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The murine gene p27Kip1 is haplo-insufficient for tumour suppression
M L Fero1, E Randel, K E Gurley
1Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Abstract:
p27Kip is a candidate human tumour-suppressor protein, because it is able to inhibit cyclin-dependent kinases and block cell proliferation. 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. 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. Thus, p27Kip1 does not fulfil Knudson's 'two-mutation' criterion for a tumour-suppressor gene. 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.
Insights
The p27 protein, a cell proliferation inhibitor, acts as a tumor suppressor in mice. Even with one functional copy, mice are prone to tumors, indicating p27
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- p27Kip is a candidate human tumor-suppressor protein that inhibits cyclin-dependent kinases and cell proliferation.
- Low p27 protein levels in human carcinomas correlate with aggressiveness and mortality.
- The causal link between p27 and tumor suppression is unclear due to rare homozygous inactivating mutations.
Purpose of the Study:
- To investigate the role of p27 in tumor suppression in vivo.
- To determine if p27 functions as a tumor suppressor in mice.
- To explore the mechanism of p27-mediated tumor suppression, including haplo-insufficiency.
Main Methods:
- Generating and challenging p27 nullizygous and heterozygous mice with gamma-irradiation and a chemical carcinogen.
- Analyzing tumor development in p27-deficient mice.
- Performing molecular analyses on tumors from p27 heterozygous mice to assess the remaining wild-type allele.
Main Results:
- p27 nullizygous and heterozygous mice showed predisposition to tumors in multiple tissues after carcinogen exposure.
- p27 functions as a multiple-tissue tumor suppressor in mice.
- Molecular analysis revealed the remaining wild-type p27 allele was not mutated or silenced in tumors of heterozygous mice, indicating haplo-insufficiency.
Conclusions:
- p27 is a haplo-insufficient tumor suppressor in mice, challenging the traditional view of recessive tumor-suppressor genes.
- The findings suggest that haplo-insufficiency should be considered when evaluating tumor-suppressor genes.
- p27's role in tumor suppression is confirmed in vivo, with implications for understanding human cancer development.
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