Mutations in a ras allele occur in 30% of all human tumors, making ras the most widely mutated human proto-oncogene. Ras mutations have also been found in oral cavity cancer, and transgenic mice with over-expression of vH-ras oncogene develop an array of mesenchymal and epithelial neoplasms including carcinomas of salivary glands and odontogenic tumors. The long- term objective of this application is to study the mechanism of ras- transformation of oral epithelial and mesenchymal cells, and to explore the possibility of gene therapy of oral cancer of blocking ras intracellular signaling pathway and initiated the tumor cell suicide (programmed cell death, apoptosis). It is well known that oncogenic Ras constitutively binds GTP resulting in the persistent synthesis and/or activation of specific transcription factors, including Ets, c-Myc, c-Jun, and Nuclear factor kappa B (NF-kappaB). It has been shown that NF-kappaB plays a critical role in Ras-mediated focus-forming activity and oncogenic Ras activities NF-kappaB-dependent gene expressing by targeting the transactivation domain of the p65/Rel A subunit of NF-kappaB. The preliminary finding presented in this application is that activation of NF-kappaB provides protection against oncogenic Ras-initiated programmed cell death.
The specific aims proposed in the application are the following: 1). identify apoptotic pathway(s) and mediator(s) initiated by oncogenic Ras under inhibition of NF-kappaB. The specific caspase inhibitors and anti-apoptotic molecules such as CrmA, p35 and Bcl-2 will be used to dissect and define the role of caspases in Ras-mediated apoptosis. Due to inactivation of NF-kappaB of ras intracellular signaling, the possibility of dysregulated JNK and p38 intracellular signaling will be examined. 2). Try to identify gene product(s) transcriptionally controlled by NF-kappaB to suppress Ras-mediated apoptosis and potentiate Ras-transformation. These studies will elucidate the anti-apoptotic mechanisms of NF-kappaB in ras transformation, provide the molecular basis to develop new anti-cancer drugs, and help to design a mew method for oral cancer gene therapy for targeting the specific anti- apoptotic genes.
| Mayo, M W; Wang, C Y; Drouin, S S et al. (1999) WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. EMBO J 18:3990-4003 |
| Wang, C Y; Guttridge, D C; Mayo, M W et al. (1999) NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol 19:5923-9 |
