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Tissue-Specific Deletion of the Retinoblastoma Protein in the Pancreatic ß-Cell Has Limited Effects on ß-Cell Replication, Mass, and Function

From the Division of Endocrinology, the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Rupangi C. Vasavada, PhD, Division of Endocrinology, BST E-1140, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213. E-mail: vasavada{at}dom.pitt.edu

Key Words: BrdU, bromodeoxyuridine • RIP, rat insulin promoter

Animal studies show that G_1/S regulatory molecules (D-cyclins, cdk-4, p18, p21, p27) are critical for normal regulation of ß-cell proliferation, mass, and function. The retinoblastoma protein, pRb, is positioned at the very end of a cascade of these regulatory proteins and is considered the final checkpoint molecule that maintains ß-cell cycle arrest. Logically, removal of pRb from the ß-cell should result in unrestrained ß-cell replication, increased ß-cell mass, and insulin-mediated hypoglycemia. Because global loss of both pRb alleles is embryonic lethal, this hypothesis has not been tested in ß-cells. We developed two types of conditional knockout (CKO) mice in which both alleles of the pRb gene were inactivated specifically in ß-cells. Surprisingly, although the pRb gene was efficiently recombined in ß-cells of both CKO models, changes in ß-cell mass, ß-cell replication rates, insulin concentrations, and blood glucose levels were limited or absent. Other pRb family members, p107 and p130, were not substantially upregulated. In contrast to dogma, the pRb protein is not essential to maintain cell cycle arrest in the pancreatic ß-cell. This may reflect fundamental inaccuracies in models of ß-cell cycle control or complementation for pRb by undefined proteins.

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