References of "Habraken, Yvette"
     in
Bookmark and Share    
See detailAn additional role for ATM in the control of NF-kappaB activation by DNA double-strand breaks.
Habraken, Yvette ULg

Conference (2012, November 13)

L’importance de la kinase ATM pour l’activation du complexe IKK suite aux dommages à l’ADN a été démontrée par de nombreuses équipes. ATM est requis pour (i) la phosphorylation de NEMO, (ii) l’activation ... [more ▼]

L’importance de la kinase ATM pour l’activation du complexe IKK suite aux dommages à l’ADN a été démontrée par de nombreuses équipes. ATM est requis pour (i) la phosphorylation de NEMO, (ii) l’activation du complexe TAK1/Tab2 et (iii) l’induction de la poly-ubiquitination de TRAF6 ou RIP1 ou ELKS. Nos travaux ont permis la mise en évidence d’une quatrième fonction d’ATM en aval du complexe IKK. Après avoir montré qu’ATM phosphorylait de manière spécifique la sérine 547 de p65, nous avons établi que la mutation S547A n’affectait pas globalement le potentiel transactivateur du NF-kappaB mais réprimait de manière spécifique la transcription de certains gènes [CXCL1, CXCL2, CCL20, IL-8, TNF, Selectine E, V-CAM1, et, A20]. La transcription d’IκBα et de Cox2 n’est pas influencée par la mutation. L’étude du mécanisme moléculaire, au niveau du promoteur de l’IL8, a montré que la phosphorylation de S547 est responsable de l’interaction avec HDCA1 dont la présence au niveau du promoteur diminue l’acétylation de l’histone H3 et donc réduit la transcription. Ces résultats ont été obtenus en cellules HEK293 exprimant p65WT ou p65S547A exogène (porteur d’une mutation silencieuse les rendant résistants au siRNA utilisé pour éteindre le p65 endogène). [less ▲]

Detailed reference viewed: 10 (0 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 44 (17 ULg)
See detailNF-kappaB activation by DNA damage
Habraken, Yvette ULg

Conference (2012, May 11)

L’importance de la kinase ATM pour l’activation du complexe IKK suite aux dommages à l’ADN a été démontrée par de nombreuses équipes. ATM est requis pour (i) la phosphorylation de NEMO, (ii) l’activation ... [more ▼]

L’importance de la kinase ATM pour l’activation du complexe IKK suite aux dommages à l’ADN a été démontrée par de nombreuses équipes. ATM est requis pour (i) la phosphorylation de NEMO, (ii) l’activation du complexe TAK1/Tab2 et (iii) l’induction de la poly-ubiquitination de TRAF6 ou RIP1 ou ELKS. Nos travaux ont permis la mise en évidence d’une quatrième fonction d’ATM en aval du complexe IKK. Après avoir montré qu’ATM phosphorylait de manière spécifique la sérine 547 de p65, nous avons observé que la mutation S547A n’affectait pas globalement le potentiel transactivateur du NF-kappaB mais réprimait de manière spécifique la transcription de certains gènes [CXCL1, CXCL2, CCL20, IL-8, TNF, Selectine E, V-CAM1, et, A20]. La transcription d’IκBα et de Cox2 n’est pas influencée par la mutation. L’étude du mécanisme moléculaire, au niveau du promoteur de l’IL8, a montré que la phosphorylation de S547 est responsable de l’interaction avec HDCA1 dont la présence au niveau du promoteur diminue l’acétylation de l’histone H3 et donc réduit la transcription. Ces résultats ont été obtenus en cellules HEK293 exprimant p65WT ou p65S547A exogène (porteur d’une mutation silencieuse les rendant résistants au siRNA utilisé pour éteindre le p65 endogène). [less ▲]

Detailed reference viewed: 8 (1 ULg)
Full Text
Peer Reviewed
See detailThe c-jun N-terminal Kinase (JNK)-binding Protein (JNKBP1) Acts as a Negative Regulator of NOD2 Protein Signaling by Inhibiting Its Oligomerization Process
Lecat, Aurore ULg; Di Valentin, Emmanuel ULg; Somja, Joan ULg et al

in Journal of Biological Chemistry (2012), 287(35), 29213-26

NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently ... [more ▼]

NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently induce various signalling pathways leading to NF- kappaB activation and autophagy, both events contributing to an efficient innate and adaptative immune response. Interestingly, loss-of-function nod2 variants were associated with a higher susceptibility for Crohn ' s disease (CD), which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-jun N-terminal kinase binding protein 1 (JNKBP1), a scaffold protein characterized by a N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following MDP activation. This interaction attenuates NOD2-mediated NF-kappaB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signalling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. [less ▲]

Detailed reference viewed: 59 (38 ULg)
Full Text
Peer Reviewed
See detailProinflammatory Cytokines Induce Bronchial Hyperplasia and Squamous Metaplasia in Smokers: Implications for chronic obstructive pulmonary disease therapy.
Herfs, Michael ULg; Hubert, Pascale ULg; POIRRIER, Anne-Lise ULg et al

in American Journal of Respiratory Cell and Molecular Biology (2012), 47(1), 67-79

