GADD45 AND P38 · Role of the p53-effector gene Gadd45 as tumor suppressor and/or autoimmune disease suppressor gene
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-04-01 → 2008-03-31
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IIF
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
The Gadd45 family plays a critical role in several cellular functions, including genomic stability, cell cycle regulation and apoptosis. Gadd45a is transcriptionally activated by the tumour suppressor gene p53, which is mutated in more than 50% of human tumours. Studies performed by the applicant have demonstrated that Gadd45a is an important negative regulator of T cell proliferation. Lack of Gadd45a leads to the development of an autoimmune disease remarkably similar to human lupus. Little is known about the molecular mechanism that leads to this autoimmune disease, which affects approximately 0.5% of the world's population. Recently, the applicant demonstrated that T cells derived from Gadd45a-null mice showed constitutive p38 activation, hyper-proliferative response and lower threshold of activation leading to lupus. Gadd45a is a p38 inhibitor in T cells.Gadd45a prevents phosphorylation of tyr323 in p38, inhibiting its activation. The applicant has obtained a patent ¿Modulating p38 Kinase activity¿ (PCT App lication# PCT/US2005/003379) that describes how inhibition of phosphorylation of tyr323 in p38 is a key therapeutic target in autoimmune diseases such as lupus, rheumatoid arthritis, Crohn's disease, multiple sclerosis and some types of leukemias. The main goals of this project are a) characterization of the Gadd45 family as autoimmune disease suppressor and/or tumour suppressor genes, and b) analysis of the molecular mechanism to obtain a therapeutic target in the treatment autoimmune diseases and/or tumours.We will generate and characterize deficient murine models in Gadd45a, Gadd45b and Gadd45g and double knockouts Gadd45ab-/-, Gadd45ag-/- and Gadd45bg-/-. We will analyse proliferation, apoptosis, differentiation and production of cytokines in T cells. The results of this project should allow us to discover new key therapeutic targets to fight against autoimmune diseases and/or cancer
Original text from CORDIS.
Participants
- CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MADRIDCoordinatorSpain
Links
Data: CORDIS, © European Union