References of "Piette, Jacques"
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See detailPromoter specific regulation of NF-kappaB by RelA phosphorylation on Ser547
Trussart, Charlotte; Orban, Tanguy; Di Valentin, Emmanuel ULg et al

Poster (2014, August 29)

NF-KB (p50/RelA) controls the expression of numerous genes involved in inflammation, survival, proliferation, and cancer initiation and progression. Both classical NF-kB activation by pro-inflammatory ... [more ▼]

NF-KB (p50/RelA) controls the expression of numerous genes involved in inflammation, survival, proliferation, and cancer initiation and progression. Both classical NF-kB activation by pro-inflammatory cytokines and ATM-dependant activation by DNA damage require IKK activation and IkBa degradation. Stimuli dependant phosphorylation of p65 controls its transcriptional potential often in a gene specific manner. Previously, we have reported a direct interaction between RelA and ATM, and, demonstrated the in vitro phosphorylation of Ser547 by this kinase. A comparative transcriptomic analysis performed in HEK cells expressing either p65WT or p65S547A identified several differentially transcribed genes after an etoposide treatment. Substitution of S547 to alanine does not affect p65 binding on the kB site of the modulated promoters but it reduces p65 interaction with HDAC1. The resulting enhanced histone H3 acetylation increases gene transcription at some specific promoters. Our data indicate that ATM regulates a sub-set of NF-kB dependent genes after a genotoxic stress by direct phosphorylation of p65. Presently, we are investigating the impact of p65S547A/D mutations after the addition of TNFa in Mefs p65 KO complemented with HA-p65WT or S547A/D. No differences are observed in the degradation of IkBb or the nuclear translocation of p50/p65. However both basal and TNFa-induced transcription levels of some kB dependent genes are elevated in Mefs expressing p65S547D. The role of ATM in NF-kB activation by TNFa is analyzed. [less ▲]

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See detailvCCL2, the third agonist ligand for the -arrestin-biased chemokine receptor CXCR7
Szpakowska, Martyna ULg; Derj, Anouar ULg; Counson, Manuel et al

Poster (2014, April)

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See detailMelanoma AntiGEn D2 (MAGED2) a new partner of the DNA damage response?
Pirlot, Céline ULg; Piette, Jacques ULg; Habraken, Yvette ULg

Poster (2014, January)

MAGED2 belongs to the Melanoma AntiGEn (MAGE) family of proteins. It is ubiquitously expressed and its overexpression in many cancers could make it a potential biomarker of tumor development and ... [more ▼]

MAGED2 belongs to the Melanoma AntiGEn (MAGE) family of proteins. It is ubiquitously expressed and its overexpression in many cancers could make it a potential biomarker of tumor development and metastasis formation. Actually, the only known function of this protein is its involvement in the p53 pathways. Indeed, MAGED2 could be a negative regulator of p53 and it increases apoptosis induced by TRAIL in a p53 dependent manner. Moreover, a phosphoproteomic experiment has shown that this protein is likely phosphorylated by ATM, ATR or DNA-PK after exposition to ionizing irradiation. These three kinases are implicated in the DNA damage response (DDR). Our lab showed by yeast two hybrids an interaction between MAGED2 and ATM. Thus, the aims of the project are to confirm and to find the function of this interaction in a DDR context. Current avenues of investigations include determining the impact of MAGED2 depletion and overexpression in the p53, NF-kappaB and cell cycle regulation following double strand break induced by etoposide treatment. Though this study we plan to confirm a new partner of ATM in the DDR pathway, which could be targeted to limit cancer progression and improve the chemotherapy relying on DNA damaging compounds. [less ▲]

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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 detailInflammation as a link between obesity, metabolic syndrome and type 2 diabetes
ESSER, Nathalie ULg; Legrand, Sylvie ULg; Piette, Jacques ULg et al

in Diabetes Research & Clinical Practice (2014)

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic ... [more ▼]

