The goals of this project are to implicate RhoA as a potential anti-cancer target in a mouse lymphomagenesis model and to dissect the mechanism of contribution of RhoA to p53-deficiency mediated lymphomagenesis. RhoA is one of the founding members of the Rho GTPase family of intracellular signal transducers. Although aberrant signaling through RhoA has been conceptually associated with many aspects of cancer cell biology, there remains a significant gap in our knowledge on the mechanism of contribution by RhoA to cancer development. To date few animal models are available to directly study the involvement of RhoA in cancer in vivo. Limited information obtained from human cancer specimen screening suggest that upregulation of expression or activity, but not mutation, of RhoA are associated with a wide spectrum of human tumors. The p53 tumor suppressor pathway, on the other hand, constitutes a check point in cell cycle progression that is responsive to proliferative signals normally required for cell growth. Disruption of p53 leads to lymphomagenesis in mice, and loss of gene function in the p53 pathway is a common feature in many human cancers including lymphoma. We have found in the preliminary studies that p53 deficiency in primary mouse embryonic fibroblasts and lymphoma cells causes RhoA activation and that the growth properties of p53-deficient lymphoma cells in part depend upon RhoA activity. We have established a bone marrow hematopoietic stem cell (HSC) transduction and transplantation protocol to allow convenient manipulation of p53 deficient HSCs for lymphomagenic studies in mice. In addition, we have devised a novel RhoA-targeting strategy to specifically downregulate RhoA activity in tumor cells. We hypothesize that RhoA provides a modifier or mediator signal in p53 deficiency-induced lymphomagenesis and thus constitutes a novel target in p53-mediated transformation. In the two specific aims, we will attempt (1) to validate a RhoA-targeting strategy in a lymphomagenic mouse model and to implicate RhoA as a useful cancer prevention and/or therapeutic target, and (2) to determine the mechanism of RhoA-targeting in p53 deficiency-mediated lymphomagenesis. These studies will provide an animal model to implicate RhoA GTPase in tumorigenesis and for testing anti-cancer strategies by targeting RhoA pathways. ? ? ?
