| First Author | Feng ZC | Year | 2013 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 304 |
| Issue | 6 | Pages | E557-65 |
| PubMed ID | 23269409 | Mgi Jnum | J:195933 |
| Mgi Id | MGI:5486248 | Doi | 10.1152/ajpendo.00453.2012 |
| Citation | Feng ZC, et al. (2013) Downregulation of Fas activity rescues early onset of diabetes in c-Kit(Wv/+) mice. Am J Physiol Endocrinol Metab 304(6):E557-65 |
| abstractText | c-Kit and its ligand stem cell factor (SCF) are important for beta-cell survival and maturation; meanwhile, interactions between the Fas receptor (Fas) and Fas ligand are capable of triggering beta-cell apoptosis. Disruption of c-Kit signaling leads to severe loss of beta-cell mass and function with upregulation of Fas expression in c-Kit(Wv/+) mouse islets, suggesting that there is a critical balance between c-Kit and Fas activation in beta-cells. In the present study, we investigated the interrelationship between c-Kit and Fas activation that mediates beta-cell survival and function. We generated double mutant, c-Kit(Wv/+);Fas(lpr/lpr) (Wv(-/-)), mice to study the physiological and functional role of Fas with respect to beta-cell function in c-Kit(Wv/+) mice. Isolated islets from these mice and the INS-1 cell line were used. We observed that islets in c-Kit(Wv/+) mice showed a significant increase in beta-cell apoptosis along with upregulated p53 and Fas expression. These results were verified in vitro in INS-1 cells treated with SCF or c-Kit siRNA combined with a p53 inhibitor and Fas siRNA. In vivo, Wv(-/-) mice displayed improved beta-cell function, with significantly enhanced insulin secretion and increased beta-cell mass and proliferation compared with Wv(+/+) mice. This improvement was associated with downregulation of the Fas-mediated caspase-dependent apoptotic pathway and upregulation of the cFlip/NF-kappaB pathway. These findings demonstrate that a balance between the c-Kit and Fas signaling pathways is critical in the regulation of beta-cell survival and function. |