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammarory therapies could have a place in prevention and treatment of type 2 diabetes. [less ▲]

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See detailObesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue
ESSER, Nathalie ULg; L'Homme, Laurent ULg; DE ROOVER, Arnaud ULg et al

in Diabetologia (2013), 56

Aims/hypothesis Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose ... [more ▼]

Aims/hypothesis Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose tissue is also heterogeneous in that its visceral component is more frequently associated with metabolic dysfunction than its subcutaneous component. The development of metabolic disorders is partly mediated by the NLR family pyrin domain containing-3 (NLRP3) inflammasome, which increases the secretion of inflammatory cytokines via activation of caspase-1. We compared the immunological profile and NLRP3 activity in adipose tissue between MUO and MHO individuals. Methods MHO and MUO phenotypes were defined, respectively, as the absence and the presence of the metabolic syndrome. Cellular composition and intrinsic inflammasome activity were investigated by flow cytometry, quantitative RTPCR and tissue culture studies in subcutaneous and visceral adipose tissue from 23 MUO, 21 MHO and nine lean individuals. Results We found significant differences between the three study groups, including an increased secretion of IL-1β, increased expression of IL1B and NLRP3, increased number of adipose tissue macrophages and decreased number of regulatory T cells in the visceral adipose tissue of MUO patients compared with MHO and lean participants. In macrophages derived from visceral adipose tissue, both caspase-1 activity and IL-1β levels were higher in MUO patients than in MHO patients. Furthermore, caspase-1 activity was higher in CD11c+CD206+ adipose tissue macrophages than in CD11c−CD206+ cells. Conclusions/interpretation The MUO phenotype seems to be associated with an increased activation of the NLPR3 inflammasome in macrophages infiltrating visceral adipose tissue, and a less favourable inflammatory profile compared with the MHO phenotype. [less ▲]

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See detailUnsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages
L'Homme, Laurent ULg; Esser, Nathalie ULg; Riva, Laura ULg et al

in Journal of Lipid Research (2013), 54

The NLRP3 inflammasome is involved in many obesity-associated diseases such as type 2 diabetes, atherosclerosis and gouty arthritis through its ability to induce IL-1β release. The molecular link between ... [more ▼]

The NLRP3 inflammasome is involved in many obesity-associated diseases such as type 2 diabetes, atherosclerosis and gouty arthritis through its ability to induce IL-1β release. The molecular link between obesity and inflammasome activation is still unclear but free fatty acids have been proposed as one triggering event. Here we reported opposite effects of saturated fatty acids (SFAs) compared to unsaturated fatty acids (UFAs) on NLRP3 inflammasome in human monocytes/macrophages. Palmitate and stearate, both SFAs, triggered IL-1β secretion in a caspase-1/ASC/NLRP3-dependent pathway. Unlike SFAs, the UFAs oleate and linoleate did not lead to IL-1β secretion. In addition, they totally prevented the IL-1β release induced by SFAs and, with less efficiency, by a broad range of NLRP3 inducers including nigericin, alum and MSU. UFAs did not affect the transcriptional effect of SFAs suggesting a specific effect on the NLRP3 activation. These results provide a new antiinflammatory mechanism of UFAs by preventing the activation of the NLRP3 inflammasome and therefore the IL-1β processing. By this way, UFAs might play a protective role in NLRP3-associated diseases. [less ▲]

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See detailDifférences d’activité de l’inflammasome NLRP3 entre sujets obèses avec et sans anomalies métaboliques
Esser, Nathalie ULg; L'Homme, Laurent ULg; DE ROOVER, Arnaud ULg et al

in Diabètes & Métabolism (2013, March), 39(suppl 1), 102

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See detailORF9p phosphorylation by ORF47p is crucial for the formation and egress of the Varicella-zoster virus (VZV) viral particles.
Riva, Laura ULg; Thiry, Marc ULg; BONTEMS, Sébastien ULg et al

in Journal of Virology (2013), 87(5), 2868-2881

The role of the tegument during the herpesvirus lytic cycle is still not clearly established, particularly at the late phase of infection, when the newly produced viral particles need to be fully ... [more ▼]

