P53 null mice: damaging the hypothesis?
P53 is extremely well characterised as a tumour suppressor gene, and many activities have been attributed to it which are consistent with this function. However, despite being the subject of intense study it still remains unclear precisely which of these functions is crucial to its in vivo role as a tumour suppressor gene. This is particularly true of its role in the induction of apoptosis. The original observation of p53-dependent apoptosis gave rise to the following hypothesis: namely, that p53 deficiency leads to a persistence of DNA damaged cells which are the potential founders of malignancy. This review summarises the data for and against this hypothesis, with specific emphasis on data obtained from studies of the murine intestine. What emerges from these studies is a complex picture, where data can be obtained in support of this hypothesis, but there are many circumstances which exist where it is not supported. Taken together this collection of data suggests that the abrogation of p53-dependent apoptosis may indeed impact upon carcinogenesis and neoplastic progression, but that the simplistic notion of p53 as the single gatekeeper of this pathway is untenable.
Sansom
O J
OJ
Department of Pathology, Medical School, Teviot Place, University of Edinburgh, EH8 9AG Edinburgh, UK.
Clarke
A R
AR
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004268:DNA-Binding Proteins; D016158:Genes, p53; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein; D009154:Mutation; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein