| First Author | Kim YC | Year | 2011 |
| Journal | EMBO J | Volume | 30 |
| Issue | 8 | Pages | 1563-76 |
| PubMed ID | 21399612 | Mgi Jnum | J:171241 |
| Mgi Id | MGI:4949030 | Doi | 10.1038/emboj.2011.57 |
| Citation | Kim YC, et al. (2011) RB regulates pancreas development by stabilizing Pdx1. EMBO J 30(8):1563-76 |
| abstractText | 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 beta-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 beta-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 beta-cell function, which involves RB-mediated stabilization of the pancreas-specific transcription factor Pdx-1. |
