title: RB regulates pancreas development by stabilizing Pdx1.
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.
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: So Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Mellado-Gil
authors.forename: Hariom
authors.initials: H
authors.lastname: Yadav
authors.forename: William
authors.initials: W
authors.lastname: Neidermyer
authors.forename: Anil K
authors.initials: AK
authors.lastname: Kamaraju
authors.forename: Sushil G
authors.initials: SG
authors.lastname: Rane
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D051358:Cyclin-Dependent Kinase 4 / Q000502:physiology; D050684:E2F Transcription Factors / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D050684:E2F Transcription Factors; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D005947:Glucose