The role of the tegument during the herpesvirus lytic cycle is still not clearly established, particularly at the late phase of infection, when the newly produced viral particles need to be fully assembled before being released from the infected cell. The Varicella-zoster virus (VZV) protein coded by ORF9 (ORF9p) is an essential tegument protein and, even though its mRNA is the most expressed during the productive infection, little is known about its functions. Using a GalK positive/negative selection technique, we modified a BAC containing the complete VZV genome creating viruses expressing mutant versions of ORF9p.We showed that ORF9p is hyper-phosphorylated during the infection, especially through its interaction with the viral Ser/Thr kinase ORF47p; we identified a consensus site within ORF9p recognized by ORF47p and demonstrated its importance for ORF9p phosphorylation. Strikingly, an ultra-structural analysis revealed that the mutation of this consensus site (Glutamate 85 to Arginine) strongly affects viral assembly and release, reproducing ORF47 kinase dead VZV phenotype. It also slightly diminishes the infectivity towards immature dendritic cells. Taken together, our results identify ORF9p as a new viral substrate of ORF47p and suggest a determinant role of this phosphorylation for viral infectivity, especially during the process of viral particle formation and egress. [less ▲]

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See detailEvaluation of a new biocompatible poly(N-(morpholino ethyl methacrylate)-based copolymer for the delivery of ruthenium oligonucleotides, targeting HPV16 E6 oncogene
Reschner, Anca ULg; Shim, Yong Ho; Dubois, Philippe et al

in Journal of Biomedical Nanotechnology (2013), 9

This study investigates the use of a new biocompatible block copolymer poly(2-(dimethylamino)ethyl methacrylate-N-(morpholino)ethyl methacrylate (PDMAEMA-b-PMEMA) for the delivery of a particular ... [more ▼]

This study investigates the use of a new biocompatible block copolymer poly(2-(dimethylamino)ethyl methacrylate-N-(morpholino)ethyl methacrylate (PDMAEMA-b-PMEMA) for the delivery of a particular antisense oligonucleotide targeting E6 gene from human papilloma virus. This antisense oligonucleotide was derivatized with a polyazaaromatic RuII complex which, under visible illumination, is able to produce an irreversible crosslink with the complementary targeted sequence. The purpose of this study is to determine whether by the use of a suitable transfection agent, it is possible to increase the efficiency of the antisense oligonucleotide targeting E6 gene, named Ru-P-4. In a recent study, we showed that Oligofectamine® transfected Ru-P-4 antisense oligonucleotide failed to inhibit efficiently the growth of cervical cancer cell line SiHa, contrarily to the Ru-P-6 antisense oligonucleotide, another sequence also targeting the E6 gene. The ability of PDMAEMA-b-PMEMA to form polyplexes with optimal physicochemical characteristics was investigated first. Then the ability of the PDMAEMA-b-PMEMA/Ru-P-4 antisense oligonucleotide polyplexes to transfect two keratinocyte cell lines (SiHa and HaCat) and the capacity of polyplexes to inhibit HPV16 + cervical cancer cell growth was evaluated. PDMAEMA-b-PMEMA base polyplexes at the optimal molar ratio of polymer nitrogen atoms to DNA phosphates (N/P), were able to deliver Ru-P-4 antisense oligonucleotide and to induce a higher growth inhibition in human cervical cancer SiHa cells, compared to other formulations based on Oligofectamine®. [less ▲]

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See detailCharacterization of chemotherapy-induced cell death in glioblastoma
Coupienne, Isabelle ULg; Fettweis, Grégory ULg; Piette, Jacques ULg

Poster (2012, December 10)

Glioblastoma constitute the most frequent and deadliest type of brain tumors. Their annual incidence is estimated between 5 and 8 cases per 100,000 people in Europe and North America. They are resistant ... [more ▼]

