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Promotor specific regulation of NF-kappaB mediated transcription by the phosphorylation of p65 on Ser547.
Trussart, Charlotte; Orban, Tanguy; Sabatel, Hélène et al.
2014Metabolism 2014: Alterations of metabolic pathways as therapeutic targets
 

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Keywords :
NF-kappaB; TNF; signal transduction
Abstract :
[en] NF-kappaB (p50/p65) is an important regulator of gene transcription as it controls the expression of hundred of genes involved in inflammatory and innate responses, proliferation, survival, cancer initiation and progression. Several modes of NF-kappaB activation are known among which the classical pathway induced by pro-inflammatory cytokines and a complex atypical pathway induced by DNA damage. Both pathways converge on the IKK activation. The stimulidependent p65 phosphorylation on several serine can control its transcriptional potential either globally or often in a gene specific manner. Lately, we have reported a direct interaction between p65 and ATM and the in vitro phosphorylation of Ser547 by this kinase. A comparative transcriptomic analysis performed in HEK-293 cells expressing either p65WT or p65S547A identified several differentially transcribed genes (IL8, A20, SELE…) after an Etoposide treatment. Substitution of Ser547 to Ala does not affect p65 binding on the kappaB site of the IL8 promoter but it reduces p65 interaction with HDAC1 leading to a higher level of histone H3 acetylated on Lys9 and therefore a higher gene induction. These data indicate that ATM regulates a sub-set of NF-kappaB dependent genes after a genotoxic stress by direct phosphorylation of p65 (1). We are now investigating the impact of the S547A mutation in the context of an inflammatory response. Mefs p65KO expressing recombinant p65WT or p65S547A were treated with TNFalpha. No differences were observed in the kinetic of degradation of IkBa or the nuclear translocation of p65. The level of transcription of a few selected genes is presently under investigation. Contrary to another study, we did not observed any role of ATM in NF-kappaB activation by TNFalpha
Research center :
Giga-Signal Transduction - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Trussart, Charlotte ;  Université de Liège - ULiège > Doct. sc. (bioch., biol. mol.&cell., bioinf.&mod.-Bologne)
Orban, Tanguy ;  Université de Liège > Département des sciences de la vie > Génétique et biologie moléculaires animales
Sabatel, Hélène ;  Université de Liège - ULiège > GIGA-R
Di Valentin, Emmanuel  ;  Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie et immunologie
Piette, Jacques ;  Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie
Habraken, Yvette ;  Université de Liège - ULiège > GIGA-R : Virologie - Immunologie
Language :
English
Title :
Promotor specific regulation of NF-kappaB mediated transcription by the phosphorylation of p65 on Ser547.
Publication date :
January 2014
Event name :
Metabolism 2014: Alterations of metabolic pathways as therapeutic targets
Event organizer :
Recherches Scientifiques Luxembourg asbl Marc Diederich and Guido Kroemer
Event place :
Esh-sur-Alzette, Luxembourg
Event date :
du 29 janvier au 31 janvier 2014
Audience :
International
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Télévie [BE]
ULiège - Université de Liège [BE]
CAC - Centre anticancéreux près l'Université de Liège asbl [BE]
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since 19 November 2014

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