Genes and membrane signals involved in neoplastic transformation

Figure 2 summarizes our current understanding of the signal transduction events that appear to be involved in promotion of transformation in JB6 cells. Among the earliest promotion-relevant events (at least for phorbol esters) appear to be C-kinase activation and superoxide anion elevation. Whether such events regulate expression of pro genes needs to be elucidated. Finally, Fig. 3 presents a model for the role of pro genes and transforming genes in inducing and maintaining neoplastic transformation in mouse JB6 cells. Our current hypothesis is that TPA interacts with its receptor (C-kinase) to trigger one or more promotion-relevant second messages, which then activate expression of pro gene(s). The product of a pro gene is postulated to then activate expression of a transforming gene so that its expression becomes constitutive in the neoplastic cell. In the P- cells the "defect" could be at the level of a missing second messenger signal to activate pro genes or a structural change in pro genes such that they are not expressed or they lack activity even though expressed. Recent evidence to be presented elsewhere indicates that pro genes are not limited to mouse cells but are found in certain human tumor and nontumor cells. If human pro homologues turn out to show biological activity for specifying sensitivity to neoplastic transformation, this finding will add a new dimension to testing the somatic mutation hypothesis of carcinogenesis.