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Role of the Gadd45 family and p38 MAPK in tumor suppression and autoimmunity

Final Report Summary - GADD45&P38SIGNALING (Role of the Gadd45 family and p38 MAPK in tumor suppression and autoimmunity)

The main goals of this project were: firstly, to study the in vivo function of the Gadd45 family and p38 in suppression and/or development of autoimmunity and cancer, and secondly, to analyze the molecular mechanism involved in these processes to identify therapeutic targets in the treatment of autoimmune diseases and cancer. To address these goals we have generated and characterized several murine models deficient in each member of the Gadd45 family (Gadd45a, Gadd45b and Gadd45g) as well as for p38 MAPK family including a conditional model deficient for p38a. We have used these models to dissect the signaling pathways involved in development and suppression of autoimmunity and/or tumors.

We found that Gadd45a-/- and Gadd45b-/- mice but not Gadd45g-/- develop clinical signs of autoimmune disease characterized by a membranoproliferative glomerulonephritis, resulting in premature death. Gadd45b but not Gadd45a is a positive modulator of apoptosis mediated by T cell receptor activation and controls negative selection in thymus. However, Gadd45a and Gadd45g are not relevant in positive or negative selection in thymus. In addition, Gadd45a and Gadd45b play a key role as negative regulators of CD4+ T cell proliferation. Dysregulation of T cell proliferation contributes to the spontaneous development of autoimmunity in Gadd45a-null mice whereas in Gadd45b the failure of central and peripheral tolerance is the main cause of autoimmunity. Regarding the role of Gadd45 family in carcinogenesis, it has been proposed that this family has a crucial role in tumour suppression based on that Gadd45a is a p53 effector gene. However, we found a novel role for Gadd45a and Gadd45b in development of hepatocellular carcinomas. Gadd45a and Gadd45b expression is required for hepatocellular carcinoma development. Gadd45b is an important regulator of hepatocytes apoptosis and the lack of Gadd45b in mice blocks tumour initiation in liver.

We have also focused on the role of p38 MAPK activation in development of human autoimmune disease. In a cross-sectional study, we have analyzed the phosphorylation level of p38a in several residues in T cells from healthy controls and patients with RA or ankylosing spondylitis (AS) and we have identified variables associated with disease activity. Our results indicate that phosphorylation status on the Tyr323p38 in T cells correlates with RA disease activity, suggesting selective inhibition of this pathway as an attractive target for specific downregulation of p38 activity in RA patients. We have developed and patented this novel methodology to measure RA disease activity in T cells by using flow cytometry.

In addition to role in suppression of autoimmunity and cancer development, the multidisciplinary approach of the project has allowed us to identify a surprising role for the Gadd45 family in embryonic development. We generated Gadd45g-null mice to study its role in autoimmunity but Gadd45g-/- mice showed an unexpected phenotype of male-to-female sex reversal. We found a specific role for Gadd45g in male fertility and testis development. The molecular cause of sex reversal was the failure of Gadd45g-/-XY gonads to achieve the SRY expression threshold necessary for testes differentiation, resulting in ovary development. The genetic basis of human male-to-female sex reversal remains unexplained in the majority of cases. Our results identify Gadd45g as a promising candidate gene in human non-syndromic male infertility and in partial or complete male-to-female primary sex reversal in 46, XY individuals.