SUSCEPTIBILITY TO RADIATION CARCINOGENESIS AND ACCUMULATION OF CHROMOSOMAL BREAKAGE IN P53 DEFICIENT MICE

The p53 tumour suppressor gene is an important participant in the cell ular response to ionizing radiation and other DNA damaging agents. Cel ls which lack p53 are unable to arrest cell cycle or enter into apopto tic cell death following irradiation. Moreover, these p53 deficient ce lls exhibit an increased resistance to DNA damaging agents, including radiation. The significance of this radiation-resistance and its relat ionship to the role that p53 plays in tumour suppression and the cellu lar radiation response has not yet been determined. In this report we have analyzed p53 deficient mice, expressing either a mutant p53 trans gene or having a targeted p53 null allele, in order to investigate the role that p53 plays in governing susceptibility to radiation-carcinog enesis and in controlling the in vivo accumulation of chromosomal abno rmalities. We show that wild-type p53 plays a critical role in control ling susceptibility to gamma-radiation-induced tumorigenesis, and sarc omas and lymphomas rapidly appear in irradiated p53 transgenic mice. M oreover, this susceptibility to radiation-carcinogenesis is associated with a two-fold increase in the in vivo accumulation of radiation-ind uced double stranded chromosomal breaks relative to that observed in w ild-type animals. Taken together, these observations suggest that p53 acts to suppress tumour formation in vivo by preventing the accumulati on of cells that have sustained radiation-induced DNA damage.