Dataset Information

Exendin-4 stimulation of cyclin A2 in beta-cell proliferation.

ABSTRACT:

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.

SUBMITTER: Song WJ

PROVIDER: S-EPMC2518488 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Publications

Exendin-4 stimulation of cyclin A2 in beta-cell proliferation.

Song Woo-Jin WJ Schreiber Weston E WE Zhong Enhong E Liu Fei-Fei FF Kornfeld Benjamin D BD Wondisford Fredric E FE Hussain Mehboob A MA

Diabetes 20080610 9

<h4>Objective</h4>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.<h4>Research design and methods</h4>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 ...[more]

PMID: 18544709

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Dataset Information

Exendin-4 stimulation of cyclin A2 in beta-cell proliferation.

Objective

Research design and methods

Results

Conclusions

Publications

Exendin-4 stimulation of cyclin A2 in beta-cell proliferation.

Similar Datasets

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