p12CDK2-AP1 mediates DNA damage responses induced by cisplatin

被引：15

作者：

Kim, Y ^{[1
]}

McBride, J ^{[1
]}

Zhang, R ^{[1
]}

Zhou, XF ^{[1
]}

Wong, DT ^{[1
]}

机构：

[1] Univ Calif Los Angeles, Sch Dent, Dent Res Inst, Los Angeles, CA 90095 USA

来源：

ONCOGENE | 2005年 / 24卷 / 03期

关键词：

p12(CDK2-AP1); DNA-damaging agent; cisplatin; cell cycle; human oral cancer;

D O I：

10.1038/sj.onc.1208222

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：

We examined the biological role of p12(CDK2-AP1) in cisplatin-mediated responses by using murine ES p12(CDK2-AP1) knockout clones generated by a targeted disruption of murine p12(CDK2-AP1). Homozygous knockout clones showed an increased cellular proliferation along with an increase in Sand a decrease in G2/M phase populations. Interestingly, ES p12(CDK2-AP1) knockout clones showed a resistance to cisplatin treatment along with an increased DNA repair activity assessed by host cell reactivation assay using a cisplatin-damaged reporter DNA and a significant reduction of apoptosis upon cisplatin treatment. By using stable p12(CDK2-AP1) short interfering RNA ( siRNA) clones from human normal oral keratinocytes, we confirmed that downregulation of p12(CDK2-AP1) resulted in a resistance to cisplatin. More interestingly, cisplatin treatment resulted in a reduction of CDK2 kinase activity in control clones, but p12(CDK2-AP1) knockout clones showed a sustained CDK2 kinase activity. These data suggest that p12(CDK2-AP1) plays a role in cisplatin-mediated cellular responses by modulating CDK2 activity. These data further suggest p12(CDK2-AP1) is a potential gene therapeutic agent for oral/head and neck cancer in conjunction with DNA-damaging agents such as cisplatin.

引用

页码：407 / 418

页数：12

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