title: Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation.
abstract: The Polycomb group protein Bmi-1 is an essential regulator of cellular senescence and is believed to function largely through the direct repression of the Ink4a/Arf locus. However, concurrent deletion of Ink4a/Arf does not fully rescue the defects detected in Bmi-1(-/-) mice, indicating that additional Bmi-1 targets remain to be identified. The expression of the chromatin-associated Sin3B protein is stimulated by oncogenic stress, and is required for oncogene-induced senescence. Here we demonstrate that oncogenic stress leads to the dissociation of Bmi-1 from the Sin3B locus, resulting in increased Sin3B expression and subsequent entry into cellular senescence. Furthermore, Sin3B is required for the senescent phenotype and elevated levels of reactive oxygen species elicited upon Bmi-1 depletion. Altogether, these results identify Sin3B as a novel direct target of Bmi-1, and establish Bmi-1-driven repression of Sin3B as an essential regulator of cellular senescence.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: DiMauro
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cantor
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bainor
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: David
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D009857:Oncogenes; D063150:Polycomb Repressive Complex 1 / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C489421:Bmi1 protein, mouse; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C115812:Sin3b protein, mouse; D063150:Polycomb Repressive Complex 1