Tissue-specific deletion of the retinoblastoma protein in the pancreatic beta-cell has limited effects on beta-cell replication, mass, and function.
Animal studies show that G(1/S) regulatory molecules (D-cyclins, cdk-4, p18, p21, p27) are critical for normal regulation of beta-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 beta-cell cycle arrest. Logically, removal of pRb from the beta-cell should result in unrestrained beta-cell replication, increased beta-cell mass, and insulin-mediated hypoglycemia. Because global loss of both pRb alleles is embryonic lethal, this hypothesis has not been tested in beta-cells. We developed two types of conditional knockout (CKO) mice in which both alleles of the pRb gene were inactivated specifically in beta-cells. Surprisingly, although the pRb gene was efficiently recombined in beta-cells of both CKO models, changes in beta-cell mass, beta-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 beta-cell. This may reflect fundamental inaccuracies in models of beta-cell cycle control or complementation for pRb by undefined proteins.
Vasavada
Rupangi C
RC
Division of Endocrinology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA. vasavada@dom.pitt.edu
Cozar-Castellano
Irene
I
Sipula
Darinka
D
Stewart
Andrew F
AF
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D017353:Gene Deletion; D005786:Gene Expression Regulation; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000235:genetics*
D016160:Retinoblastoma Protein