Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21CDKN1A

Mlynarczyk, Coraline; Fåhræus, Robin

doi:10.1038/ncomms6067

Cited by 62 publications

(76 citation statements)

References 64 publications

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“…Results from recent studies have provided evidence that the expression of P21 exhibits an inverse correlation with ER-stress induction and CHOP expression ). This result is indicative of a role for this cell cycle regulator in the commitment of the UPR to the adaptive or the proapoptotic program that follows ER stress , Yi et al 2012, Mlynarczyk & Fåhraeus 2014. P21 is a cell cycle regulator that in addition to the inhibition of cell cycle progression also exhibits strong anti-apoptotic activities that can affect the decision about life or death of a cell under conditions associated with genotoxic stress (Blagosklonny 2002, Roninson 2002, Weiss 2003, Trimis et al 2008.…”

Section: Introductionmentioning

confidence: 99%

Regulation of P21 during diabetes-associated stress of the endoplasmic reticulum

Mihailidou

Chatzistamou

Papavassiliou

et al. 2015

Endocrine-Related Cancer

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Endoplasmic reticulum (ER) stress plays a major role in the pathogenesis of diabetes by inducing b-cell apoptosis in the islets of Langerhans. In this study, we show that the transcription factor CHOP, which is instrumental for the induction of ER-stress-associated apoptosis and the pancreatic dysfunction in diabetes, regulates the expression of P21 (WAF1), a cell cycle regulator with anti-apoptotic activity that promotes cell survival. Deficiency of P21 sensitizes pancreatic b-cells to glucotoxicity, while in mice genetic ablation of P21 accelerates experimental diet-induced diabetes, results indicative of a protective role for P21 in the development of the disease. Conversely, pharmacological stimulation of P21 expression by nutlin-3a, an inhibitor of P53-MDM2 interaction, restores pancreatic function and facilitates glucose homeostasis. These findings indicate that P21 acts as an inhibitor of ER-stress-associated tissue damage and that stimulation of P21 activity can be beneficial for the management of diabetes and probably of other conditions in which ER-stress-associated death is undesirable.

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Section: Introductionmentioning

confidence: 99%

Regulation of P21 during diabetes-associated stress of the endoplasmic reticulum

Mihailidou

Chatzistamou

Papavassiliou

et al. 2015

Endocrine-Related Cancer

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“…Cross-talk between the UPR and p53 has been reported in many studies (see examples in refs. [122][123][124][125], which may infl uence gene expression toward cell adaptation or induction of apoptosis, and thus determine cancer cell fate. For example, a recent report provided evidence suggesting that UPR signaling modulates the function of a p53 isoform ( 122 ).…”

Section: Er Stress and Dna Damage/repairmentioning

confidence: 99%

“…[122][123][124][125], which may infl uence gene expression toward cell adaptation or induction of apoptosis, and thus determine cancer cell fate. For example, a recent report provided evidence suggesting that UPR signaling modulates the function of a p53 isoform ( 122 ). In addition, ER stress may affect the cell cycle and protein translation in a p53-dependent manner ( 123,124 ).…”

Section: Er Stress and Dna Damage/repairmentioning

confidence: 99%

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

2015

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Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many human diseases, including cancers. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. The UPR has emerged as a major pathway in remodeling cancer gene expression, thereby either preventing cell transformation or providing an advantage to transformed cells. UPR sensors are highly regulated by the formation of dynamic protein scaffolds, leading to integrated reprogramming of the cells. Herein, we describe the regulatory mechanisms underlying UPR signaling upon cell intrinsic or extrinsic challenges, and how they engage cell transformation programs and/or provide advantages to cancer cells, leading to enhanced aggressiveness or chemoresistance. We discuss the emerging crosstalk between the UPR and related metabolic processes to ensure maintenance of protein homeostasis and its impact on cell transformation and tumor growth.Signifi cance: ER stress signaling is dysregulated in many forms of cancer and contributes to tumor growth as a survival factor, in addition to modulating other disease-associated processes, including cell migration, cell transformation, and angiogenesis. Evidence for targeting the ER stress signaling pathway as an anticancer strategy is compelling, and novel agents that selectively inhibit the UPR have demonstrated preliminary evidence of preclinical effi cacy with an acceptable safety profi le. Cancer Discov; 5(6);

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“…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. Recently, the suppression of P21 expression by the P53 isoform P53/47 during ER stress has been demonstrated and has been linked to the reduction of the apoptotic threshold during anticancer therapy (Mlynarczyk & Fåhraeus 2014). In this study, we explored the regulation of P21 through the transcription factor CHOP at the level of transcription and evaluated how P21 activity affects the sensitivity of cells to the ER stress inducer tunicamycin (TUN), the conventional anticancer agent doxorubicin (DOX), or a combination of the two.…”

Section: Introductionmentioning

confidence: 99%

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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Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21CDKN1A

Cited by 62 publications

References 64 publications

Regulation of P21 during diabetes-associated stress of the endoplasmic reticulum

Regulation of P21 during diabetes-associated stress of the endoplasmic reticulum

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress

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