Intrinsic Cooperation between p16INK4a and p21Waf1/Cip1 in the Onset of Cellular Senescence and Tumor Suppression In vivo
Intrinsic Cooperation between p16INK4a and p21Waf1/Cip1 in the Onset of Cellular Senescence and Tumor Suppression In vivo
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DOI：
10.1158/0008-5472.can-10-0801
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发表时间：
2010-11-15
期刊：
影响因子：
11.2
通讯作者：
Ohtani, Naoko
中科院分区：
文献类型：
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作者：
Takeuchi, Shinji;Takahashi, Akiko;Ohtani, Naoko
虽然p16（INK 4a）和p21（Waf 1/Cip 1）细胞周期蛋白依赖性激酶（CDK）抑制剂在体外细胞衰老中起关键作用，但它们在体内衰老中的作用仍然知之甚少。这种情况部分是由于p16（INK 4a）和p21（Waf 1/Cip 1）之间可能存在代偿效应，或由于功能相关的CDK抑制剂上调。为了直接解决p16（INK 4a）和p21（Waf 1/Cip 1）在体内衰老中的协同作用，我们产生了一个简单缺乏p16（INK 4a）和p21（Waf 1/Cip 1）基因的小鼠系[双敲除（DKO）]。小鼠胚胎成纤维细胞（MEF）来自DKO小鼠显示细胞衰老的证据时，在体外连续培养。此外，DKO MEFs很容易逃脱Ras诱导的衰老，并推翻了接触抑制培养。在缺乏p16（INK 4a）或p21（Waf 1/Cip 1）的MEFs中，情况并非如此，表明p16（INK 4a）和p21（Waf 1/Cip 1）在体外细胞衰老和接触抑制中起协同作用。值得注意的是，我们发现DKO小鼠对7，12-二甲基苯并（a）蒽/12-O-十四烷酰基佛波醇-13-乙酸酯诱导的皮肤癌发生极其敏感，该皮肤癌发生涉及H-ras基因的致癌突变。机制研究表明，DKO小鼠中癌症的高发病率可能反映了p21（Waf 1/Cip 1）缺失引起的良性皮肤肿瘤形成增加与p16（INK 4a）缺失引起的良性皮肤肿瘤恶性转化增加的协同效应。我们的研究结果建立了p16（INK 4a）和p21（Waf 1/Cip 1）在体内细胞衰老和肿瘤抑制中的内在合作。癌症研究; 70（22）; 9381-90。(C)2010年AACR。
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.