Three major cell signaling pathways have been identified that play key roles in controlling cell growth and cell fate decisions. These pathways include the c-Myc transcription factor, the Ras signaling molecule, and the G1 Cyclin kinase/retinoblastoma/E2F pathway. Taken together, lesions in these pathways can account for the development of virtually all human tumors described to date. An analysis of how these molecular pathways interact and synergize to control cell growth is essential for our understanding of cancer development, and for the establishment of successful treatments. Recent work in our laboratory has established important links between these three cell regulatory pathways. We have demonstrated that Ras activation leads to stabilization and accumulation of transcriptionally active Myc protein, and we have identified the E2F transcription factors as important downstream effectors that mediate c-Myc function. The research outlined in this grant proposal is intended to further our understanding of how these cell signaling pathways interact. We propose the following specific aims. 1) Investigate molecular mechanisms that mediate Ras-induced stabilization of c-Myc and determine its effects on Myc function. 2) Identify an F-box protein specifically involved in targeting c-Myc for multiubiquitination and degradation and study its function. 3) Examine the roles downstream effectors play in regulating c-Myc function. The experiments proposed to address these aims will initially be conducted under the mentorship of Dr. Nevins in order to develop several new systems to help with our analyses. This phase of the proposal will require one year. After this, the remainder of the proposal will be conducted in a completely independent environment. I will initially be given laboratory space at Duke, but I intend to look for a position at another university as soon as possible. My career goal is to operate an independent laboratory dedicated to increasing our understanding of how multiple oncogenic lesions that occur in the multi-step development of cancer can collaborate and synergize at the molecular level.
