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 transactivation of gene expression. Phorbol ester- sensitive and -resistant JB6 cells show no differences in PKC isotypes expressed or in PKC translocation or down regulation following activation, suggesting that the basis for differential sensitivity is distal to the receptor. Our studies on tumor promoter-inducible genes have focused on those regulated by the transcriptional factor AP-1 (Jun/Fos complex). Phorbol ester and EGF induce AP-1-regulated gene expression in promotion-sensitive (P+) but not promotion-resistant (P-) JB6 cells, suggesting that AP-1-regulated gene expression may be required for tumor promoter-induced transformation. New understanding of kinase regulation of gene expression has come from the observation that mitogen- activated protein kinases bind to Jun and Fos family proteins in JB6 cells, thus ruling in the possibility that these kinases phosphorylate and regulate the activity of AP-1 in vivo. Inhibition of induced 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. This presents an opportunity for protection of cells and people against carcinogenesis by targeting transcription factors such as AP-1. Overexpression of c-jun, while not sufficient for P- to P+ progression is, however, sufficient for P+ to tumor cell progression. The P+ to Tx progression can apparently occur through a Jun-dependent, AP-1-independent pathway, suggesting that c-Jun overexpression does not necessarily model tumor promotion triggered by phorbol esters or growth factors. Examination of a second set of tumor promoter-inducible genes, namely TIS genes, reveals that some of them are induced preferentially in P- cells, thus suggesting their possible roles as inhibitors of transformation.