Carcinogenesis is a multistep process that results from pathological defects in the control of cellular proliferation and differentiation and from the acquisition of invasive and metastatic potentialities. Equally important, carcinogenesis is associated with the development of abnormalities in mechanisms that antagonize the process of carcinogenesis. Numerous studies support the. existence and significance of anticancer/cancer suppressor (AC/CS) mechanisms and multiple AC/CS genes have been identified including Rb-1, p53, Wilm's suppressor gene, the DCC gene associated with colon cancer, and genes that antagonize the transforming effect of EJras, i.e. Krev-1 and rrg. Despite the unequivocal importance of these observations, a very important question remains unanswered.How is the expression of anticancer/cancer suppressor activity biologically and molecularly regulated? The specific aims of this grant are to answer these questions. The proposed experiments are based on our recent discoveries Chat without changing a cell's proliferative potential, differentiation and related processes can induce multiple types of AC/CS activity. Differentiation can make nontransformed cells resistant to carcinogenesis induced by physical/chemical agents and EJras; differentiation can make spontaneously and SV40 transformed cells revert to a nontransformed state and become resistant to retransformation.Differentiation can also repress expression of the transforming SV40 large T oncoprotein as can treatment with DMSO. The molecular mechanisms that mediate many of these regulatory events appear to primarily involve transcriptional processes. Recent results in fact suggest that differentiation may effect AC/CS activity by modulating the composition of transacting factors that control the activity of SV40 and metallothionein II, genetic regulatory sequences. Our goals in this grant are therefore to investigate more precisely the biological basis for induction of these activities and to identify and characterize the transacting factors that regulate the expression of AC/CS activity. These studies should provide important information concerning the pathology of carcinogenesis and new approaches for cancer therapy and prevention.
