Targeted disruption of the Chop gene delays endoplasmic reticulum stress–mediated diabetes

Oyadomari, Seiichi; Koizumi, Akio; Takeda, Kohsuke; Gotoh, Tomomi; Akira, Shizuo; Araki, Eiichi; Mori, Masataka

doi:10.1172/jci14550

Cited by 469 publications

(376 citation statements)

References 30 publications

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“…26 Conversely, apoptosis may also be the causal factor in diabetes development, as shown in Perk − / − and Pdx-1 − / − mouse models of diabetes. [27][28][29][30] In E2F1/E2F2-deficient cells, altered expression of proapoptotic mediators and mitochondrial membrane depolarization preceded the onset of diabetes, suggesting that apoptosis is a triggering event for pancreatic degeneration and diabetes in our mouse model. Furthermore, our results demonstrate that apoptosis in mice lacking E2F1/E2F2 is exclusively dependent on p53, since targeted inactivation of p53 hinders apoptosis and restores normal pancreas phenotype.…”

Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 84%

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

et al. 2015

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Tissue homeostasis requires tight regulation of cellular proliferation, differentiation and apoptosis. E2F1 and E2F2 transcription factors share a critical role in tissue homeostasis, since their combined inactivation results in overall organ involution, specially affecting the pancreatic gland, which subsequently triggers diabetes. We have examined the mechanism by which these E2Fs regulate tissue homeostasis. We show that pancreas atrophy in E2F1/E2F2 double-knockout (DKO) mice is associated with mitochondrial apoptosis and activation of the p53 pathway in young animals, before the development of diabetes. A deregulated expression of E2F target genes was detected in pancreatic cells of young DKO animals, along with unscheduled DNA replication and activation of a DNA damage response. Importantly, suppression of DNA replication in vivo with aphidicolin led to a significant inhibition of the p53 pathway in DKO pancreas, implying a causal link between DNA replication stress and p53 activation in this model. We further show that activation of the p53 pathway has a key role in the aberrant phenotype of DKO mice, since targeted inactivation of p53 gene abrogated cellular apoptosis and prevented organ involution and insulin-dependent diabetes in mice lacking E2F1/E2F2. Unexpectedly, p53 inactivation unmasked oncogenic features of E2F1/E2F2-depleted cells, as evidenced by an accelerated tumor development in triple-knockout mice compared with p53 − / − mice. Collectively, our data reveal a role for E2F1 and E2F2 as suppressors of replicative stress in differentiating cells, and uncover the existence of a robust E2F-p53 regulatory axis to enable tissue homeostasis and prevent tumorigenesis. These findings have implications in the design of approaches targeting E2F for cancer therapy.

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Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 84%

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

et al. 2015

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“…89 We found that disruption of the CHOP gene markedly delayed the onset of disease in heterozygous Akita mice. 59 This indicates that progressive hyperglycemia in Akita mice is caused by b-cell apoptosis through CHOP induction. Since disruption of the CHOP gene cannot delay the onset of disease in homozygous Akita mice, it is obvious that other pathway(s) are involved in this process.…”

Section: Diabetesmentioning

confidence: 98%

“…31 CHOP À/À mice exhibit reduced apoptosis in response to ER stress. 56,58,59 Thus, CHOP plays an important role in ER stress-induced apoptosis. Concerning the downstream of CHOP in the apoptosis pathway, cells lacking CHOP's major dimerization partner C/EBPb are also resistant to ER stress-induced apoptosis, suggesting that CHOP works as a transcriptional factor that regulates genes involved in either survival or death.…”

Section: Downstream Of Chop In Er Stress-induced Apoptosismentioning

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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“…For example, defects in the heat shock response compromise early development in mice (Xiao et al, 1999), and overexpressing the heat shock transcription factor in Caenorhabditis elegans results in increased longevity (Garigan et al, 2002;Lund et al, 2002). Defects in systems associated with the stress responses contribute to human diseases such as cancer, diabetes (Oyadomari et al, 2002), Alzheimer disease (Terro et al, 2002), Parkinson disease (Imai et al, 2000), Osteogenesis Imperfecta (Lamande and Bateman, 1999), cardiovascular disease (Pockley, 2002), and others. A compre-hensive understanding of how cells lines respond to common stresses would also be a useful tool for the interpretation of other large-scale gene expression data.…”

Section: Introductionmentioning

confidence: 99%

Diverse and Specific Gene Expression Responses to Stresses in Cultured Human Cells

Murray

Whitfield

Trinklein

et al. 2004

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270

233

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We used cDNA microarrays in a systematic study of the gene expression responses of HeLa cells and primary human lung fibroblasts to heat shock, endoplasmic reticulum stress, oxidative stress, and crowding. Hierarchical clustering of the data revealed groups of genes with coherent biological themes, including genes that responded to specific stresses and others that responded to multiple types of stress. Fewer genes increased in expression after multiple stresses than in free-living yeasts, which have a large general stress response program. Most of the genes induced by multiple diverse stresses are involved in cell-cell communication and other processes specific to higher organisms. We found substantial differences between the stress responses of HeLa cells and primary fibroblasts. For example, many genes were induced by oxidative stress and dithiothreitol in fibroblasts but not HeLa cells; conversely, a group of transcription factors, including c-fos and c-jun, were induced by heat shock in HeLa cells but not in fibroblasts. The dataset is freely available for search and download at http://microarray-pubs.stanford.edu/human_stress/Home.shtml.

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Targeted disruption of the Chop gene delays endoplasmic reticulum stress–mediated diabetes

Cited by 469 publications

References 30 publications

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

Roles of CHOP/GADD153 in endoplasmic reticulum stress

Diverse and Specific Gene Expression Responses to Stresses in Cultured Human Cells

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