CHOP Mediates Endoplasmic Reticulum Stress-Induced Apoptosis in Gimap5-Deficient T Cells

Pino, Steven C.; O’Sullivan-Murphy, Bryan; Lidstone, Erich A.; Yang, Chyun-Yu; Lipson, Kathryn L.; Jurczyk, Agata; Diiorio, Philip J.; Brehm, Michael A.; Mordes, John P.; Greiner, Dale L.; Rossini, Aldo A.; Bortell, Rita

doi:10.1371/journal.pone.0005468

Cited by 49 publications

(35 citation statements)

References 54 publications

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“…Impairment of ER function and activation of ER stress responses have been implicated in lipoapoptosis pathways in various cell types including liver cells (2,7,22,24,26,38,39,43). With regard to lipids, saturated FFA, but not unsaturated FFA, result in an ER stress response with the induction of the transcription factor CHOP in liver cells (2,39).…”

Section: Discussionmentioning

confidence: 99%

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CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis

Cazanave

Elmi

Akazawa

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

164

168

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Endoplasmic reticulum (ER) stress-mediated apoptosis is a key feature of hepatocyte cytotoxicity by saturated free fatty acids (FFA). This lipoapoptosis is dependent, in part, on the transcriptional upregulation of the BH3-only protein PUMA (p53 upregulated modulator of apoptosis). Although the activator protein (AP)-1 complex facilitates PUMA expression by saturated FFA, the transcription factor CAAT/enhancer binding homologous protein (CHOP) is also induced by ER stress and promotes apoptosis. To integrate the role of these two transcription factors in ER stress-induced apoptosis, we examined the relative contribution of CHOP and AP-1 in mediating PUMA induction by saturated FFA. Our results demonstrate that short-hairpin RNA-targeted knockdown of CHOP attenuates palmitate-induced apoptosis in Huh-7 cells. Loss of CHOP induction also reduced the increase in PUMA mRNA and protein levels as well as Bax activation by palmitate. No functional CHOP binding sites were identified in the PUMA promoter sequence. Rather, we observed that CHOP physically interacts with the AP-1 complex protein c-Jun upon palmitate treatment, and a CHOP:phosphorylated c-Jun heteromeric complex binds to the AP-1 consensus binding sequence within the PUMA promoter region. Finally, loss of function studies suggest that both transcription factors are necessary for maximal PUMA induction. Collectively, these data suggest that CHOP and AP-1 cooperatively mediate PUMA induction during hepatocyte lipoapoptosis.

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Section: Discussionmentioning

confidence: 99%

“…CHOP has been implicated as a key mediator of ER stress-induced cell death in various cell types including murine fibroblasts (43), lymphocytes (26) and pancreatic ␤-cells (8,22,24). Indeed, CHOP knockdown confers protection against lipoapoptosis in pancreatic ␤-cells (8) and reduces hepatocyte apoptosis in alcoholinduced liver injury (13).…”

mentioning

confidence: 99%

CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis

Cazanave

Elmi

Akazawa

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

164

168

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“…CHOP (CCAAT/enhancer-binding protein homologous protein, also known as growth arrest and DnA damage-inducible protein) is a transcription factor which is up-regulated and plays a critical role in ERS-mediated apoptosis (17,38). The fact that overexpression of CHOP results in growth arrest and apoptosis has been demonstrated in a rat model (39) and in Hl-60 cells (40).…”

Section: Discussionmentioning

confidence: 99%

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

Ye²,

Huang³

et al. 2011

Oncol Rep

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Abstract. endoplasmic reticulum stress (ers)-mediated cell apoptosis has been implicated in the development of multiple diseases such as cancer, neurodegenerative diseases and ischemic reperfusion damage. previous studies have demonstrated the adenosine-induced apoptosis in several tumor cell lines. However, the role of ers in adenosine-induced human hepatoma Hepg2 cell apoptosis remains unclear. the present study was designed to determine whether ers is involved in adenosine-induced Hepg2 cell apoptosis. the Mtt assay was used to determine proliferation, and DApI staining of cell nuclei was performed to determine cell apoptosis. the translocation of cHop and caspase-3 was observed by immunofluorescence analysis, and the protein expression of CHOP, caspase-4 and caspase-3 was detected by Western blotting. the Mtt assay demonstrated that adenosine inhibited Hepg2 cell proliferation in a dose-dependent manner. DApI staining of cell nuclei and cell cycle analysis verified cell apoptosis. The immunofluorescence assay demonstrated that adenosine induced the translocation of cHop and of caspase-3 from the cytoplasm to the nucleus. Western blotting confirmed that cHop, caspase-4 and caspase-3 were up-regulated in Hepg2 cells after treatment with adenosine. However, JnK protein expression was not altered. These results show that ERS is involved in the adenosine-induced Hepg2 cell apoptosis.

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“…However, prolonged activation of ER stress ultimately initiates the apoptotic pathway. C/EBP homologous protein (CHOP) is an important protein in ER stress-mediated apoptosis (15). A number of previous studies have demonstrated that the ER is the major cell death organelle in cadmium-induced mesangial cell apoptosis (16), glomerular and tubular damage in kidney disease and renal injury (17,18).…”

Section: Introductionmentioning

confidence: 99%

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia

Zhao

et al. 2012

Molecular Medicine Reports

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Abstract. Diabetes mellitus is known to cause kidney impairment; however, the mechanism remains elusive. The aim of this study was to investigate the role of C/EBP homologous protein (CHOP), an important protein in endoplasmic reticulum stress-mediated mesangial cell apoptosis in hyperglycemia. Mesangial cells were cultured in normal (control group) and high glucose medium (high glucose group). TUNEL staining was performed to assess apoptotic cells in the groups. The expression of CHOP and caspase-3 was also assayed by immunohistochemistry and western blot analysis. Following 24 h culture in high glucose medium, TUNEL-positive cells were observed to be significantly increased (P<0.01). The expression of CHOP and caspase-3 in mesangial cells was also found to be significantly enhanced under high glucose conditions compared with the normal group (P<0.01). The results indicate that CHOP mediates apoptosis in mesangial cells under hyperglycemia and may play a role in the development of diabetic nephropathy.

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CHOP Mediates Endoplasmic Reticulum Stress-Induced Apoptosis in Gimap5-Deficient T Cells

Cited by 49 publications

References 54 publications

CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis

CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia

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