Stress-Inducible Transcription Factor CHOP/gadd153 Induces Apoptosis in Mammalian Cells via p38 Kinase-Dependent and -Independent Mechanisms

Maytin, Edward V.; Ubeda, Mariano; Lin, Julia C.; Habener, Joel F.

doi:10.1006/excr.2001.5248

Cited by 215 publications

(174 citation statements)

References 38 publications

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“…CHOP is upregulated in some colorectal cancers, and correlates with the invasiveness of these tumours in situ (Rask et al, 2000). However, the available evidence strongly indicates that CHOP is an antiproliferative and proapoptitic protein (Barone et al, 1992;Maytin et al, 2001). This hypothesis is supported by the finding that the apoptosis inducing agent curcumin upregulates endogenous CHOP (Scott and Loo, 2004), and represses TCFdependent transcription (Jaiswal et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Murine and human CHOP constructs were cloned into the EcoRI/XhoI sites of pXT7 and pCDNA3 vectors. Wild-type and deletion constructs of murine CHOP were amplified by polymerase chain reaction from vectors pGFPCHOP, pGFPbZIP, pGFPLZ(À) and pGFPTA(À) (Maytin et al, 2001) and cloned into the EcoRI/XhoI sites of pCDNA3 and pXT7 vectors. Wild-type and deletion constructs of XTCF-3 were amplified by polymerase chain reaction from vector pT7Ts-XTcf-3 (kindly provided by Dr Sokol, Harvard Medical School, Boston, USA) and cloned into the MluI/NotI sites of a modified pCDNA3 vector with Flag epitope.…”

Section: Plasmid Constructsmentioning

confidence: 99%

“…CHOP induces cell cycle arrest and apoptosis in response to cellular stress factors (Zinszner et al, 1998;Maytin et al, 2001), and was therefore also termed 'growth arrest and DNA damageinducible gene' (GADD153). CHOP transcripts are present in early blastula stage mouse embryos (Fleming et al, 1997;Fontanier-Razzaq et al, 1999), and the protein plays a role in the differentiation of osteoblasts, keratinocytes, during hematopoesis, and in the control of adipogenesis (Maytin and Habener, 1998;Tang and Lane, 2000;Pereira et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

et al. 2006

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CHOP (GADD153) is a protein of the C/EBP family of transcriptional regulators, which dimerizes with other C/EBP members and changes their DNA-binding and transactivation properties. It induces growth arrest and apoptosis after endoplasmatic reticulum stress or DNA damage. CHOP is also expressed during early embryogenesis and upregulated in tumour tissues with defective Wnt signals. We report here that CHOP functions as a specific inhibitor of Wnt/T-cell factor (TCF) signalling. CHOP inhibits TCF-dependent transcription in human embryonic and colon cancer cell lines. Injection of CHOP mRNA into early Xenopus laevis embryos suppresses dorsal organizer formation and inhibits secondary axis formation and TCF-dependent transcription in response to Wnt-8, Dishevelled, b-Catenin and TCF-VP16. In embryos and human cells, this inhibition depends on the N-terminal transactivation domain of CHOP, whereas the C-terminal dimerization domain is dispensable. CHOP binds to TCF factors, thereby preventing the binding of TCF to its DNA recognition site. Our findings demonstrate a novel function of CHOP as a Wnt repressor.

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Section: Discussionmentioning

confidence: 99%

Section: Plasmid Constructsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

et al. 2006

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“…26 Deletion mutant analysis of CHOP revealed that bZIP domain is important for CHOP-induced apoptosis. 23,27 The high conservation (490%) in the bZIP domain of the C/EBP members allows for formation of homodimers and heterodimers of the members. CHOP is a heterodimer with other C/ EBPs that strongly prefer to homodimerize.…”

Section: Structure and Properties Of Chopmentioning

confidence: 99%

“…53,54 Under ER stress conditions, CHOP protein undergoes phosphorylation of Ser78 and Ser81 by the p38 MAP kinase family. 26,27 Studies making use of the inhibition of p38 MAP kinase by SB20580, overexpression of p38 MAP kinase and mutation of phosphorylation sites indicate that the phosphorylation enhances transcriptional activation and elicits a maximal apoptotic effect of CHOP. 23,26,27 MAPKKK ASK1, which is required for activation of JNK by Ire1 during ER stress, can also activate the p38 pathway.…”

Section: Post-transcriptional Regulation Of Chopmentioning

confidence: 99%

Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrestand DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/ GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.

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