期刊
CANCER RESEARCH
卷 70, 期 22, 页码 9381-9390出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-0801
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资金
- Ministry of Education, Science, Sports and Technology of Japan
- Astellas Foundation for Research on Metabolic Disorders
- Vehicle Racing Commemorative Foundation
- Takeda Science Foundation
- Uehara Memorial Foundation
- Mishima Kaiun Memorial Foundation
- Grants-in-Aid for Scientific Research [21390290] Funding Source: KAKEN
Although the p16(INK4a) and p21(Waf1/Cip1) cyclin-dependent kinase (CDK) inhibitors are known to play key roles in cellular senescence in vitro, their roles in senescence remain rather poorly understood in vivo. This situation is partly due to the possibility of compensatory effect(s) between p16(INK4a) and p21(Waf1/Cip1) or to the upregulation of functionally related CDK inhibitors. To directly address the cooperative roles of p16(INK4a) and p21(Waf1/Cip1) in senescence in vivo, we generated a mouse line simply lacking both p16(INK4a) and p21(Waf1/Cip1) genes [double-knockout (DKO)]. Mouse embryonic fibroblasts (MEF) derived from DKO mice displayed no evidence of cellular senescence when cultured serially in vitro. Moreover, DKO MEFs readily escaped Ras-induced senescence and overrode contact inhibition in culture. This was not the case in MEFs lacking either p16(INK4a) or p21(Waf1/Cip1), indicating that p16(INK4a) and p21(Waf1/Cip1) play cooperative roles in cellular senescence and contact inhibition in vitro. Notably, we found the DKO mice to be extremely susceptible to 7,12-dimethylbenz (a) anthracene/12-O-tetradecanoyIphorbol-13-acetate-induced skin carcinogenesis that involves oncogenic mutation of the H-ras gene. Mechanistic investigations suggested that the high incidence of cancer in DKO mice likely reflected a cooperative effect of increased benign skin tumor formation caused by p21(Waf1/Cip1) loss, with increased malignant conversion of benign skin tumors caused by p16(INK4a) loss. Our findings establish an intrinsic cooperation between p16(INK4a) and p21(Waf1/Cip1) in the onset of cellular senescence and tumor suppression in vivo. Cancer Res; 70(22); 9381-90. (C) 2010 AACR.
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