The objective of the project is to explore the molecular basis of cancer, approaching this problem by the study of normal and aberrant functions of molecules that participate in the transduction of proliferative signals. We began demonstrating that mutated genes for certain classes of G proteins are transforming, and that a number of G protein-coupled receptors (GPCRs) behave as potent agonist-dependent oncogenes. Subsequently, we focused on critical molecules conveying mitogenic signals from the cytoplasm to the nucleus, including the family of MAP kinases. Our work led to the discovery of a new biochemical route connecting GPCRs to MAP kinases, involving the activation of Ras by G protein beta gamma. We also demonstrated that GPCRs can stimulate the activity of jun kinase (JNK), a novel enzyme closely related to MAP kinases which phosphorylates the c-jun proto-oncogene product thereby increasing its transcriptional activity. We next found that whereas Ras weakly activates JNK, the small GTP-binding proteins Rac1 and Cdc42 initiate an independent kinase cascade leading to JNK activation, and that Rac and Cdc42 are an integral part of the signaling route, linking many cell surface receptors and naturally occurring human oncogenes to JNK. The emerging picture from these and other studies is that cell surface receptors regulate the activity of parallel kinase cascades which, in turn, control the expression of genetic programs leading to normal or aberrant cell growth. We believe that these findings have helped to identify a number of potential candidates as targets for therapeutic intervention in cancer.
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