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The retinoblastoma protein and its homolog p130 regulate the G1/S transition in pancreatic beta-cells.

Harb G, Vasavada RC, Cobrinik D, Stewart AF - Diabetes (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

ABSTRACT

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.

Research design and 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.

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β-cell replication in p130- islets and compensatory upregulation of pocket protein family members. A: Quantification of β-cell replication (%BrdU+-insulin+ cells). Replication was not significantly increased in p130-deficient β-cells (n = 5) compared with WT (n = 9) or HT (n = 5) mice. B: Representative immunoblots of RbCKO, p107, or p130 WT or KO islet protein extracts probed for pRb, p107, and p130. Note that the data for RbCKO mice have been previously published by Vasavada et al. (14) and are included for comparison of the data on p107 and p130. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 3: β-cell replication in p130- islets and compensatory upregulation of pocket protein family members. A: Quantification of β-cell replication (%BrdU+-insulin+ cells). Replication was not significantly increased in p130-deficient β-cells (n = 5) compared with WT (n = 9) or HT (n = 5) mice. B: Representative immunoblots of RbCKO, p107, or p130 WT or KO islet protein extracts probed for pRb, p107, and p130. Note that the data for RbCKO mice have been previously published by Vasavada et al. (14) and are included for comparison of the data on p107 and p130. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Like pRb, p130 and p107 also regulate cell cycle progression (9). Adult differentiated β-cells that have exited the cell cycle and entered a state of quiescence express both p130 and p107 (Fig. 3B) (14,20). Therefore, we speculated that loss of p130 or p107 in β-cells might result in aberrant cell cycle reentry. Instead, loss of either p130 or p107 failed to affect β-cell replication rates (Fig. 3A; supplementary Fig. S4A, available in the online-only appendix) and islet cell cycle phase distribution (supplementary Figs. S1 and S4B, available in the online-only appendix). This may result from functional compensation within the retinoblastoma family because there was a striking upregulation of p107 protein in p130- islets (82.4 ± 4.0%) (Fig. 3B). These findings demonstrate that p130 and p107 are individually dispensable for maintaining β-cell cycle arrest in adult mouse β-cells.


The retinoblastoma protein and its homolog p130 regulate the G1/S transition in pancreatic beta-cells.

Harb G, Vasavada RC, Cobrinik D, Stewart AF - Diabetes (2009)

β-cell replication in p130- islets and compensatory upregulation of pocket protein family members. A: Quantification of β-cell replication (%BrdU+-insulin+ cells). Replication was not significantly increased in p130-deficient β-cells (n = 5) compared with WT (n = 9) or HT (n = 5) mice. B: Representative immunoblots of RbCKO, p107, or p130 WT or KO islet protein extracts probed for pRb, p107, and p130. Note that the data for RbCKO mice have been previously published by Vasavada et al. (14) and are included for comparison of the data on p107 and p130. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2712776&req=5

Figure 3: β-cell replication in p130- islets and compensatory upregulation of pocket protein family members. A: Quantification of β-cell replication (%BrdU+-insulin+ cells). Replication was not significantly increased in p130-deficient β-cells (n = 5) compared with WT (n = 9) or HT (n = 5) mice. B: Representative immunoblots of RbCKO, p107, or p130 WT or KO islet protein extracts probed for pRb, p107, and p130. Note that the data for RbCKO mice have been previously published by Vasavada et al. (14) and are included for comparison of the data on p107 and p130. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Like pRb, p130 and p107 also regulate cell cycle progression (9). Adult differentiated β-cells that have exited the cell cycle and entered a state of quiescence express both p130 and p107 (Fig. 3B) (14,20). Therefore, we speculated that loss of p130 or p107 in β-cells might result in aberrant cell cycle reentry. Instead, loss of either p130 or p107 failed to affect β-cell replication rates (Fig. 3A; supplementary Fig. S4A, available in the online-only appendix) and islet cell cycle phase distribution (supplementary Figs. S1 and S4B, available in the online-only appendix). This may result from functional compensation within the retinoblastoma family because there was a striking upregulation of p107 protein in p130- islets (82.4 ± 4.0%) (Fig. 3B). These findings demonstrate that p130 and p107 are individually dispensable for maintaining β-cell cycle arrest in adult mouse β-cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

ABSTRACT

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus