Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

  1. Woo-Jin Song,
  2. Weston E. Schreiber,
  3. Enhong Zhong,
  4. Fei-Fei Liu,
  5. Benjamin D. Kornfeld,
  6. Fredric E. Wondisford and
  7. Mehboob A. Hussain
  1. From the Metabolism Division, Departments of Pediatrics and Medicine, Johns Hopkins University, Baltimore, Maryland
  1. Corresponding author: Mehboob A. Hussain, mhussai4{at}


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.


  • Published ahead of print at on 10 June 2008.

    W.-J.S. and W.E.S. contributed equally to this work.

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    • Accepted May 22, 2008.
    • Received October 31, 2007.
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