Absence of caspase-3 protects pancreatic {beta}-cells from c-Myc-induced apoptosis without leading to tumor formation.
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.
Radziszewska
Anna
A
Department of Medical Biophysics and Institute of Medical Science, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
Schroer
Stephanie A
SA
Choi
Diana
D
Tajmir
Panteha
P
Radulovich
Nikolina
N
Ho
James C
JC
Wang
Linyuan
L
Liadis
Nicole
N
Hakem
Razqallah
R
Tsao
Ming-Sound
MS
Penn
Linda Z
LZ
Evan
Gerard I
GI
Woo
Minna
M
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*
D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc; D053148:Caspase 3