Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21(WAF1/CiP1)

被引:465
作者
Somasundaram, K
Zhang, HB
Zeng, YX
Houvras, Y
Peng, Y
Zhang, HX
Wu, GS
Licht, JD
Weber, BL
ElDeiry, WS
机构
[1] UNIV PENN,SCH MED,HOWARD HUGHES MED INST,LAB MOL ONCOL & CELL CYCLE REGULAT,PHILADELPHIA,PA 19104
[2] UNIV PENN,SCH MED,DEPT MED,PHILADELPHIA,PA 19104
[3] UNIV PENN,SCH MED,DEPT GENET,PHILADELPHIA,PA 19104
[4] UNIV PENN,SCH MED,CTR CANC,PHILADELPHIA,PA 19104
[5] CUNY MT SINAI SCH MED,BROOKDALE CTR DEV & MOL BIOL,NEW YORK,NY 10029
[6] CUNY MT SINAI SCH MED,DEPT MED,NEW YORK,NY 10029
关键词
D O I
10.1038/38291
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Much of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in the BRCA1 tumour-suppressor gene(1-3). The nuclear protein BRCA1 has the properties of a transcription factor(4-7), and can interact with the recombination and repair protein pAD51 (ref. 8), Young women with germline alterations in BRCA1 develop breast cancer at rates 100-fold higher than the general population(3), and BRCA1-null mice die before day 8 of development(9,10). However, the mechanisms of BRCA1-mediated growth regulation and tumour suppression remain unknown, Here we show that BRCA1 transactivates expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in a p53-independent manner, and that BRCA1 inhibits cell-cycle progression into the S-phase following its transfection into human cancer cells, BRCA1 does not inhibit S-phase progression in p21(-/-) cells, unlike p21(+/+) cells, and tumour-associated, transactivation-deficient mutants of BRCA1 are defective in both transactivation of p21 and cell-cycle inhibition, These data suggest that one mechanism by which BRCA1 contributes to cell-cycle arrest and growth suppression is through the induction of p21.
引用
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页码:187 / 190
页数:4
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