Exendin-4 stimulation of cyclin A2 in beta-cell proliferation.
Exendin-4 stimulation of cyclin A2 in beta-cell proliferation.
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DOI：
10.2337/db07-1541
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发表时间：
2008-09
期刊：
影响因子：
7.7
通讯作者：
Hussain MA
中科院分区：
文献类型：
--
作者：
Song WJ;Schreiber WE;Zhong E;Liu FF;Kornfeld BD;Wondisford FE;Hussain MA
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.
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DOI：
10.1073/pnas.0608703104
发表时间：
2007-05-22
影响因子：
11.1
作者：
Okada, Terumasa;Liew, Chong Wee;Kulkarni, Rohit N.
通讯作者：
Kulkarni, Rohit N.
影响因子：
15.9
作者：
Bernal-Mizrachi, E;Wen, W;Permutt, MA
通讯作者：
Permutt, MA
DOI：
10.1073/pnas.0406789102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Huang, H;Regan, KM;Tindall, DJ
通讯作者：
Tindall, DJ
影响因子：
5.3
作者：
Hussain, Mehboob A.;Porras, Delia L.;Wondisford, Fredric E.
通讯作者：
Wondisford, Fredric E.
影响因子：
11.4
作者：
Ravnskjaer, Kim;Kester, Henri;Montminy, Marc
通讯作者：
Montminy, Marc