Molecular Control of Cell Cycle Progression in the Pancreatic β-Cell

Type 1 and type 2 diabetes both result from inadequate production of insulin by the -cells of the pancreatic islet. Accordingly, strategies that lead to increased pancreatic -cell mass, as well as retained or enhanced function of islets, would be desirable for the treatment of diabetes. Although pancreatic -cells have long been viewed as terminally differentiated and irreversibly arrested, evidence now indicates that -cells can and do replicate, that this replication can be enhanced by a variety of maneuvers, and that -cell replication plays a quantitatively significant role in maintaining pancreatic -cell mass and function. Because -cells have been viewed as being unable to pro-liferate, the science of -cell replication is undeveloped. In the past several years, however, this has begun to change at a rapid pace, and many laboratories are now focused on elucidating the molecular details of the control of cell cycle in the -cell. In this review, we review the molecular details of cell cycle control as they relate to the pancreatic -cell. Our hope is that this review can serve as a common basis and also a roadmap for those interested in developing novel strategies for enhancing -cell replication and improving insulin production in animal models as well as in human pancreatic -cells. (Endocrine Reviews 27: 356 -370, 2006) I. Introduction II. Basic Cell Cycle Machinery in the -Cell A. E2F proteins B. pRb and the "pocket proteins" C. p53 and MDM2 D. Large T-antigen E. cdk-4 and cdk-6 F. The D-cyclins G. cdk-2 and cyclins A and E H. The INK family I. The CIP/KIP/WAF family J. Menin III. Developing Models of Cell Cycle Control in the -Cell IV. Are We Looking for