A novel p53 mutant retained functional activity in lung carcinomas

The gene p53 is a critical tumor suppressor that can respond to multiple signals of cellular gatekeepers for growth and division. The mdm2 gene is one of the downstream target genes for transcriptional activation by the product of p53 tumor suppressor gene. Transactivation of mdm2 gene is represented by the presence of a functional P53 protein. To understand the biological function of mutant p53 in tumorigenesis, we constructed a number of p53 mutants by site-directed mutagenesis (H179Y, L194R, S240R, R249S, A276D, E286Q), followed by characterization of each P53 mutant's ability to transactivate mdm2, bax and p21waf. The transactivation properties of p53 mutants were compared by co-transfection with pGL-3-mdm2, pGL-3-bax and pGL-3-p21waf into the P53 null cell line H 299 derived from a non-small cell lung carcinoma. Among them mtp53 S240R and E286Q were shown to have enhanced transactivating activity of pGL3-mdm2, at about 43.2 and 28.2% of the wtp53 vector, respectively, while the remaining four had nearly the same level of activity as the negative control did. Furthermore, data indicated that mtp53 S240R had as high an ability to suppress the growth of the p53 null cell line H 1299 as wild type p53. Therefore, mutant p53 alone is an insufficient indicator of poor prognosis. Instead, functional p53 may affect lung cancer prognosis. (C) 2002 Elsevier Science B.V. All rights reserved.