Ras-mediated signal transduction pathways are highly conserved among metazoan and play key roles in controlling cell proliferation and differentiation. Mutant forms of two members of the pathway, ras and raf, are among the most commonly seen oncogenes involved in many types of cancers. Through a genetic suppresser-of-ras screen in the nematode C. elegans, several conserved regulators of Ras-Raf activation were discovered. One such gene, sur-8, encodes a conserved Leucine-Rich Repeat protein that binds directly to Ras and plays an important role in Ras regulation. I propose to study the regulation of signaling activity transmitted by Ras by focusing on two genes which have been shown to act positively to regulate Ras-Raf activation. C. elegans genetics, in vitro biochemistry, and possibly mammalian cell culture systems will be used. I will study the role of the sur-8 gene in mediating ras signal transduction by examining the nature of SUR-8 interactions with both Ras and Raf. I will also use molecular methods including two-hybrid techniques to identify other protein(s) that I may interact and function with SUR-8 to facilitate Ras-pathway activation. I will also genetically and molecularly characterize another suppresser gene, sur-7, which appears to also function as a positive regulator in the pathway. Work in the past several years demonstrated that vulval induction in C. elegans provides a specific assay system to identify new genes and elucidate their functions in signal transduction.
| Fay, David S; Keenan, Sean; Han, Min (2002) fzr-1 and lin-35/Rb function redundantly to control cell proliferation in C. elegans as revealed by a nonbiased synthetic screen. Genes Dev 16:503-17 |
| Fay, D S; Han, M (2000) The synthetic multivulval genes of C. elegans: functional redundancy, Ras-antagonism, and cell fate determination. Genesis 26:279-84 |
| Fay, D S; Han, M (2000) Mutations in cye-1, a Caenorhabditis elegans cyclin E homolog, reveal coordination between cell-cycle control and vulval development. Development 127:4049-60 |
