FUNCTION AND CONFORMATION OF WILD-TYPE P53 PROTEIN ARE INFLUENCED BY MUTATIONS IN BOVINE LEUKEMIA VIRUS-INDUCED B-CELL LYMPHOSARCOMA

The mutations of the p53 gene previously represented one of several ge netic changes involved in the development of bovine leukemia virus (BL V)-induced lymphosarcoma, while the effects of these mutations on the function of p53 are unknown. We identified four mutations of p53 gene in BLV-infected cattle with lymphosarcoma and demonstrated clearly the existence of two functionally distinct groups of mutants: (i) the mut ant forms with substitutions at codons 241 and 242, which were mapped within an evolutionally conserved region and corresponded to the human ''hot-spot'' mutations, had completely lost the capacities for transa ctivation and growth suppression and gained transdominant repression a ctivity in p53-null SAOS-2 cells; and (ii) the mutations al codons 206 and 207 were located outside the evolutionally conserved regions. The se mutants partially retained the capacity for transactivation and gro wth suppression and failed to inhibit the transactivation activity of coexpressed wild-type p53, instead showing an enhancement of this acti vity. In addition, protein analysis using an antibody specific for the mutant form revealed that the mutations at codons 206 and 242 induced a ''mutant'' conformation of the bovine p53 proteins. Collectively, t hese results show that mutations of p53 gene in BLV-infected cattle wi th lymphosarcoma can potentially alter its physiological function and may play an important role in BLV-induced leukemogenesis. (C) 1998 Aca demic Press.