The murine gene p27Kip1 is haplo-insufficient for tumour suppression

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Abstract
P27Kip is a candidate human tumour-suppressor protein, because it is able to inhibit cyclin-dependent kinases and block cell proliferation1,2,3,4,5. 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 mortality6,7,8,9,10. However, it has not been possible to establish a causal link between p27 and tumour suppression, because only rare instances of homozygous inactivating mations of the p27 gene have been found in human tumours11,12,13,14. Thus, p27Kip1 does not fulfil Knudson's ‘two-mutation’ criterion for a tumour-suppressor gene15. Here we show that both p27 nullizygous and p27 heterozygous mice are predisposed to tumours in multiple tissues when challenged with γ-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.