TUMOR-DERIVED P16 ALLELES ENCODING PROTEINS DEFECTIVE IN CELL-CYCLE INHIBITION
TUMOR-DERIVED P16 ALLELES ENCODING PROTEINS DEFECTIVE IN CELL-CYCLE INHIBITION
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DOI：
10.1038/375506a0
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发表时间：
1995-06-08
期刊：
影响因子：
64.8
通讯作者：
HARLOW, E
中科院分区：
文献类型：
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作者：
KOH, J;ENDERS, GH;HARLOW, E
细胞周期蛋白依赖性激酶抑制剂 p16 是一种候选肿瘤抑制蛋白，映射到与家族性黑色素瘤和其他肿瘤类型密切相关的基因组位点(1-3)。原发性肿瘤的筛查和家族性黑色素瘤谱系的连锁分析已鉴定出 p16 中的许多潜在突变，但这些序列变异的功能意义仍不清楚(1,3-9)。我们在此报告，p16 可以作为细胞周期 G1 期进展的有效且特异性抑制剂，并且我们证明 p16 的几个肿瘤衍生等位基因编码功能受损的蛋白质。 p16 阻止细胞周期进展的能力通常与体外细胞周期蛋白 D1/Cdk4 激酶活性的抑制相关，但测试的等位基因中有两个例外。在体内，功能性视网膜母细胞瘤蛋白的存在似乎是必要的，但可能不足以赋予对 p16 介导的生长停滞的完全敏感性。我们的结果支持了这样的观点：p16 是一种重要的细胞周期调节因子，其失活有助于人类肿瘤的生长。
THE cyclin-dependent kinase inhibitor p16 is a candidate tumour-suppressor protein that maps to a genomic locus strongly associated with familial melanoma and other tumour types(1-3). Screening of primary tumours and linkage analysis of familial melanoma pedigrees have identified many potential mutations in p16, but the functional significance of these sequence variants has remained unclear(1,3-9). We report here that p16 can act as a potent and specific inhibitor of progression through the G1 phase of the cell cycle, and we demonstrate that several tumour-derived alleles of p16 encode functionally compromised proteins. The ability of p16 to arrest cell-cycle progression generally correlates with inhibition of cyclin D1/Cdk4 kinase activity irt vitro, with two exceptions among the alleles tested. In vivo, the presence of functional retinoblastoma protein appears to be necessary but may not be sufficient to confer full sensitivity to p16-mediated growth arrest. Our results provide support for the notion that p16 is an important cell-cycle regulator whose inactivation contributes to the outgrowth of human tumours.