Gadd45 family proteins play a critical role in genomic stability, cell cycle regulation proliferation and apoptosis. Gadd45a is activated by the tumor suppressor gene p53, which is mutated in >50% of human tumors. The lack of GADD45a in mice leads to spontaneous development of an autoimmune disease similar to systemic lupus erythematosus. The molecular mechanisms that cause autoimmunity are poorly understood. Recent evidence suggests that p38 activation is involved in autoimmune development and tumor suppression. We found that Gadd45a negatively regulates p38 activity in T cells by preventing phosphorylation on Tyr323. Inhibition of Tyr323p38 phosphorylation is a potential therapeutic target in several types of leukemia and autoimmune diseases, including lupus and rheumatoid arthritis. The main goals of this project are a) to study the in vivo function of the Gadd45 family and p38 in tumor suppression and autoimmunity, and b) to analyze their molecular mechanisms to identify targets for disease treatment. We will dissect the signaling pathways involved in development of autoimmunity and cancer using a multidisciplinary approach that combines mouse genetic, human epigenetic, biochemical, molecular biological and immunological techniques. Our project involves the characterization of murine models deficient in each member of the Gadd45 family (Gadd45a, Gadd45b, Gadd45g), as well as double- and triple-knockout mice, development of a knock-in model for p38a, in vivo and in vitro analysis of T cell activation, proliferation, apoptosis and differentiation, epigenetic studies of potential targets, and finally, validation of these results in autoimmune disease and cancer patients. The results of this project will help identify new therapeutic targets for autoimmune diseases and/or cancer.
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