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Exendin-4 stimulation of cyclin A2 in β-cell proliferation

Metabolism Division, Departments of Pediatrics and Medicine, Johns Hopkins University

Objective.: β-cell proliferation is an important mechanism underlying β-cell mass adaptation to metabolic demands. We have examined effects - in particular those mediated through intracellular cyclic AMP signaling - of the incretin hormone analogue exendin-4 on cell cycle regulation in β-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 β-cell proliferation (CBP-S436A mouse). Because cyclin A2 was stimulated by cyclic AMP, we assessed the role of cylcin A2 in cell cycle progression in Min6 and isolated islet β-cells.

Results.: Mice treated with exendin-4 showed increased β-cell proliferation, elevated islet protein levels of cyclin A2 with unchanged D-type cyclins, and elevated PDX-1, Skp2 and reduced p27 levels. Exendin-4 stimulated cyclin A2 promoter activity via the cyclic AMP (cAMP) - cyclic AMP 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, 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 β-cell proliferation, exendin-4 stimulates cyclin A2 expression via the cAMP pathway, and exendin-4 stimulation of cAMP requires PDX-1.

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