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Polycomb complexes regulate cellular senescence by repression of ARF in cooperation with E2F3
Author(s) -
Miki Jun,
Fujimura Yuichi,
Koseki Haruhiko,
Kamijo Takehiko
Publication year - 2007
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2007.01135.x
Subject(s) - senescence , biology , bmi1 , microbiology and biotechnology , psychological repression , genetics , gene expression , stem cell , gene
Cellular senescence is a program in normal cells triggered in response to various types of stress that cells experience when they are explanted into culture. In this study, functional analyses on the role of the class II polycomb complex in cellular senescence were performed using mouse embryo fibroblasts (MEFs) with a genetically deleted member of the complex, Mel18 . Mel18 ‐null MEFs undergo typical premature senescence accompanied by the up‐regulation of ARF/p53/p16 INK4a and decrease of Ring1b/Bmi1. Our results demonstrated that ARF or p53 deletion cancels the senescence in Mel18 ‐null MEFs, and the fact that p16 INK4a is up‐regulated in double‐null MEFs suggests that the ARF/p53 pathway plays a central role in stress‐induced senescence. The in vivo binding of Ring1b and E2F3b to the ARF promoter decreased progressively in senescence, and Mel18 inactivation accelerated the exfoliation of Ring1b/E2F3b from the promoter sequence, indicating the cooperation of polycombs/E2F3b on ARF expression and cellular senescence. Taken together, it seems that class II polycomb proteins and E2F3b dually control cellular senescence via the ARF/p53 pathway.