Objectif Apoptosis (Programmed Cell Death) accounts for the strictly controlled disposal of superfluous, damaged, mutated or ectopic cells. Indeed, deficient apoptosis is frequently involved in early cancer development, and the resistance of tumours to chemo- or radiotherapy. Thus, the comprehension of normal and pathological regulation of apoptosis should provide conceptual advances for therapeutic interventions on deficient cell death. Evidence from an increasing number of experimental systems supports the notion that apoptosis can proceed in a caspase-independent manner. However, there is no exhaustive work characterizing both the principal agents involved and the pathways implicated in caspase-independent cell death. This is the goal of the proposal. One of the main agents of caspase-independent cell death is AIF (Apoptosis Inducing Factor). Following an apoptotic stimulus, AIF translocates from mitochondria to the cytosol and the nucleus, where it induces in cooperation with unknown factor/s. mitochondrial swelling, loss of the mitochondrial transmembrane potential, phosphatydilserine exposure, and large-scale DNA fragmentation. Recently, it has been demonstrated that the activation via antigen CD47 in B-lymphocytes from B-chronic lymphocytic leukaemia induces a form of cell death, without caspase activation, characterized by the externalisation of phosphatydilserines and the fall in mitochondrial transmembrane potential. Thus, CD47-induced cell death is an ideal model to study the signalling pathways implicated in caspase-independent apoptosis and the contribution of AIF to the execution of this kind of cell death both in normal and pathological situations. The combination of a through knowledge of the biochemical and molecular mechanisms involved in CD47 cell death, and a better understanding of the mechanism of AIF function should provide conceptual advances for the development of new therapeutic and diagnostic approaches to combat cancer. Champ scientifique natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologyleukemia Mots‑clés Apoptosis CD47 Cancer Signalling death independent cell inducing factor (AIF) Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Thème(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Appel à propositions FP6-2002-MOBILITY-5 Voir d’autres projets de cet appel Régime de financement EIF - Marie Curie actions-Intra-European Fellowships Coordinateur INSTITUT PASTEUR Contribution de l’UE Aucune donnée Adresse Rue de Docteur Roux 28 PARIS France Voir sur la carte Coût total Aucune donnée
