title: Absence of caspase-3 protects pancreatic {beta}-cells from c-Myc-induced apoptosis without leading to tumor formation.
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-x(L) 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.
authors.affiliation: Department of Medical Biophysics and Institute of Medical Science, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Radziszewska
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.forename: Diana
authors.initials: D
authors.lastname: Choi
authors.forename: Panteha
authors.initials: P
authors.lastname: Tajmir
authors.forename: Nikolina
authors.initials: N
authors.lastname: Radulovich
authors.forename: James C
authors.initials: JC
authors.lastname: Ho
authors.forename: Linyuan
authors.initials: L
authors.lastname: Wang
authors.forename: Nicole
authors.initials: N
authors.lastname: Liadis
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Linda Z
authors.initials: LZ
authors.lastname: Penn
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental; D004789:Enzyme Activation; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc; D053148:Caspase 3