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EMBO J. 2011 Apr 20;30(8):1563-76. doi: 10.1038/emboj.2011.57. Epub 2011 Mar 11.

RB regulates pancreas development by stabilizing Pdx1.

Author information

  • 1Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Abstract

RB is a key substrate of Cdks and an important regulator of the mammalian cell cycle. RB either represses E2Fs that promote cell proliferation or enhances the activity of cell-specific factors that promote differentiation, although the mechanism that facilitates this dual interaction is unclear. Here, we demonstrate that RB associates with and stabilizes pancreatic duodenal homeobox-1 (Pdx-1) that is essential for embryonic pancreas development and adult β-cell function. Interestingly, Pdx-1 utilizes a conserved RB-interaction motif (RIM) that is also present in E2Fs. Point mutations within the RIM reduce RB-Pdx-1 complex formation, destabilize Pdx-1 and promote its proteasomal degradation. Glucose regulates RB and Pdx-1 levels, RB/Pdx-1 complex formation and Pdx-1 degradation. RB occupies the promoters of β-cell-specific genes, and knockdown of RB results in reduced expression of Pdx-1 and its target genes. Further, RB-deficiency in vivo results in reduced pancreas size due to decreased proliferation of Pdx-1(+) pancreatic progenitors, increased apoptosis and aberrant expression of regulators of pancreatic development. These results demonstrate an unanticipated regulatory mechanism for pancreatic development and β-cell function, which involves RB-mediated stabilization of the pancreas-specific transcription factor Pdx-1.

PMID:
21399612
[PubMed - indexed for MEDLINE]
PMCID:
PMC3102287
Free PMC Article
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