Exendin-4 Stimulation of Cyclin A2 in beta-Cell Proliferation Export

@article{citeulike:3579091, 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. 10.2337/db07-1541}, author = {Song, Woo-Jin and Schreiber, Weston E. and Zhong, Enhong and Liu, Fei-Fei and Kornfeld, Benjamin D. and Wondisford, Fredric E. and Hussain, Mehboob A.}, citeulike-article-id = {3579091}, citeulike-linkout-0 = {http://dx.doi.org/10.2337/db07-1541}, citeulike-linkout-1 = {http://diabetes.diabetesjournals.org/cgi/content/abstract/57/9/2371}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18544709}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18544709}, day = {1}, doi = {10.2337/db07-1541}, journal = {Diabetes}, keywords = {diabetes, diabetestype1, incretins, molecular, physiology}, month = {September}, number = {9}, pages = {2371--2381}, posted-at = {2008-11-19 20:53:11}, priority = {2}, title = {Exendin-4 Stimulation of Cyclin A2 in {beta}-Cell Proliferation}, url = {http://dx.doi.org/10.2337/db07-1541}, volume = {57}, year = {2008} }

TY - JOUR ID - citeulike:3579091 L3 - citeulike-article-id:3579091 N2 - 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. 10.2337/db07-1541 IS - 9 JF - Diabetes EP - 2381 TI - Exendin-4 Stimulation of Cyclin A2 in {beta}-Cell Proliferation VL - 57 SP - 2371 KW - diabetes KW - diabetestype1 KW - incretins KW - molecular KW - physiology AU - Song, Woo-Jin AU - Schreiber, Weston AU - Zhong, Enhong AU - Liu, Fei-Fei AU - Kornfeld, Benjamin AU - Wondisford, Fredric AU - Hussain, Mehboob PY - 2008/09/01/ UR - http://dx.doi.org/10.2337/db07-1541 ER -