REDD1-mediated mTOR regulation in ovarian tumorigenesis in a murine genetic model

Activation of the AKT oncogene is an important step in pathogenesis of several human cancers, including ovarian cancer. One of the main downstream effectors of AKT signaling is the checkpoint kinase mTOR, the mammalian target of rapamycin. The mechanism of mTOR regulation by AKT involves the tuberous sclerosis tumor suppressors TSC1 (hamartin) and TSC2 (tuberin), which form a protein complex that functions as a negative regulator of mTOR activity. Recent data have identified the REDD1 protein as an additional essential regulator of mTOR activity through the TSC1/2 complex. REDD1 was shown to inhibit mTOR activity in a TSC1/2-dependent manner in response to hypoxia or energy stress, though the exact mechanism of this regulation remains unknown. REDD1 encodes a 232 amino acid cytosolic protein with no recognizable functional domains, however its physiologic role in regulation of cell growth (that is, cell size) through the mTOR pathway has been demonstrated in Drosophila as well as mammalian cells. Importantly, loss of REDD1 in Drosophila dramatically enchances the cell growth phenotype induced by AKT activation, which suggests that dysregulation of REDD1 and AKT may cooperate to promote mTOR activation and tumorigenesis in mammalian cells. We will use a recently developed murine serous ovarian cancer model based on the TVA-RCAS retroviral system. This model is highly suitable for examining cooperating genetic events and for determining the contribution of REDD1-mediated mTOR regulation to ovarian cancer pathogenesis. We will assess proliferation, tumorigenesis, angiogenesis, and rapamycin- sensitivity in cells exhibiting different combinations of cooperating events (involving REDD1, AKT, c-Myc, and p53 pathways) in vivo and in vitro. It is predicted that REDD1 loss will cooperate with AKT activation in tumorigenesis. It is also likely that loss of REDD1 will alter the phenotype of tumors that result from both c-Myc and AKT expression, particularly with regard to angiogenesis and rapamycin sensitivity. To summarize, we will determine the contribution of REDD1 and its cooperation with other genetic events in ovarian cancer tumorigenesis. The results of these studies will direct future efforts to determine the subset of human tumors in which REDD1 inactivation may be most relevant.