title: Regulation of E2Fs and senescence by PML nuclear bodies.
abstract: The tumor suppressor PML (promyelocytic leukemia protein) regulates cellular senescence and terminal differentiation, two processes that implicate a permanent exit from the cell cycle. Here, we show that the mechanism by which PML induces a permanent cell cycle exit and activates p53 and senescence involves a recruitment of E2F transcription factors bound to their promoters and the retinoblastoma (Rb) proteins to PML nuclear bodies enriched in heterochromatin proteins and protein phosphatase 1α. Blocking the functions of the Rb protein family or adding back E2Fs to PML-expressing cells can rescue their defects in E2F-dependent gene expression and cell proliferation, inhibiting the senescent phenotype. In benign prostatic hyperplasia, a neoplastic disease that displays features of senescence, PML was found to be up-regulated and forming nuclear bodies. In contrast, PML bodies were rarely visualized in prostate cancers. The newly defined PML/Rb/E2F pathway may help to distinguish benign tumors from cancers, and suggest E2F target genes as potential targets to induce senescence in human tumors.
authors.affiliation: Biochemistry Department, Université de Montréal, Montréal, Québec H3C3J7, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vernier
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourdeau
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Gaumont-Leclerc
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.forename: Virginie
authors.initials: V
authors.lastname: Bégin
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology*; D050684:E2F Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011470:Prostatic Hyperplasia / Q000378:metabolism; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human