MEMBRANE SIGNAL TRANSDUCTION IN TUMOR PROMOTION

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The goal of these studies is to determine the required biochemical events that occur between tumor promoter or growth factor-receptor interaction and the activation of effectors of neoplastic transformation. Candidate second messengers include protein phosphorylation dependent on protein kinase C (PKC) or epidermal growth factor (EGF) receptor kinase and kinase-regulated trans-activation of gene expression. Phorbol ester sensitive and resistant JB6 cells show no differences in PKC isotypes expressed, suggesting that the basis for differential sensitivity is distal to the receptor. Recent studies on 12-0-tetradecanoyl-phorbol-13- acetate (TPA)-inducible genes have focused on those regulated by the transacting transcriptional factor AP-1 (Jun/Fos complex). The tumor promoters TPA and EGF induce AP-1-regulated gene expression in P+ but not P- JB6 cells. This suggests that AP-1-regulated gene expression may be required for tumor promoter-induced transformation. The mechanism of differential trans-activation and transformation by TPA appears to involve differential basal and induced levels of c-Jun mRNA and protein but does not involve differential induction of c-fos, fos B, jun D, or jun B. A novel Fra-1 related protein is induced in P- but not in P+ cells. These observations suggest that c-Jun enhances and the Fra-1 related protein inhibits AP-1 activation and the transformation response to tumor promoters. In addition, the phosphorylation of c-Jun and Fra-1 is differentially regulated in P- and P+ cells, suggesting a second promotion-relevant mode of regulation. Recent observation with knockout of c-jun-dependent AP-1 activity by overexpression of a dominant negative c-jun mutant, suggests that AP-1 is required for tumor promoter-induced transformation; i.e., for P+ response. Overexpression of c-jun and AP-1, while not sufficient for P- to P+ progression, is, however, sufficient for P+ to tumor cell (Tx) progression.