The role of the p53 and Rb-1 genes in cancer, development and apoptosis.

Abstract

Gene targeting using embryonal stem cells has been used to generate strains of mice with inactivating mutations at the Rb-1 and p53 tumour suppressor loci. Mice heterozygous for a null allele of Rb-1 do not show retinoblastomas but instead develop pituitary tumours. Homozygotes die at between 10 and 14 days' gestation and show increased levels of both cell division and cell death by apoptosis in the haematopoietic and nervous systems. This is consistent with the view that the Rb-1 gene product plays a general role in the maturation of precursor cells. In contrast, mice heterozygous for a null allele of p53 are predisposed to a spectrum of tumours, while the corresponding homozygotes are viable but show a very high tumour incidence. Thymocytes from p53 homozygotes, unlike wild-type thymocytes, do not show increased levels of apoptosis following treatment with DNA-damaging agents, while response to its induction by other agents is unaltered. Similarly, epithelial cells from the crypts of both small and large intestine of p53-deficient mice are resistant to the induction of apoptosis by gamma-irradiation. In contrast, two other early responses of wild-type crypts to gamma-irradiation, namely the G2 block and the reduction in bromodeoxyuridine incorporation, are both largely intact in p53-deficient mice. These observations are consistent with the view that p53 is responsible for monitoring DNA damage so that damaged cells can be either repaired or eliminated prior to division.