Tracheobronchial squamous metaplasia is common in smokers and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Whereas this ... [more ▼]

Tracheobronchial squamous metaplasia is common in smokers and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Whereas this reversible epithelial replacement is almost always observed in association with chronic inflammation, the role of inflammatory mediators in the pathogenesis of squamous metaplasia is still unclear. In the present study, we investigated the implication of cigarette smoke-mediated pro-inflammatory cytokine up-regulation in the development and treatment of tracheobronchial epithelial hyperplasia and squamous metaplasia. By using immunohistological techniques, we showed a higher epithelial expression of TNFalpha, IL-1beta and IL-6 as well as an activation of NF-kappaB and AP-1/MAPK signalling pathways in the respiratory tract of smoking patients compared to the normal ciliated epithelium of non-smoking patients. In addition, we demonstrated that these signalling pathways strongly influence the proliferation and the differentiation state of in vitro generated normal human airway epithelial basal cells. Finally, we exposed mice to cigarette smoke for 16 weeks and demonstrated that anti-TNFalpha (etanercept), anti-IL-1beta (anakinra) and/or anti-IL-6R (tocilizumab) therapies significantly reduced epithelial hyperplasia and squamous metaplasia development. These data highlight the importance of soluble inflammatory mediators in the pathogenesis of tracheobronchial squamous metaplasia. Therefore, administration of pro-inflammatory cytokine antagonists may have clinical application in the management of COPD patients. [less ▲]

Detailed reference viewed: 63 (21 ULg)
Full Text
Peer Reviewed
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

Detailed reference viewed: 29 (7 ULg)
Full Text
Peer Reviewed
See detailNF-kappaB inhibition improves the sensitivity of human glioblastoma cells to 5-aminolevulinic acid-based photodynamic therapy.
Coupienne, Isabelle ULg; Bontems, Sébastien ULg; Dewaele, M. et al

in Biochemical Pharmacology (2011)

Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are very resistant to all current therapies and are associated with a huge rate of recurrence. In most cases ... [more ▼]

Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are very resistant to all current therapies and are associated with a huge rate of recurrence. In most cases, this type of tumor is characterized by a constitutive activation of the nuclear factor-kappaB (NF-kappaB). This factor is known to be a key regulator of various physiological processes such as inflammation, immune response, cell growth or apoptosis. In the present study, we explored the role of NF-kappaB activation in the sensitivity of human glioblastoma cells to a treatment by 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT). 5-ALA is a physiological compound widely used in PDT as well as in tumor photodetection (PDD). Our results show that inhibition of NF-kappaB improves glioblastoma cell death in response to 5-ALA-PDT. We then studied the molecular mechanisms underlying the cell death induced by PDT combined or not with NF-kappaB inhibition. We found that apoptosis was induced by PDT but in an incomplete manner and that, unexpectedly, NF-kappaB inhibition reduced its level. Oppositely PDT mainly induces necrosis in glioblastoma cells and NF-kappaB is found to have anti-necrotic functions in this context. The autophagic flux was also enhanced as a result of 5-ALA-PDT and we demonstrate that stimulation of autophagy acts as a pro-survival mechanism confering protection against PDT-mediated necrosis. These data point out that 5-ALA-PDT has an interesting potential as a mean to treat glioblastoma and that inhibition of NF-kappaB renders glioblastoma cells more sensitive to the treatment. [less ▲]

Detailed reference viewed: 30 (5 ULg)
Full Text
Peer Reviewed
See detailThe varicella-zoster virus ORF47 kinase interferes with host innate immune response by inhibiting the activation of IRF3.
Vandevenne, Patricia ULg; Lebrun, Marielle ULg; El Mjiyad, Nadia et al

in PLoS ONE (2011), 9(2),

The innate immune response constitutes the first line of host defence that limits viral spread and plays an important role in the activation of adaptive immune response. Viral components are recognized by ... [more ▼]

The innate immune response constitutes the first line of host defence that limits viral spread and plays an important role in the activation of adaptive immune response. Viral components are recognized by specific host pathogen recognition receptors triggering the activation of IRF3. IRF3, along with NF-kappaB, is a key regulator of IFN-beta expression. Until now, the role of IRF3 in the activation of the innate immune response during Varicella-Zoster Virus (VZV) infection has been poorly studied. In this work, we demonstrated for the first time that VZV rapidly induces an atypical phosphorylation of IRF3 that is inhibitory since it prevents subsequent IRF3 homodimerization and induction of target genes. Using a mutant virus unable to express the viral kinase ORF47p, we demonstrated that (i) IRF3 slower-migrating form disappears; (ii) IRF3 is phosphorylated on serine 396 again and recovers the ability to form homodimers; (iii) amounts of IRF3 target genes such as IFN-beta and ISG15 mRNA are greater than in cells infected with the wild-type virus; and (iv) IRF3 physically interacts with ORF47p. These data led us to hypothesize that the viral kinase ORF47p is involved in the atypical phosphorylation of IRF3 during VZV infection, which prevents its homodimerization and subsequent induction of target genes such as IFN-beta and ISG15. [less ▲]

