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-receptor interaction and the activation of effectors of neoplastic transformation. Candidate second messengers include protein phosphorylation by protein kinase C (PKC) and PKC-regulated trans-activation of gene expression. A putative C-kinase substrate of 80 kDa has been found to be differentially phosphorylated in promotion-resistant (P-), -sensitive (P+), and neoplastically transformed JB6 mouse epidermal cells, with little or no phosphorylated 80-kDa phosphoprotein (pp8O) seen in transformed cells. Western analysis indicates that p8O is regulated at the level of synthesis with little or no p8O protein detectable in transformed JB6 cells. A cDNA clone of p8O has recently been isolated by screening a JB6 P- library with p8O antibody. This p8O cDNA, when used as a probe, detects a 2.8-Kb RNA that progressively decreases during the progression from P- to transformed (Tx) phenotype. When compared with GenBank the sequence emerges as novel. We will test the hypothesis that p8O functions as a tumor suppressor. Recent studies on 12-0-tetradecanoyl-phorbol-13-acetate (TPA)-inducible genes have focused on those regulated by the trans-acting transcriptional factor AP-1 (Jun/Fos Complex). The tumor promoters TPA and epidermal growth factor (EGF) induce AP-1-regulated gene expression in P+ but not P- JB6 cells. This indicates that AP-1-regulated gene expression (1) may be required for tumor promoter-induced transformation; and (2) may be controlled by activated pro genes found in P+ but not P- cells. Evidence favoring such a role for pro genes comes from the observation that in P-cells transfected with activated pro 1, the cells acquire both P+ phenotype and AP-1 trans-activation response. The mechanism of differential trans-activation by TPA appears to involve differential basal and induced levels of c-jun mRNA and Jun protein. A c-jun differential was not found after EGF treatment thus suggesting that TPA and EGF induce AP-1-dependent trans-activation of gene expression by different pathways.