PREFERENTIAL PRIMARY-RESPONSE GENE-EXPRESSION IN PROMOTION-RESISTANT VERSUS PROMOTION-SENSITIVE JB6 CELLS

The 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible sequence (TIS ) genes are a set of primary response genes induced in Swiss 3T3 cells by TPA. They include three transcription factors, a prostaglandin syn thase, and three proteins of unknown function. To ascertain which, if any TIS genes might be involved in tumor promotion, we examined the ex pression of these genes in response to tumor promoters in transformati on promotion-sensitive (P+) and -resistant (P-) JB6 murine epidermal c ells, a model used to identify events relevant to promotion. A subset of TIS genes (TIS1, TIS10, and TIS21) was preferentially induced by TP A in P- cells. in addition, TIS1 and TIS21 mRNAs were preferentially i nduced in P- cells by epidermal growth factor, another transformation promoter that distinguishes P+ from P- cells. TIS1 and TiS21 protein l evels were also greater in TPA-treated P- cells than P+ cells. Forskol in, a cAMP-elevating anti-promoter, increased TPA-induced levels of TI S1, TIS10 and TIS21 mRNAs in P+ cells, ruling in potential roles for t hese genes in modulating tumor promotion. The anti-promoters fluocinol one acetonide, retinoic acid, and superoxide dismutase did not enhance TPA-induced levels of TIS1 and TIS21 mRNAs in P+ cells, suggesting th at these inhibitors may act on other promotion-relevant genes. TIS1 en codes a member of the steroid receptor superfamily. TIS21 encodes a pr otein of unknown function with strong sequence similarity to BTG1, a p roposed ''anti-proliferative gene'' (Rouault JP, Rimokh R, Tessa C, et al., EMBO J 11:1663-1670, 1992). Preferential induction by multiple p romoters of these TIS genes in P- cells and enhancement of their induc tion in P+ cells by the anti-promoter forskolin make TIS1 and TIS21 ca ndidates for promotion suppressor genes. (C) 1994 Wiley-Liss, Inc.