The murine gene p27Kip1 is haplo-insufficient for tumour suppression. This study shows that both p27 nullizygous and heterozygous mice are predisposed to tumours in multiple tissues when exposed to γ-irradiation or a chemical carcinogen. Molecular analyses reveal that the remaining wild-type allele is neither mutated nor silenced, indicating that p27 is haplo-insufficient for tumour suppression. This challenges the traditional two-mutation model for tumour suppressor genes, as it excludes genes like p27 that exhibit haplo-insufficiency. Tumour-suppressor proteins affect multiple cellular pathways, including proliferation, apoptosis, differentiation, and genomic integrity. The identification of a tumour-suppressor gene is usually based on genetic evidence rather than functional criteria. The common definition requires mutations in both copies of a candidate gene in tumours. However, this definition is too restrictive, as it excludes genes like p27 that exhibit haplo-insufficiency. The study examined the tumour-suppressor function of p27Kip1 by assessing the susceptibility of p27-deficient mice to tumorigenesis induced by γ-irradiation and the chemical carcinogen N-ethyl-N-nitrosourea (ENU). p27-null mice showed decreased tumour-free survival following γ-irradiation compared to p27++ controls. p27-null mice also showed increased tumour-related mortality, mainly due to pituitary tumours and intestinal adenomas. In p27++ mice, lymphoma and liver adenomas were the most frequent causes of tumour morbidity. However, in p27-null mice, the increased tumour-related mortality was mainly due to increased numbers of intestinal and pituitary adenomas. Lesions of female reproductive organs occurred more frequently in p27-deficient mice, often associated with histological evidence of neoplasia. Adrenal tumours also occurred at higher frequency in p27-deficient animals. The incidence of adenomas in both the small and large intestine was increased in p27-null mice, as was the number of malignant tumours. The number of lung adenomas was increased in p27-null animals following both irradiation and ENU treatment. In three p27-null animals, lung tumours completely consolidated one or more lung lobes and exhibited dysplasia typical of adenocarcinomas. p27-heterozygous mice were also significantly more susceptible than wild-type mice to γ-irradiation and ENU-induced tumorigenesis of the lung, intestine, and pituitary. However, the tumours were histologically similar to those in p27-null animals. The study found no deletions or rearrangements of the wild-type p27 allele in 33 tumours from p27 heterozygotes. No point mutations were present inThe murine gene p27Kip1 is haplo-insufficient for tumour suppression. This study shows that both p27 nullizygous and heterozygous mice are predisposed to tumours in multiple tissues when exposed to γ-irradiation or a chemical carcinogen. Molecular analyses reveal that the remaining wild-type allele is neither mutated nor silenced, indicating that p27 is haplo-insufficient for tumour suppression. This challenges the traditional two-mutation model for tumour suppressor genes, as it excludes genes like p27 that exhibit haplo-insufficiency. Tumour-suppressor proteins affect multiple cellular pathways, including proliferation, apoptosis, differentiation, and genomic integrity. The identification of a tumour-suppressor gene is usually based on genetic evidence rather than functional criteria. The common definition requires mutations in both copies of a candidate gene in tumours. However, this definition is too restrictive, as it excludes genes like p27 that exhibit haplo-insufficiency. The study examined the tumour-suppressor function of p27Kip1 by assessing the susceptibility of p27-deficient mice to tumorigenesis induced by γ-irradiation and the chemical carcinogen N-ethyl-N-nitrosourea (ENU). p27-null mice showed decreased tumour-free survival following γ-irradiation compared to p27++ controls. p27-null mice also showed increased tumour-related mortality, mainly due to pituitary tumours and intestinal adenomas. In p27++ mice, lymphoma and liver adenomas were the most frequent causes of tumour morbidity. However, in p27-null mice, the increased tumour-related mortality was mainly due to increased numbers of intestinal and pituitary adenomas. Lesions of female reproductive organs occurred more frequently in p27-deficient mice, often associated with histological evidence of neoplasia. Adrenal tumours also occurred at higher frequency in p27-deficient animals. The incidence of adenomas in both the small and large intestine was increased in p27-null mice, as was the number of malignant tumours. The number of lung adenomas was increased in p27-null animals following both irradiation and ENU treatment. In three p27-null animals, lung tumours completely consolidated one or more lung lobes and exhibited dysplasia typical of adenocarcinomas. p27-heterozygous mice were also significantly more susceptible than wild-type mice to γ-irradiation and ENU-induced tumorigenesis of the lung, intestine, and pituitary. However, the tumours were histologically similar to those in p27-null animals. The study found no deletions or rearrangements of the wild-type p27 allele in 33 tumours from p27 heterozygotes. No point mutations were present in