The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to play a crucial role in adipogenesis. In recent years, there has been an interest in the role of PPARgamma in cancer. Colon cancer represents one of the leading causes of death in the United States. PPARgamma is expressed at high levels in normal and malignant colonic tissue. Therefore, we have been interested in understanding the role of this receptor in the colon.. Interestingly, the role of PPARgamma in the colon has been controversial with studies indicating both anti- and pro-cancer effects. Recently we have demonstrated in mice heterozygous at the PPAR? locus, that PPARgamma is playing a tumor suppressor role in the colon. Since PPARgamma is a tumor suppressor, the presence of PPARgamma in colonic tumors and cells suggests a disconnect between PPARgamma function and expression. Several studies have shown that PPARgamma is inactivated following MAPKinase-mediated phosphorylation of a conserved serine residue. Several pathways that lead to activation of the MAPKinase pathway have been shown have increased activity in colon cancer. This suggests that one possible reason for the presence of PPARgamma in colon cancer, and discrepancy in response to PPARgamma ligands could be due to PPARgamma phosphorylation. This proposal describes several experiments to critically evaluate the role of PPARgamma phosphorylation in colon cancer. Using pharmacological and eventually genetic approaches we will examine the role phosphorylation of PPARgamma on colon cancer cell growth and gene expression both in vitro and in vivo. A crucial aspect of these studies will be to determine possible mechanisms for the loss of PPARgamma activity due to phosphorylation. This will entail examining the ability of cofactors, both known and potentially novel, to interact in a phospho-dependent manner. Understanding the mechanism of phosphorylation-mediated inactivation of PPARgamma will not only provide insight in to the role of PPARgamma phosphorylation in colon cancer, but also other diseases where PPARgamma has been shown to play a role such as atherosclerosis and diabetes.
