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Analysis of the signaling pathway regulating T-cell receptor-induced NF-kB activation and lymphocyte proliferation

English title Analysis of the signaling pathway regulating T-cell receptor-induced NF-kB activation and lymphocyte proliferation
Applicant Thome-Miazza Margot
Number 118993
Funding scheme SNSF Professorships
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Biochemistry
Start/End 01.05.2008 - 30.04.2010
Approved amount 649'565.00
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All Disciplines (4)

Discipline
Biochemistry
Experimental Cancer Research
Molecular Biology
Immunology, Immunopathology

Keywords (13)

T-cell activation; immune response; TCR; Carmal; Bc110; MALT1; NF-kB; adhesion; CARMA1; Bcl-10; lymphoma; signalling; proliferation

Lay Summary (English)

Lead
Lay summary
The activation of lymphocytes is vital to the successful elimination of pathogens, but also plays a deleterious role in auto-immunity and transplant rejection. Moreover, abnormal lymphocyte activation and proliferation has been associated with the formation of lymphomas and leukemias. Signaling pathways initiated by the antigen receptor on the surface of lymphocytes play a key role in the control of lymphocyte activation and proliferation and therefore represent interesting targets of therapeutic immuno-modulation. My research group is studying the molecular function of the proteins CARMA1, Bcl-10 and MALT1, which play a crucial role in the signaling pathway that links antigen receptor engagement to the activation of the transcription factor NF-?B and the control of lymphocyte proliferation. Moreover, chromosomal translocations and/or altered expression levels of these proteins have been associated with the formation or progression of lymphomas of the mucosa-associated tissue (MALT lymphomas) or of activated B-cell type diffuse large B cell lymphomas (ABC-DLBCL). Recently, we have identified MALT1 as a protease that is activated upon T-cell stimulation and cuts target proteins after Arginine. We have developed a specific cell permeable inhibitor for this proteolytic activity. In vitro, this inhibitor significantly reduces the activation of NF-kB in human T-cells, which is key to efficient T-cell activation. Moreover, we could show that MALT1 cleaves its binding partner Bcl-10, and that cleavage of Bcl-10 is required for T-cell adhesion, another hallmark of T-cell activation. A future focus of my lab will be to characterize the mechanisms that control the enzymatic activity of MALT1 and to identify and characterize additional substrates for MALT1 that contribute to the control of T-cell activation. The elucidation of the precise regulation of this pathway should significantly contribute to our understanding of the mechanisms that control the adaptive immune response. Moreover, a deeper understanding of these mechanisms is key to the comprehension of molecular defects underlying autoimmune diseases or lymphomas, and therefore holds the potential for the rational design of MALT1 inhibitors with immunosuppressive or anti-lymphoma activity.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
102880 Analysis of the signaling pathway regulating T-cell receptor-induced NF-kB activation and lymphocyte proliferation 01.05.2004 SNSF Professorships

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