| First Author | Song WJ | Year | 2008 |
| Journal | Diabetes | Volume | 57 |
| Issue | 9 | Pages | 2371-81 |
| PubMed ID | 18544709 | Mgi Jnum | J:141784 |
| Mgi Id | MGI:3819734 | Doi | 10.2337/db07-1541 |
| Citation | Song WJ, et al. (2008) Exendin-4 stimulation of cyclin A2 in beta-cell proliferation. Diabetes 57(9):2371-81 |
| abstractText | OBJECTIVE: Beta-cell proliferation is an important mechanism underlying beta-cell mass adaptation to metabolic demands. We have examined effects, in particular those mediated through intracellular cAMP signaling, of the incretin hormone analog exendin-4 on cell cycle regulation in beta-cells. RESEARCH DESIGN AND METHODS: Changes in islet protein levels of cyclins and of two critical cell cycle regulators cyclin kinase inhibitor p27 and S-phase kinase-associated protein 2 (Skp2) were assessed in mice treated with exendin-4 and in a mouse model with specific upregulation of nuclear cAMP signaling exhibiting increased beta-cell proliferation (CBP-S436A mouse). Because cyclin A2 was stimulated by cAMP, we assessed the role of cylcin A2 in cell cycle progression in Min6 and isolated islet beta-cells. RESULTS: Mice treated with exendin-4 showed increased beta-cell proliferation, elevated islet protein levels of cyclin A2 with unchanged D-type cyclins, elevated PDX-1 and Skp2 levels, and reduced p27 levels. Exendin-4 stimulated cyclin A2 promoter activity via the cAMP-cAMP response element binding protein pathway. CBP-S436A islets exhibited elevated cyclin A2, reduced p27, and no changes in D-type cyclins, PDX-1, or Skp2. In cultured islets, exendin-4 increased cyclin A2 and Skp2 and reduced p27. Cyclin A2 overexpression in primary islets increased proliferation and reduced p27. In Min6 cells, cyclin A2 knockdown prevented exendin-4-stimulated proliferation. PDX-1 knockdown reduced exendin-4-stimulated cAMP synthesis and cyclin A2 transcription. CONCLUSIONS: Cyclin A2 is required for beta-cell proliferation, exendin-4 stimulates cyclin A2 expression via the cAMP pathway, and exendin-4 stimulation of cAMP requires PDX-1. |
