The long term goals are to contribute to an understanding of the role of protein kinase C in neoplastic transformation, and cellular regulation by signal transduction processes. Protein kinase C functions to transduce sn-1,2-diacylglycerol second messengers produced in response to growth factors, neurotransmitters, hormones, and some oncogene products, and is the receptor of tumor promoters. The hypothesis that protein kinases C may be the target of anti-tumor and other therapeutic agents will be tested by 1) refining mixed micellar assay methods to screen for protein kinase C agonists and antagonists and their mechanism of action; 2) to apply these methods to the pilot testing of 500 compounds submitted to the NCI which possess anti-tumor activity (limited tests of some anti-psychotics, anti-convulsives, anti-psoriatic and non-steroidal anti-inflammatories will also be done); and 3) to refine methods of sn-1,2-diacylglycerol quantitation and to apply these to normal and diseased tissues. These studies are directly related to oncogenesis and anti-tumor therapeutic development programs. Importantly, such analyses would establish the desirability of biochemical prescreens of compounds submitted to the NCI and toward causative agents of cellular transformation. The central involvement of protein kinase C and sn-1,2-diacylglycerol second messengers is relevant to endocrinology, neurology, growth, differentiation and development, arthritis and other inflammatory responses, smooth muscle contraction, psoriasis, diabetes, and other human conditions.
