K-ras modulates the cell cycle via both positive and negative regulatory pathways

被引:59
作者
Fan, JG [1 ]
Bertino, JR [1 ]
机构
[1] MEM SLOAN KETTERING CANC CTR,PROGRAM MOL PHARMACOL & THERAPEUT,NEW YORK,NY 10021
关键词
ras; cell cycle; gene regulation;
D O I
10.1038/sj.onc.1201105
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
The effect of activated human K-ras on cell cycle proteins was studied by use of a stable MCF-7 transfectant expressing inducible activated K-ras under the control of a tetracycline (Tet)-responsive promoter. Induction of activated K-ras by Tet withdrawal accelerated cell growth and entry into S-phase, To understand the mechanism(s) by which activated K-ras exerts its effect on the cell cycle, expression of both cell cycle stimulatory proteins as well as cell cycle inhibitors was examined. Upon induction of activated K-ras, several cell cycle stimulators were up-regulated, including cyclins A, D3, and E, and the E2F family of transcription factors, which was accompanied by increased cyclin A-associated kinase activity and E2F transcriptional activity, respectively. Up-regulation of cyclin A occurred at the transcriptional level and in a serum-dependent manner, Furthermore, induction of activated K-ras down-regulated p27(Kip1) and up-regulated p53. Up-regulation of p53 was correlated with enhanced p53 transactivation and accompanied by up-regulation of p21(Waf1) and Gadd 45, two p53 effecters and negative cell cycle regulators. In addition, activated K-ras upregulates bcl-2 but has no effect on bax or bcl-x expression. Taken together, these data indicate that activated K-ras affects the cell cycle by modulating both positive and negative cell cycle regulatory pathways.
引用
收藏
页码:2595 / 2607
页数:13
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