Glioblastoma constitute the most frequent and deadliest type of brain tumors. Their annual incidence is estimated between 5 and 8 cases per 100,000 people in Europe and North America. They are resistant to all current therapies and are associated with a very high rate of recurrence. The associated prognosis is generally very poor and most patients die within a year after diagnosis. Unfortunately, despite extensive research and use of multimodality treatments combining surgical resection, chemotherapy and radiotherapy, survival hasn’t really much improved over the last 20 years. Indeed, these tumors were shown to be characterized by a high radio- and chemo-resistance. Glioblastoma cells exhibit overexpression of the anti-apoptotic Bcl-2 family proteins and downregulation of its pro-apoptotic members, high expression of the IAPs (Inhibitors of Apoptosis Proteins) and constitutive activation of the pro-survival NF-κB pathway. Currently, the most commonly used treatment offering the best prognosis to patients consists in a combination of maximal surgical tumor resection (when feasible) with subsequent radio- and/or chemotherapy. Among the most commonly used chemotherapeutic agents, the alkylating agent temozolomide and the topoisomerase I inhibitor camptothecin occupy a central position. Therefore, in this study, the impact of both temozolomide and irinotecan (a soluble derivative of camptothecin) on glioma cell survival will be investigated. Important progress was made in the comprehension of the molecular mechanisms underlying tumor development and progression however, survival benefits conferred by the use of new drugs and therapeutic strategies are counted in months rather than years. Consequently, there is an urge to rapidly improve the efficiency of the currently used treatments. This research project consists in (i) the study of the mechanisms implicated in glioblastoma cell death induced by two chemotherapeutic agents : temozolomide and irinotecan, (ii) the identification of the mechanisms underlying the resistance of glioblastoma to these treatments, (iii) the use of pharmacological tools to interfere with those resistance strategies to enhance chemotherapy efficiency. Necrosis was, until recently, long thought to be only accidental. However, it was shown to be finely regulated by specific signalling pathways. Programmed necrosis often takes place in cells in which apoptosis cannot be properly activated and serves as a back-up cell death pathway. Previous work from our lab having already demonstrated that glioblastoma are, at least partially, apoptosis-defective, special emphasis is put on the study of necrotic parameters. Results from survival tests performed on several glioblastoma cell lines in the presence of necrotic inhibitors like necrostatin-1 (an inhibitor of the central regulator of the necrotic pathway RIP1) allows to partially overcome temozolomide and irinotecan-induced glioblastoma cell death, highlighting the role played by programmed necrosis in chemotherapy sensitivity. [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 detailThe inositol phosphatase SHIP-1 inhibits NOD2-induced NF-κB activation by disturbing the interaction of XIAP with RIP2
Condé, Claude ULg; Rambout, Xavier ULg; Lebrun, Marielle ULg et al

in PLoS ONE (2012)

SHIP-1 is an inositol phosphatase predominantly expressed in hematopoietic cells. Over the ten past years, SHIP-1 has been described as an important regulator of immune functions. Here, we characterize a ... [more ▼]

SHIP-1 is an inositol phosphatase predominantly expressed in hematopoietic cells. Over the ten past years, SHIP-1 has been described as an important regulator of immune functions. Here, we characterize a new inhibitory function for SHIP-1 in NOD2 signaling. NOD2 is a crucial cytoplasmic bacterial sensor that activates proinflammatory and antimicrobial responses upon bacterial invasion. We observed that SHIP-1 decreases NOD2-induced NF-κB activation in macrophages. This negative regulation relies on its interaction with XIAP. Indeed, we observed that XIAP is an essential mediator of the NOD2 signaling pathway that enables proper NF-κB activation in macrophages. Upon NOD2 activation, SHIP-1 C-terminal proline rich domain (PRD) interacts with XIAP, thereby disturbing the interaction between XIAP and RIP2 in order to decrease NF-κB signaling. [less ▲]

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