p19ARF prevents G1 cyclin-dependent kinase activation by interacting with MDM2 and activating p53 in mouse fibroblasts

被引:35
作者
Kurokawa, K [1 ]
Tanaka, T [1 ]
Kato, J [1 ]
机构
[1] Nara Inst Sci & Technol, Grad Sch Biol Sci, Nara 6300101, Japan
关键词
p19(ARF); G1; cyclin-cdks; arrest; MDM2; p53; p21(Cip1);
D O I
10.1038/sj.onc.1202628
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
p19(ARF) encoded by the INK4a tumor suppressor gene locus functions upstream of p53 to induce cell cycle arrest, p19(ARF) can interact with MDM2 and p53 in cells ectopically overexpressing these three components, but the biochemical cascades from p19(ARF) to cell cycle arrest has not been fully elucidated, In this study, we generated stably transfected NIH3T3 cells that express exogenous p19(ARF); under the control of a heavy metal-inducible metalothionine promoter. Cells arrested in G1 by ectopically expressed p19(ARF) contained considerably reduced G1 cyclin dependent kinase (cdk2 and cdk4) activities, The expression of cyclin A (a regulatory subunit of cdk2) markedly decreased, while cyclin D1, the major cdk4 partner in fibroblasts, expressed at a slightly higher level and formed complexes with cdk2 and cdk6 in addition to cdk4. Induction of p19(ARF) activated p53 by increasing its stability; and allowed the expression of p21(Cip1) which bound to all of the cyclin D1-cdk complexes (cyclin D1-cdk2, -cdk4, and -cdk6) thereby inhibiting their kinase activities. p19(ARF) formed complexes with several cellular proteins including mouse MDM2. The majority of MDM2 was found in the complex with p19(ARF), while no p53 was detected in association with p19(ARF). Thus, we propose that p19(ARF) neutralizes MDM2 by sequestration from p53, which results in activation of p53, inhibition of G1 cyclin-cdk activities, and G1 arrest.
引用
收藏
页码:2718 / 2727
页数:10
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