title: Redundant role of the cytochrome c-mediated intrinsic apoptotic pathway in pancreatic β-cells.
abstract: Cytochrome c is one of the central mediators of the mitochondrial or the intrinsic apoptotic pathway. Mice harboring a 'knock-in' mutation of cytochrome c, impairing only its apoptotic function, have permitted studies on the essential role of cytochrome c-mediated apoptosis in various tissue homeostasis. To this end, we examined the role of cytochrome c in pancreatic β-cells under homeostatic conditions and in diabetes models, including those induced by streptozotocin (STZ) and c-Myc. Previous studies have shown that both STZ- and c-Myc-induced β-cell apoptosis is mediated through caspase-3 activation; however, the precise mechanism in these modes of cell death was not characterized. The results of our study show that lack of functional cytochrome c does not affect glucose homeostasis or pancreatic β-cell mass under basal conditions. Moreover, the cytochrome c-mediated intrinsic apoptotic pathway is required for neither STZ- nor c-Myc-induced β-cell death. We also observed that the extrinsic apoptotic pathway mediated through caspase-8 was not essential in c-Myc-induced β-cell destruction. These findings suggest that cytochrome c is not required for STZ-induced β-cell apoptosis and, together with the caspase-8-mediated extrinsic pathway, plays a redundant role in c-Myc-induced β-cell apoptosis.
authors: Ontario Cancer Institute, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada.
authors: Diana
authors: D
authors: Choi
authors: Stephanie A
authors: SA
authors: Schroer
authors: Shun Yan
authors: SY
authors: Lu
authors: Erica P
authors: EP
authors: Cai
authors: Zhenyue
authors: Z
authors: Hao
authors: Minna
authors: M
authors: Woo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D053181:Caspase 8 / Q000378:metabolism; D045304:Cytochromes c / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D016259:Genes, myc; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D045304:Cytochromes c; C505526:Casp8 protein, mouse; D053181:Caspase 8; D005947:Glucose