| First Author | Winnay JN | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 3 | Pages | 1192-7 |
| PubMed ID | 24395790 | Mgi Jnum | J:206472 |
| Mgi Id | MGI:5550324 | Doi | 10.1073/pnas.1322564111 |
| Citation | Winnay JN, et al. (2014) p85alpha deficiency protects beta-cells from endoplasmic reticulum stress-induced apoptosis. Proc Natl Acad Sci U S A 111(3):1192-7 |
| abstractText | In insulin resistant states such as type 2 diabetes, there is a high demand on the beta-cell to synthesize and secrete insulin, which challenges the ability of the endoplasmic reticulum (ER) to synthesize and fold nascent proteins. This creates a state of ER stress that triggers a coordinated program referred to as the unfolded protein response (UPR) that attempts to restore ER homeostasis. We identified a role for the p85alpha regulatory subunit of PI3K to modulate the UPR by promoting the nuclear localization of X-box binding protein 1, a transcription factor central to the UPR. In the present study we demonstrate that reducing p85alpha expression in beta-cells can markedly delay the onset and severity of the diabetic phenotype observed in Akita(+/-) mice, which express a mutant insulin molecule. This is due to a decrease in activation of ER stress-dependent apoptotic pathways and a preservation of beta-cell mass and function. These data demonstrate that modulation of p85alpha can protect pancreatic beta-cells from ER stress, pointing to a potentially therapeutic target in diabetic states. |
