TRANSIENT STABILIZATION OF P53 IN NONSMALL CELL LUNG-CARCINOMA CULTURES ARRESTED FOR GROWTH BY RETINOIC ACID

Proliferation of five non-small cell lung carcinoma (NSCLC) cultures w as inhibited after 16 h exposure to retinoic acid. We investigated whe ther expression of the p53 protein correlated with the growth pattern of NSCLC lines observed in the presence of retinoic acid. Levels of wi ld-type p53 protein underwent fivefold increases in lines H460a and H2 26b after 16 to 48 h treatment with 5 mu M retinoic acid but then decr eased to undetectable amounts in these cell lines after 72 h retinoic acid treatment. Levels of p53 transcripts remained unchanged during th e time of increases in protein expression in retinoic acid-treated H46 0a cells, suggesting that a post-translational mechanism was involved in the increased expression of the protein. Pulse-chase analysis demon strated that wild-type p53 was significantly more stabile in H460a cel ls treated with retinoic acid, exhibiting a half-life greater than 6 h , in contrast to 3 h for the protein in untreated control cells. The r etinoic acid-mediated effect was specific for wild-type p53, since exp ression of mutant p53 in the H596b and H322j cell lines remained relat ively unchanged even after 72 h exposure to retinoic acid. We conclude that retinoic acid induces stabilization of wild-type p53 in NSCLC ce lls by a post-translational mechanism. Furthermore, increases in expre ssion of p53 were not responsible for the retinoic acid-induced transi ent inhibition of growth of NSCLC cells, since the growth of H358 p53- null cells also was inhibited by retinoic acid. (C) 1994 Academic Pres s, Inc.