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Absence of Caspase-3 Protects Pancreatic beta-Cells from c-Myc-induced Apoptosis without Leading to Tumor Formation

Radziszewska, A; Schroer, SA; Choi, D; Tajmir, P; Radulovich, N; Ho, JC; Wang, LY; ... Woo, M; + view all (2009) Absence of Caspase-3 Protects Pancreatic beta-Cells from c-Myc-induced Apoptosis without Leading to Tumor Formation. J BIOL CHEM , 284 (16) 10947 - 10956. 10.1074/jbc.M806960200. Gold open access

Abstract

c-Myc is a powerful trigger of beta-cell apoptosis, proliferation, and dedifferentiation in rodent islets in vivo. In a transgenic mouse model, c-Myc induction causes rapid beta-cell apoptosis and overt diabetes. When suppression of apoptosis is achieved by overexpression of Bcl-xL in an inducible model of c-Myc activation, a full spectrum of tumor development, including distant metastasis, occurs. Caspase-3 is a key pro-apoptotic protein involved in the execution phase of multiple apoptotic pathways. To test whether caspase-3 is an essential mediator of apoptosis in this model of tumorigenesis, we generated caspase-3 knock-out mice containing the inducible c-myc transgene (c-Myc(+) Casp3(-/-)). In contrast to Bcl-x(L)-overexpressing c-Myc(+) mice, c-Myc(+) Casp3(-/-) mice remained euglycemic for up to 30 days of c-Myc activation, and there was no evidence of tumor formation. Interestingly, caspase-3 deletion also led to the suppression of proliferation, perhaps through regulation of the cell cycle inhibitory protein p27, suggesting a possible mechanism for maintaining a balance between suppression of apoptosis and excessive proliferation in the context of c-Myc activation. Additionally, c-Myc-activated Casp3(-/-) mice were protected from streptozotocin-induced diabetes. Our studies demonstrate that caspase-3 deletion confers protection from c-Myc-induced apoptosis and diabetes development without unwanted tumorigenic effects. These results may lead to further elucidation of the mechanisms of c-Myc biology relevant to beta-cells, which may result in novel therapeutic strategies for diabetes.

Type: Article
Title: Absence of Caspase-3 Protects Pancreatic beta-Cells from c-Myc-induced Apoptosis without Leading to Tumor Formation
Open access status: An open access publication
DOI: 10.1074/jbc.M806960200
Keywords: IN-VIVO, GENE-EXPRESSION, DOWN-REGULATION, CULTURE, MICE, REQUIREMENT, ACTIVATION, RECEPTOR, CYCLE, FAS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/70544
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