REGULATION OF RAS FUNCTION

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Mutations in the ras proto-oncogenes have been implicated in the development of greater than 20% of all human cancers. The elucidation of the biochemical pathways which regulate the activity of the normal ras proteins as well as the pathways which the activated ras proteins stimulate is critical to our understanding of normal cell growth as well as of the defective regulation of biochemical pathway in ras-induced tumors. While the normal ras proteins regulate growth and cell division for most cell types, ras protein can also induce terminal differentiation of certain cell types. Ras proteins are highly expressed in the non-dividing cells of the brain. There is evidence suggesting ras is critical for the maintenance of the neuronal phenotype. However, ras proteins could have additional biological role(s) in the biology of the neuronal cell. The understanding of the regulation of ras function in the brain is key to defining more precisely the biological role of ras protein in neurons. One aim of this proposal is to examine the mechanism by which the recently-identified vertebrate ras-specific nucleotide-exchange factors regulate ras function. We will employ in vitro biochemical and molecular genetic techniques to address this aim. Another aim is to characterize the brain-specific NEF (cdc25). We will examine the oncogenic potential of cdc25 and investigate how cdc25-NEF is regulated, using biochemical techniques as well as the NIH-3T3 cell oncogenicity assay. Another aim is to identify novel NEFs which regulate ras and ras-related proteins. We will use biochemical means to purify known NEFs; we will also employ molecular genetic screens to discover novel NEFs. The identification of novel NEFs and the understanding of how they regulate the function of ras or ras-related proteins is all-important to an understanding of the complexity of ras pathway signaling. Further, because ras is implicated in a large percent of human tumors, it is a potential target for chemotherapeutic agents. it is critical to understand the function of ras in neurons (and other non- proliferating tissues) before anti-ras chemotherapeutic agents can be successfully developed.