasmic reticulum (ER) stress, has been used to improve anticancer drug efficacy, but the underlying mechanism remains obscure. In this study, we show that acute administration of TUN in mice induces the unfolded protein response and suppresses the levels of P21, a cell cycle regulator with anti-apoptotic activity. The inhibition of P21 after ER stress appears to be C/EBP homologous protein (CHOP)-dependent because in CHOP-deficient mice, TUN not only failed to suppress, but rather induced the expression of P21. Results of promoter-activity reporter assays using human cancer cells and mouse fibroblasts indicated that the regulation of P21 by CHOP operates at the level of transcription and involves direct binding of CHOP transcription factor to the P21 promoter. The results of cell viability and clonogenic assays indicate that ER-stress-related suppression of P21 expression potentiates caspase activation and sensitizes cells to doxorubicin treatment, while administration of TUN to mice increases the therapeutic efficacy of anticancer therapy for HepG2 liver and A549 lung cancers.

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CHOP-dependent Regulation of p21/waf1 During ER Stress

Cited by 59 publications

References 20 publications

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

Targeting unfolded protein response in cancer and diabetes

Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress

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