Cancer is a malady of genes, many scores of which have been found to undergo some change in the process of neoplastic transformation. The cellular response to external signals required to initiate the process of proliferation and differentiation culminates in inducing a host of genes collectively referred to as early response genes. We are proposing to study the function and regulation of protooncogenes fos, jun and rel, members of the early response gene family. We want to study the mechanism by which fos protein regulates the transcription of fos gene. The product of protooncogene rel is related to the NF-kappaB transcription factors which reside in the cytoplasm, and can activate transcription of genes containing the canonical decameric site. The activity of rel/NF-kappaB proteins is regulated by their association with inhibitory protein IkappaB. We are proposing to study the molecular mechanism by which the activity of rel/NF-kappaB/IkappaB complexes is regulated. We are planning to study the role of nuclear oncoproteins fos and jun in normal cell by generating transdominant negative mutants. Experiments are proposed to study the direct interaction of nuclear oncoproteins with the basal factors involved in the transcription machinery. We have also proposed to identify and study genes whose transcription is directly influenced by fos, jun and rel gene products. We have also undertaken a project to elucidate the higher order structure of fos, jun and rel/IkappaB proteins by generating large amounts of these proteins in bacteria. We also plan to explore the role of oncoproteins fos, jun and rel in the neuronal cells, particularly in response to many excitatory amino acids and neurotransmitters. We plan to continue our endeavors to generate high efficiency vectors to deliver genes into somatic tissues with a view towards gene therapy. We are specifically interested in introducing genes into muscle cells, where sustained expression of a foreign secretory protein can be obtained. We will also use retroviral vectors to generate cDNA libraries from tumor cells with the hope of identifying new oncogenes. The studies proposed here will allow a molecular dissection of the mechanism of carcinogenesis, and therefore make significant contributions to understand, and consequently combat, the scourge of cancer.
