Objectif In this coordinated research proposal, the role and function of the transcription factor NFkappaB (and associated and/or related factors) and its interaction with genomic DNA for the onset of gene expression will be studied in different cell systems and for different genes using multi-disciplinary approaches. The genuine heterodimeric NFkappaB may be, depending on the cell type, in competition with other inducible or constitutively expressed kappaB sequence-binding protein complexes, which have slightly different binding affinities for the kappaB-responsive sequence in different gene promoters. The subtle interplay of all these elements, in addition to the interaction of cooperative or co-activated protein factors, will determine whether or not and to what extent a particular gene will be induced or repressed in a given cellular system. By detailed study and cooperative analysis of such well-defined inducible genes and cell systems, we hope to arrive at a general and integrated understanding of how gene expression might be regulated in response to major inflammatory cytokines, such as TNF and IL1.* Identification of the nature, formation and regulation of stable heterodimeric NFkappaB molecules* Identification of the mechanism of heterodimeric NFkappaB transcription factor selection and analysis of their differential functions* Deciphering the molecular mechanism of NFkappaB activation involving a phosphorylation-controlled degradation of IkappaB. Identification of the proteasome as being responsible for IkappaB degradation. Identification of serines 32 and 36 in IkappaB-alpha as regulatory phosphorylation sites* Characterization of the p65/RelA transactivation domains. Structural studies and demonstration of interaction with basal transcription factors TFIIB and TBP* Discovery of a novel signal transduction pathway between endoplasmic reticulum and cell nucleus that is induced by the accumulation of membrane proteins in the organelle* Deciphering the role of reactive ovygen intermediates in NFkappaB signaling in reponse to hypoxia, hydrogen peroxide, CD28, okadaic acid, anthralin and prostaglandin synthase-1 overexpression* Deciphering the role of NFkappaB in the nervous system. Discovery that NFkappaB is constitutively active in some neurons, is activated in neurons by the neurotransmitter glutamate, is transiently activated during cerebellum development and is activated in Schwann cells by NGF via p75 receptor* Demonstration that NFkappaB is activated in vivo in various diseases, such as atherosclerosis, rheumatoid arthritis, Alzheimer disease and autoimmune encephalomyelitis* Investigating the role of NFkappaB in apoptosis. Demonstration that NFkappaB is activated under certain apoptotic conditions and inhibited by expression of the anti-apoptotic proteins Bcl-2 and Adenovirus E1B* Identification and localization of constitutive NFkappaB activities 2 in human thymocytes* Development of T cell clones expressing a dominant negative mutant of IkappaB-alpha* Development of transgenic mice with a targeted expression of the mutated IkappaB-alpha in T cells* Demonstration of the essential role of NFkappaB (p50/p65) in the expression of IL2 and IL6, but not c-myc* Demonstration that PKC isoform expression is determining for the dependence on Ca2+ influx of the activation of NFkappaB by phorbol esters * Identification of the constitutively present, cellular factor RBP-Jkappa as a specific binding factor for the IL6-kappaB responsive sequence with a modulatory function on basal as well as on induced IL6 gene expression* Demonstration that the p38 MAP kinase pathway is a necessary element for TNF-mediated IL6 gene expression as a regulator for the p65 kappaB subunit transactivation potential* To develop a method that can be used for the selection of promoter proximal DNA fragments that have affinity for AP-1* To identify the neurone specific promoter of the SEZ-6 gene and study the organization of the gene and its patterns of expression within the brain Champ scientifique medical and health sciencesbasic medicineneurologydementiaalzheimermedical and health sciencesclinical medicinerheumatologynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosisnatural sciencesbiological sciencesbiochemistrybiomoleculesproteins Programme(s) FP3-BIOTECH 1 - Specific research and technological development programme (EEC) in the field of biotechnology, 1990-1994 Thème(s) 1.3 - Expression of genes Appel à propositions Data not available Régime de financement CSC - Cost-sharing contracts Coordinateur Universiteit Gent Contribution de l’UE Aucune donnée Adresse 35,K.L. Ledeganckstraat 35 9000 Gent Belgique Voir sur la carte Coût total Aucune donnée Participants (5) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire Centre National de la Recherche Scientifique (CNRS) France Contribution de l’UE Aucune donnée Adresse 91 boulevard de l'Hôpital 75634 Paris Voir sur la carte Coût total Aucune donnée Centre National de la Recherche Scientifique (CNRS) France Contribution de l’UE Aucune donnée Adresse 7 rue Guy Môquet 94802 Villejuif Voir sur la carte Coût total Aucune donnée Ludwig-Maximilians-Universität München Allemagne Contribution de l’UE Aucune donnée Adresse Würmtalstraße 221 81375 München Voir sur la carte Coût total Aucune donnée THE UNIVERSITY OF MILANO Italie Contribution de l’UE Aucune donnée Adresse Via Celoria 26 20133 MILANO Voir sur la carte Coût total Aucune donnée UNIVERSITY OF SHEFFIELD Royaume-Uni Contribution de l’UE Aucune donnée Adresse WESTERN BANK S10 2TN SHEFFIELD Voir sur la carte Coût total Aucune donnée
