Skip to main content

Role of the p53-effector gene Gadd45 as tumor suppressor and/or autoimmune disease suppressor gene

Final Activity Report Summary - GADD45 AND P38 (Role of the p53-effector gene Gadd45 as tumor suppressor and/or autoimmune disease suppressor gene)

The main goals of our project are:
a) to study the role of the growth arrest and DNA damage inducible genes (Gadd45) in suppression of autoimmunity and cancer; and
b) the analysis of the molecular mechanism to obtain a therapeutic target.

We have generated murine models deficient in each isoform of the Gadd45 family, Gadd45a, Gadd45b and Gadd45g. We have used these models to dissect the signalling pathways involved in development of autoimmunity and / or cancer. We found that lack of Gadd45a and Gadd45b leads to spontaneous development of an autoimmune disease similar to lupus-like syndrome. Gadd45a and Gadd45b play a key role as negative regulators of T cell proliferation after T cell receptor (TCR) activation.

In addition, Gadd45b but not Gadd45a is a modulator of TCR-mediated apoptosis. Gadd45a regulates p38 MAPK activation through inhibition of Tyr323p38 phosphorylation and constitutive p38 activation in CD4+T cells leads to spontaneous development of autoimmune disease.

In summary, Gadd45 family play a major role in the immune system as autoimmune disease suppressor genes by regulating T cell proliferation and apoptosis after TCR activation.