MUTANT-P53 CAN INDUCE TUMORIGENIC CONVERSION OF HUMAN BRONCHIAL EPITHELIAL-CELLS AND REDUCE THEIR RESPONSIVENESS TO A NEGATIVE GROWTH-FACTOR, TRANSFORMING GROWTH FACTOR-BETA(1)

Loss of normal functions and gain of oncogenic functions when the p53 tumor suppressor gene is mutated are considered critical events in the development of the majority of human cancers. Human bronchial epithel ial cells (BEAS-2B) provide an in vitro model system to study growth, differentiation, and neoplastic transformation of progenitor cells of lung carcinoma. When wild-type (WT) or mutant (MT; codon 143Val-Ala) h uman p53 cDNA was transfected into non-tumorigenic BEAS-2B cells, we o bserved that (i) transfected WT p53 suppresses and MT p53 enhances the colony-forming efficiency of these cells, (ii) MT p53 increases resis tance to transforming growth factor beta(1), and (iii) clones of MT p5 3 transfected BEAS-2B cells are tumorigenic when inoculated into athym ic nude mice. These results are consistent with the hypothesis that ce rtain mutations in p53 may function in multistage lung carcinogenesis by reducing the responsiveness of bronchial epithelial cells to negati ve growth factors.