A CDKN2A mutation in familial melanoma that abrogates binding of p16INK4a to CDK4 but not CDK6
A CDKN2A mutation in familial melanoma that abrogates binding of p16INK4a to CDK4 but not CDK6
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DOI：
10.1158/0008-5472.can-07-1528
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Peters, Gordon
中科院分区：
文献类型：
--
作者：
Jones, Rebecca;Ruas, Margarida;Peters, Gordon
CDKN2A基因座编码两种不同的蛋白质，p16（INK4a）和pI4（ARF），这两种蛋白质都涉及不同背景下的复制衰老和肿瘤抑制。在这里，我们描述了一种新的人二倍体成纤维细胞株（命名为米兰HDFs）的特征，该株来自p16（INK4a）中R24 P突变纯合的个体。由于该突变发生在INK4a的第一个外显子（外显子1 α），因此对p14（ARE）的一级序列没有影响。基于体外和体内分析，R24 P变体特异性地缺陷于与CDK4的结合，但仍然能够与CDK6缔合。然而，米兰HDFs的行为，如果他们是p16（INK4a）缺陷，在自发性和癌基因诱导的衰老的敏感性方面，和R24 P变异体在正常成纤维细胞异位表达时对增殖的影响不大。然而，它可以损害U20S细胞的增殖，可能是因为它们比原代成纤维细胞表达更多的CDK6。这些观察结果表明，CDK4和CDK6在功能上不是冗余的，并强调了CDK4在黑色素瘤发展中的重要性。
The CDKN2A locus encodes two distinct proteins, p16(INK4a) and pI4(ARF), both of which are implicated in replicative senescence and tumor suppression in different contexts. Here, we describe the characterization of a novel strain of human diploid fibroblasts (designated Milan HDFs) from an individual who is homozygous for the R24P mutation in p16(INK4a) As this mutation occurs in the first exon of INK4a (exon 1 alpha), it has no effect on the primary sequence of p14(ARE). Based on both in vitro and in vivo analyses, the R24P variant is specifically defective for binding to CDK4 but remains able to associate with CDK6. Nevertheless, Milan HDFs behave as if they are p16(INK4a) deficient, in terms of sensitivity to spontaneous and oncogene-induced senescence, and the R24P variant has little effect on proliferation when ectopically expressed in normal fibroblasts. It can, however, impair the proliferation of U20S cells, presumably because they express more CDK6 than primary fibroblasts. These observations suggest that CDK4 and CDK6 are not functionally redundant and underscore the importance of CDK4 in the development of melanoma.