Functions of a novel suppressor of oncogenic Ras Oncogenic Ras accounts for more than 30% of all human cancers. Ras normally controls mitogenic pathways and functions as an on/off switch controlling cell proliferation. Heterochromatin appears to be a form of cellular restraint in both flies and humans that oncogenic Ras has to overcome to induce cell proliferation. Many tumor suppressors, such as Rb and BRCAs, play a role in heterochromatin formation, and an inability to form heterochromatin formation itself permits tumorigenesis in response to oncogenic Ras. However, how heterochromatin formation counteracts oncogenic Ras and how Ras can overcome heterochromatin-mediated tumor suppression remain unclear. Understanding how heterochromatin counteracts oncogenic signals and how oncogenic pathways overcome heterochromatin to induce growth and proliferation may lead to novel epigenetic cancer therapeutics. To investigate the connection from oncogenic mutations to epigenetic alterations, we have used Drosophila genetics to identify new players mediating cellular responses to oncogenic Ras, with a particular attention to nonconventional Ras signaling components. Among the novel suppressors of oncogenic Ras, we found that CRIF regulates both cell proliferation and heterochromatin formation. The objective of this project is to understand the mechanism by which the putative tumor suppressor CRIF antagonizes the effects of oncogenic Ras on cell proliferation. The long-term goal of the research is to elucidate how heterochromatin formation functions in epigenetic tumor suppression and how oncoproteins reorganize chromatin to induce cell proliferation and tumorigenesis. We hypothesize that CRIF counteracts oncogenic Ras by inhibiting cell proliferation and increasing heterochromatin formation, an epigenetic tumor suppression system. In this proposal, we plan to elucidate the molecular functions CRIF in counteracting oncogenic Ras-induced proliferation and in heterochromatin regulation. Specifically, we will investigate how CRIF resist oncogenic Ras in controlling proliferation, and the role of CRIF in regulating heterochromatin. Results from these studies will break new grounds for investigating the molecular mechanisms underlying the epigenetic effects of oncogenic Ras, the role of epigenetic dysregulation in cancer development, and the role heterochromatin in tumor suppression.