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See detailPromotor specific regulation of NF-kappaB mediated transcription by the phosphorylation of p65 on Ser547.
Trussart, Charlotte; Orban, Tanguy; Sabatel, Hélène ULg et al

Poster (2014, January)

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 ... [more ▼]

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 [less ▲]

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See detailPhosphorylation of p65(RelA) on Ser547 by ATM represses NF-κB-dependent transcription of specific genes after genotoxic stress.
Sabatel, Hélène ULg; Di Valentin, Emmanuel ULg; Gloire, Geoffrey ULg et al

in PLoS ONE (2012)

The NF-κB pathway is involved in immune and inflammation responses, proliferation, differentiation and cell death or survival. It is activated by many external stimuli including genotoxic stress. DNA ... [more ▼]

The NF-κB pathway is involved in immune and inflammation responses, proliferation, differentiation and cell death or survival. It is activated by many external stimuli including genotoxic stress. DNA double-strand breaks activate NF-κB in an ATM-dependent manner. In this manuscript, a direct interaction between p65(RelA) and the N-terminal extremity of ATM is reported. We also report that only one of the five potential ATM-(S/T)Q target sites present in p65, namely Ser547, is specifically phosphorylated by ATM in vitro. A comparative transcriptomic analysis performed in HEK-293 cells expressing either wild-type HA-p65 or a non-phosphorylatable mutant HA-p65S547A identified several differentially transcribed genes after an etoposide treatment (e.g. IL8, A20, SELE). The transcription of these genes is increased in cells expressing the mutant. Substitution of Ser547 to alanine does not affect p65 binding abilities on the κB site of the IL8 promoter but reduces p65 interaction with HDAC1. Cells expressing p65S547A have a higher level of histone H3 acetylated on Lys9 at the IL8 promoter, which is in agreement with the higher gene induction observed. These results indicate that ATM regulates a sub-set of NF-κB dependent genes after a genotoxic stress by direct phosphorylation of p65. [less ▲]

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See detailRole of NF-κB p65 subunit phosphorylation by ATM in DNA damage-regulated gene expression
Sabatel, Hélène ULg

Doctoral thesis (2012)

DNA damage, induced by several genotoxic agents, challenge genome integrity. Among the different types of DNA lesions, DNA double-strand breaks (DSB) are the most deleterious. Indeed, if not correctly ... [more ▼]

DNA damage, induced by several genotoxic agents, challenge genome integrity. Among the different types of DNA lesions, DNA double-strand breaks (DSB) are the most deleterious. Indeed, if not correctly repaired, they can lead to cell death or carcinogenesis. Upon DSB, cells activate a complex signaling network, the DNA damage response (DDR), to counteract those threats. The DDR coordinates DSB repair, checkpoint activation, apoptosis and transcription factors regulation, including NF-κB.   NF-κB family is composed of 5 proteins (RelA/p65, RelB, c-Rel, p105/p50 and p100/p52) which assemble in dimers to form active NF-κB transcription factor. In resting cells, NF-κB complexes are bound to inhibitor proteins such as IκBα, and maintained inactive in the cytoplasm. Classical NF-κB activation requires activation of IκB kinase (IKK) complex, which phosphorylates IκBα, finally leading to its degradation. NF-κB transcription factor is then free to translocate to the nucleus where it regulates a wide array of target genes. NF-κB is an important regulator of diverse cellular processes, including immune response, inflammation, cell survival, proliferation, differentiation, adhesion and apoptosis. NF-κB activation is associated to several pathogenesis and especially contributes to the growth and malignancy of cancer cells. NF-κB also affects the tumor response to many types of chemotherapy and ionizing radiation. Therefore the understanding of the regulation mechanisms of this transcription factor represent a major concern.   This work was interested in the regulation mechanism of DSB-induced NF-κB via the direct phosphorylation of the NF-κB subunit p65 by ATM kinase, the main mediator protein of the DDR. Indeed, rapidly activated in response to DSB, this kinase phosporylates a huge amount of substrates involved in different cellular functions. It had been previously shown that ATM was required for DSB-induced NF-κB activation by acting at two levels. On the one hand, activated ATM phosphorylates the IKK regulatory subunit NEMO. On the other hand, ATM is important for TAK1 activation and TRAF6 poly-ubiquitination, two steps necessary for full IKK complex activation too. The present work therefore highlighted a third ATM-mediated NF-κB regulation mechanism. This study showed that following DNA damage, the phosphorylation of p65 on Ser547 by ATM lead to the lower expression of a set of specific genes mainly involved in inflammation. Phosphorylated p65 was shown to interact with the co-repressor HDAC1, leading to specific promoter deacetylation and subsequent decreased gene expression.   In a second time, we also showed for the first time the requirement of MDC1 protein in DNA damage-induced NF-κB activation. MDC1 protein is mainly described as playing an important role in DSB-induced nuclear foci, which consist in large protein structures that assemble at the site of the DSB. Nevertheless, it appeared in this study that the role of MDC1 in NF-κB activation pathway is foci-independent. [less ▲]

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See detailImportance of the PIKKs in NF-kappaB activation by genotoxic stress
Sabatel, Hélène ULg; Pirlot, Céline ULg; Piette, Jacques ULg et al

in Biochemical Pharmacology (2011), 82(10), 1371-83

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