$ z! R' k1 w: e, d6 n+ {Mathieu Vernier1,3, Véronique Bourdeau1,3, Marie-France Gaumont-Leclerc1, Olga Moiseeva1, Virginie Bégin1, Fred Saad2, Anne-Marie Mes-Masson2 and Gerardo Ferbeyre1,4/ C5 y% Z! I; R: W. c
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1Biochemistry Department, Université de Montréal, Montréal, Québec H3C3J7, Canada; # ]# z; G" \- w' v" W! x& }% g % f1 y% ^) N5 e( P- O8 ?2Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal, Montréal, Québec H1L4M1, Canada j+ t8 J1 ?2 U3 }+ }5 C& X3 ^
. L, o$ S" E; W% G2 }3 These authors contributed equally to this work.# _1 J5 c: Y8 O) e
1 S. c- f4 d4 ?2 l0 A# eAbstract 2 `) x$ B: E; N" E2 f) X0 q, u# R9 k- [( t6 H. i8 d: _9 p3 w
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. F+ C9 G! Y* P: d2 @8 t2 s4 p# [0 T m& _. F ~& V" q6 I http://www.bioon.com/biology/cancer/470911.shtml作者: mbjane 时间: 2011-1-12 12:59