The murine gene p27Kip1 is haplo-insufficient for tumour suppression
The murine gene p27Kip1 is haplo-insufficient for tumour suppression
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作者：
Fero, ML;Randel, E;Kemp, CJ
p27（Kip）是一种候选人肿瘤抑制蛋白，因为它能够抑制细胞周期蛋白依赖性激酶并阻断细胞增殖（1-5）。异常低水平的p27蛋白常见于人类癌症，这些低水平与组织学侵袭性和患者死亡率直接相关（6-10）。然而，目前尚不可能在p27和肿瘤抑制之间建立因果关系，因为在人类肿瘤中仅发现了罕见的p27基因纯合失活突变（11-14）。因此，p27（Kip 1）不符合Knudson的肿瘤抑制基因“两突变”标准（15）。在这里，我们表明，p27缺失和p27杂合子小鼠易患肿瘤的多个组织时，挑战与γ射线或化学致癌物。因此，p27在小鼠中是多组织肿瘤抑制因子。对p27杂合子小鼠肿瘤的分子分析表明，剩余的野生型等位基因既没有突变也没有沉默。因此，p27对于肿瘤抑制是单倍不足的。肿瘤抑制基因中的无效突变是隐性的这一假设排除了那些表现出单倍不足的基因。
p27(Kip) is a candidate human tumour-suppressor protein, because it is able to inhibit cyclin-dependent kinases and block cell proliferation(1-5). Abnormally low levels of the p27 protein are frequently found in human carcinomas, and these low levels correlate directly with both histological aggressiveness and patient mortality(6-10). However, it has not been possible to establish a causal link between p27 and tumour suppression, because only rare instances of homozygous inactivating mutations of the p27 gene have been found in human tumours(11-14). Thus, p27(Kip1) does not fulfil Knudson's 'two-mutation' criterion for a tumour-suppressor gene(15). Here we show that both p27 nullizygous and p27 heterozygous mice are predisposed to tumours in multiple tissues when challenged with gamma-irradiation or a chemical carcinogen. Therefore p27 is a multiple-tissue tumour suppressor in mice. Molecular analyses of tumours in p27 heterozygous mice show that the remaining wild-type allele is neither mutated nor silenced. Hence, p27 is haplo-insufficient for tumour suppression. The assumption that null mutations in tumour-suppressor genes are recessive excludes those genes that exhibit haplo-insufficiency.