The retinoblastoma protein and its homolog p130 regulate the G1/S transition in pancreatic beta-cells.
OBJECTIVE
The retinoblastoma protein family (pRb, p130, p107) plays a central role in the regulation of cell cycle progression. Surprisingly, loss of pRb in the beta-cell has no discernible effect on cell cycle control. Therefore, we explored the effects of individual loss of either p130 or p107 in addition to the simultaneous loss of both pRb/p130 on the beta-cell.


METHODS
Adult mice deficient in either p130 or p107 or both pRb/p130 were examined for effects on beta-cell replication, function, and survival. The Cre-Lox system was also used to inactivate pRb in wild-type and p130-deficient beta-cells in vitro.


RESULTS
In vivo loss of either p107 or p130 did not affect beta-cell replication or function. Combined pRb/p130 loss, however, resulted in dramatically accelerated proliferation as well as apoptotic cell death. Pancreas and beta-cell mass were significantly reduced in double mutants. Despite this, overall glucose tolerance was normal, except for mild postprandial hyperglycemia. Ex vivo, acute deletion of pRb in p130-deficient beta-cells also caused a striking increase in proliferation. The combined deletion of pRb/p130 upregulated islet expression of E2F2 but not E2F1.


CONCLUSIONS
These studies define an essential role for the pocket proteins in controlling the G(1)/S transition in beta-cells. When deficient in both pRb and p130, beta-cells undergo unrestrained cell cycle reentry and activation of apoptosis. These studies underscore the central role of the pRb pathway in controlling beta-cell turnover and provide new cellular targets for beta-cell regeneration.
Harb
George
G
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Vasavada
Rupangi C
RC
Cobrinik
David
D
Stewart
Andrew F
AF
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division; D016193:G1 Phase / Q000502:physiology*; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050720:Retinoblastoma-Like Protein p107 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016196:S Phase / Q000502:physiology*
D001786:Blood Glucose; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130