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Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27
Author(s) -
Bouchard Caroline,
Thieke Katja,
Maier Antje,
Saffrich Rainer,
HanleyHyde Joan,
Ansorge Wilhelm,
Reed Steve,
Sicinski Piotr,
Bartek Jiri,
Eilers Martin
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.19.5321
Subject(s) - biology , cyclin a2 , cyclin d , cyclin d2 , ectopic expression , cyclin a , cyclin b , trichostatin a , microbiology and biotechnology , cell cycle , cyclin , cyclin e , cyclin dependent kinase , cancer research , cyclin d1 , cell culture , histone deacetylase , histone , cell , gene , genetics
Ectopic expression of Myc induces Cdk2 kinase activity in quiescent cells and antagonizes association of p27 kip1 with Cdk2. The target gene(s) by which Myc mediates this effect is largely unknown. We now show that p27 is rapidly and transiently sequestered by cyclin D2–Cdk4 complexes upon activation of Myc and that cyclin D2 is a direct target gene of Myc. The cyclin D2 promoter is repressed by Mad–Max complexes and de‐repressed by Myc via a single highly conserved E‐box element. Addition of trichostatin A to quiescent cells mimics activation of Myc and induces cyclin D2 expression, suggesting that cyclin D2 is repressed in a histone deacetylase‐dependent manner in quiescent cells. Inhibition of cyclin D2 function in established cell lines, either by ectopic expression of p16 or by antibody injection, inhibits Myc‐dependent dissociation of p27 from Cdk2 and Myc‐induced cell cycle entry. Primary mouse fibroblasts that are cyclin D2‐deficient undergo accelerated senescence in culture and are not immortalized by Myc; induction of apoptosis by Myc is unimpaired in such cells. Our data identify a downstream effector pathway that links Myc directly to cell cycle progression.