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

Woo Jin Song, Weston E. Schreiber, Enhong Zhong, Fei Fei Liu, Benjamin D. Kornfeld, Fredric E. Wondisford, Mehboob A. Hussain

Research output: Contribution to journalArticle

Abstract

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 cAMP signaling, of the incretin hormone analog 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 cAMP, 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, 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 (β-cell proliferation, exendin-4 stimulates cyclin A2 expression via the cAMP pathway, and exendin-4 stimulation of cAMP requires PDX-1.

Original languageEnglish (US)
Pages (from-to)2371-2381
Number of pages11
JournalDiabetes
Volume57
Issue number9
DOIs
StatePublished - Sep 1 2008

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Song, W. J., Schreiber, W. E., Zhong, E., Liu, F. F., Kornfeld, B. D., Wondisford, F. E., & Hussain, M. A. (2008). Exendin-4 stimulation of cyclin A2 in β-cell proliferation. Diabetes, 57(9), 2371-2381. https://doi.org/10.2337/db07-1541