| First Author | Golson ML | Year | 2014 |
| Journal | Mol Endocrinol | Volume | 28 |
| Issue | 9 | Pages | 1435-47 |
| PubMed ID | 25073103 | Mgi Jnum | J:216217 |
| Mgi Id | MGI:5608524 | Doi | 10.1210/me.2014-1024 |
| Citation | Golson ML, et al. (2014) Activated FoxM1 attenuates streptozotocin-mediated beta-cell death. Mol Endocrinol 28(9):1435-47 |
| abstractText | The forkhead box transcription factor FoxM1, a positive regulator of the cell cycle, is required for beta-cell mass expansion postnatally, during pregnancy, and after partial pancreatectomy. Up-regulation of full-length FoxM1, however, is unable to stimulate increases in beta-cell mass in unstressed mice or after partial pancreatectomy, probably due to the lack of posttranslational activation. We hypothesized that expression of an activated form of FoxM1 could aid in recovery after beta-cell injury. We therefore derived transgenic mice that inducibly express an activated version of FoxM1 in beta-cells (RIP-rtTA;TetO-hemagglutinin (HA)-Foxm1(Delta)(NRD) mice). This N-terminally truncated form of FoxM1 bypasses 2 posttranslational controls: exposure of the forkhead DNA binding domain and targeted proteasomal degradation. Transgenic mice were subjected to streptozotocin (STZ)-induced beta-cell ablation to test whether activated FoxM1 can promote beta-cell regeneration. Mice expressing HA-FoxM1(DeltaNRD) displayed decreased ad libitum-fed blood glucose and increased beta-cell mass. beta-Cell proliferation was actually decreased in RIP-rtTA:TetO-HA-Foxm1(NRD) mice compared with that in RIP-rtTA mice 7 days after STZ treatment. Unexpectedly, beta-cell death was decreased 2 days after STZ treatment. RNA sequencing analysis indicated that activated FoxM1 alters the expression of extracellular matrix and immune cell gene profiles, which may protect against STZ-mediated death. These studies highlight a previously underappreciated role for FoxM1 in promoting beta-cell survival. |
