Bcl-2 retards cell cycle entry through p27Kip1, pRB relative p130, and altered E2F regulation

被引:127
作者
Vairo, G
Soos, TJ
Upton, TM
Zalvide, J
DeCaprio, JA
Ewen, ME
Koff, A
Adams, JM [1 ]
机构
[1] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia
[2] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA
[3] Dana Farber Canc Inst, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Boston, MA 02115 USA
关键词
D O I
10.1128/MCB.20.13.4745-4753.2000
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Independent of its antiapoptotic function, Bcl-2 can, through an undetermined mechanism, retard entry into the cell cycle. Cell cycle progression requires the phosphorylation by cyclin-dependent kinases (Cdks) of retinoblastoma protein (pRB) family members to free E2F transcription factors. We have explored whether retarded cycle entry is mediated by the Cdk inhibitor p27 or the pRB family. In quiescent fibroblasts, enforced Bcl-2 expression elevated levels of both p27 and the pRB relative p130. Bcl-2 still slowed G(1) progression in cells deficient in pRB but not in those lacking p27 or p130. Hence, pRB is not required, but both p27 and p130 are essential mediators. The ability of p130 to form repressive complexes with E2F4 is implicated, because the retardation by Bcl-2 was accentuated by coexpressed E2F4. A plausible relevant target of p130/E2F4 is the E2F1 gene, because Bcl-2 expression delayed E2F1 accumulation during G(1) progression and overexpression of E2F1 overrode the Bcl-2 inhibition. Hence, Bcl-2 appears to retard cell cycle entry by increasing p27 and p130 levels and maintaining repressive complexes of p130 with E2F4, perhaps to delay E2F1 expression.
引用
收藏
页码:4745 / 4753
页数:9
相关论文
共 51 条
[1]   The Bcl-2 protein family: Arbiters of cell survival [J].
Adams, JM ;
Cory, S .
SCIENCE, 1998, 281 (5381) :1322-1326
[2]  
Agrawal D, 1996, MOL CELL BIOL, V16, P4327
[3]   Expression of bcl-2 protein is decreased in colorectal adenocarcinomas with microsatellite instability [J].
Biden, KG ;
Simms, LA ;
Cummings, M ;
Buttenshaw, R ;
Schoch, E ;
Searle, J ;
Gobe, G ;
Jass, JR ;
Meltzer, SJ ;
Leggett, BA ;
Young, J .
ONCOGENE, 1999, 18 (05) :1245-1249
[4]   Bax alpha perturbs T cell development and affects cell cycle entry of T cells [J].
Brady, HJM ;
GilGomez, G ;
Kirberg, J ;
Berns, AJM .
EMBO JOURNAL, 1996, 15 (24) :6991-7001
[5]   Dual cyclin-binding domains are required for p107 to function as a kinase inhibitor [J].
Castaño, E ;
Kleyner, Y ;
Dynlacht, BD .
MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (09) :5380-5391
[6]  
Claudio PP, 1996, CANCER RES, V56, P2003
[7]   A new pathway for mitogen-dependent Cdk2 regulation uncovered in p27Kip1-deficient cells [J].
Coats, S ;
Whyte, P ;
Fero, ML ;
Lacy, S ;
Chung, G ;
Randel, E ;
Firpo, E ;
Roberts, JM .
CURRENT BIOLOGY, 1999, 9 (04) :163-173
[8]   Shared role of the pRB-related p130 and p107 proteins in limb development [J].
Cobrinik, D ;
Lee, MH ;
Hannon, G ;
Mulligan, G ;
Bronson, RT ;
Dyson, N ;
Harlow, E ;
Beach, D ;
Weinberg, RA ;
Jacks, T .
GENES & DEVELOPMENT, 1996, 10 (13) :1633-1644
[9]   Distinct roles for E2F proteins in cell growth control and apoptosis [J].
DeGregori, J ;
Leone, G ;
Miron, A ;
Jakoi, L ;
Nevins, JR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (14) :7245-7250
[10]   The regulation of E2F by pRB-family proteins [J].
Dyson, N .
GENES & DEVELOPMENT, 1998, 12 (15) :2245-2262