HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fatrai, S. Articles by Bernal-Mizrachi, E. Search for Related Content PubMed PubMed Citation Articles by Fatrai, S. Articles by Bernal-Mizrachi, E. Social Bookmarking                What's this?

Akt Induces ß-Cell Proliferation by Regulating Cyclin D1, Cyclin D2, and p21 Levels and Cyclin-Dependent Kinase-4 Activity

¹ Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri
² Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois, Chicago, Illinois

Address correspondence and reprint requests to Ernesto Bernal-Mizrachi, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110. E-mail: ebernal{at}wustl.edu

Key Words: BrdU, bromodeoxyuridine • cdk4, cyclin-dependent kinase-4 • FOXO1, forkhead box factor 1 • GSK, glycogen synthase kinase • INK4, inhibitor of cdk4 • PI 3-kinase, phosphoinositide 3-kinase

Proliferation is the major component for maintenance of ß-cell mass in adult animals. Activation of phosphoinositide 3-kinase/Akt-kinase pathway is a critical regulator of ß-cell mass. Pancreatic ß-cell overexpression of constitutively active Akt in mice (caAkt^Tg) resulted in marked expansion of ß-cell mass by increase in ß-cell proliferation and size. The current studies provide new insights into the molecular mechanisms involved in ß-cell proliferation by Akt. Proliferation of ß-cells in caAkt^Tg was associated with increased cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 (cdk4) activity. To determine the role of cdk4 in ß-cell proliferation induced by Akt, we generated caAkt^Tg mice that were homozygous, heterozygous, or nullizygous for cdk4. The results of these studies showed that deletion of one cdk4 allele significantly reduced ß-cell expansion in caAkt^Tg mice by decreased proliferation. CaAkt^Tg mice deficient in cdk4 developed ß-cell failure and diabetes. These experiments suggest that Akt induces ß-cell proliferation in a cdk4-dependent manner by regulation of cyclin D1, cyclin D2, and p21 levels. These data also indicate that alteration in levels of these cell cycle components could affect the maintenance of ß-cell mass in basal states and the adaptation of ß-cells to pathological states resulting in diabetes.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Kato, H. Shimano, T. Yamamoto, M. Ishikawa, S. Kumadaki, T. Matsuzaka, Y. Nakagawa, N. Yahagi, M. Nakakuki, A. H. Hasty, et al. Palmitate Impairs and Eicosapentaenoate Restores Insulin Secretion Through Regulation of SREBP-1c in Pancreatic Islets Diabetes, September 1, 2008; 57(9): 2382 - 2392. [Abstract] [Full Text] [PDF]

				K. Fulzele, D. J. DiGirolamo, Z. Liu, J. Xu, J. L. Messina, and T. L. Clemens Disruption of the Insulin-like Growth Factor Type 1 Receptor in Osteoblasts Enhances Insulin Signaling and Action J. Biol. Chem., August 31, 2007; 282(35): 25649 - 25658. [Abstract] [Full Text] [PDF]

				L. C. Alonso, T. Yokoe, P. Zhang, D. K. Scott, S. K. Kim, C. P. O'Donnell, and A. Garcia-Ocana Glucose Infusion in Mice: A New Model to Induce {beta}-Cell Replication Diabetes, July 1, 2007; 56(7): 1792 - 1801. [Abstract] [Full Text] [PDF]

				R. Mussmann, M. Geese, F. Harder, S. Kegel, U. Andag, A. Lomow, U. Burk, D. Onichtchouk, C. Dohrmann, and M. Austen Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells J. Biol. Chem., April 20, 2007; 282(16): 12030 - 12037. [Abstract] [Full Text] [PDF]

				A. M Ackermann and M. Gannon Molecular regulation of pancreatic {beta}-cell mass development, maintenance, and expansion J. Mol. Endocrinol., February 1, 2007; 38(2): 193 - 206. [Abstract] [Full Text] [PDF]

				R. C. Vasavada, I. Cozar-Castellano, D. Sipula, and A. F. Stewart Tissue-Specific Deletion of the Retinoblastoma Protein in the Pancreatic {beta}-Cell Has Limited Effects on {beta}-Cell Replication, Mass, and Function Diabetes, January 1, 2007; 56(1): 57 - 64. [Abstract] [Full Text] [PDF]

				I. Cozar-Castellano, M. Haught, and A. F. Stewart The Cell Cycle Inhibitory Protein p21cip Is Not Essential for Maintaining {beta}-Cell Cycle Arrest or {beta}-Cell Function In Vivo Diabetes, December 1, 2006; 55(12): 3271 - 3278. [Abstract] [Full Text] [PDF]

				M. Peshavaria, B. L. Larmie, J. Lausier, B. Satish, A. Habibovic, V. Roskens, K. LaRock, B. Everill, J. L. Leahy, and T. L. Jetton Regulation of Pancreatic {beta}-Cell Regeneration in the Normoglycemic 60% Partial-Pancreatectomy Mouse Diabetes, December 1, 2006; 55(12): 3289 - 3298. [Abstract] [Full Text] [PDF]

				I. Cozar-Castellano, N. Fiaschi-Taesch, T. A. Bigatel, K. K. Takane, A. Garcia-Ocana, R. Vasavada, and A. F. Stewart Molecular Control of Cell Cycle Progression in the Pancreatic {beta}-Cell Endocr. Rev., June 1, 2006; 27(4): 356 - 370. [Abstract] [Full Text] [PDF]