Detailed reference viewed: 31 (6 ULg)
See detailRole of MDC1 in NF-kappaB activation by DNA double-strand breaks.
Sabatel, Hélène; Piette, Jacques ULg; Habraken, Yvette ULg

Poster (2011, January 25)

Detailed reference viewed: 7 (0 ULg)
Full Text
Peer Reviewed
See detailNewly identified biologically active and proteolysis-resistant VEGF-A isoform VEGF111 is induced by genotoxic agents
Mineur, Pierre ULg; Colige, Alain ULg; Deroanne, Christophe ULg et al

in Journal of Cell Biology (2007), 179(6), 1261-1273

Ultraviolet B and genotoxic drugs induce the expression of a vascular endothelial growth factor A (VEGF-A) splice variant (VEGF111) encoded by exons 1-4 and 8 in many cultured cells. Although not detected ... [more ▼]

Ultraviolet B and genotoxic drugs induce the expression of a vascular endothelial growth factor A (VEGF-A) splice variant (VEGF111) encoded by exons 1-4 and 8 in many cultured cells. Although not detected in a series of normal human and mouse tissue, VEGF111 expression is induced in MCF-7 xenografts in nude mice upon treatment by camptothecin. The skipping of exons that contain proteolytic cleavage sites and extracellular matrix-binding domains makes VEGF111 diffusible and resistant to proteolysis. Recombinant VEGF111 activates VEGF receptor 2 (VEGF-R2) and extracellularly regulated kinase 1/2 in human umbilical vascular endothelial cells and porcine aortic endothelial cells expressing VEGF-R2. The mitogenic and chemotactic activity and VEGF111's ability to promote vascular network formation during embyonic stem cell differentiation are similar to those of VEGF121 and 165. Tumors in nude mice formed by HEK293 cells expressing VEGF111 develop a more widespread network of numerous small vessels in the peritumoral tissue than those expressing other isoforms. Its potent angiogenic activity and remarkable resistance to proteolysis makes VEGF111 a potential adverse factor during chemotherapy but a beneficial therapeutic tool for ischemic diseases. [less ▲]

Detailed reference viewed: 79 (20 ULg)
Full Text
Peer Reviewed
See detailHistone deacetylase inhibitor trichostatin A sustains sodium pervanadate-induced NF-kappa B activation by delaying IkappaBalpha mRNA resynthesis : comparison with tumor necrosis factor alpha
Horion, Julie ULg; Gloire, Geoffrey ULg; El Mjiyad, Nadia et al

in Journal of Biological Chemistry (2007), 282(21), 15383

NF-kappaB is a crucial transcription factor tightly regulated by protein interactions and post-translational modifications, like phosphorylation and acetylation. A previous study has shown that ... [more ▼]

NF-kappaB is a crucial transcription factor tightly regulated by protein interactions and post-translational modifications, like phosphorylation and acetylation. A previous study has shown that trichostatin A (TSA), a histone deacetylase inhibitor, potentiates tumor necrosis factor (TNF) alpha-elicited NF-kappaB activation and delays IkappaBalpha cytoplasmic reappearance. Here, we demonstrated that TSA also prolongs NF-kappaB activation when induced by the insulino-mimetic pervanadate (PV), a tyrosine phosphatase inhibitor that initiates an atypical NF-kappaB signaling. This extension is similarly correlated with delayed IkappaBalpha cytoplasmic reappearance. However, whereas TSA causes a prolonged IKK activity when addedtoTNFalpha, it does notwhenaddedtoPV.Instead, quantitative reverse transcriptase-PCR revealed a decrease of ikappabalphamRNAlevel after TSA addition to PV stimulation. This synthesis deficit of the inhibitor could explain the sustained NF-kappaB residence in the nucleus. In vivo analysis by chromatin immunoprecipitation assays uncovered that, forPVinduction but not forTNFalpha, the presence of TSA provokes several impairments on the ikappabalphapromoter: (i) diminution of RNA Pol II recruitment; (ii) reduced acetylation and phosphorylation of histone H3-Lys14 and -Ser10, respectively; (iii) decreased presence of phosphorylated p65-Ser536; and (iv) reduction of IKKalphabinding. The recruitment of these proteins on the icam-1 promoter, another NF-kappaB-regulated gene, is not equally affected, suggesting a promoter specificity of PV with TSA stimulation. Taken together, these data suggest that TSA acts differently depending on the NF-kappaB pathway and the targeted promoter in question. This indicates that one overall histone deacetylase role is to inhibit NF-kappaB activation by molecular mechanisms specific of the stimulus and the promoter. [less ▲]

Detailed reference viewed: 29 (8 ULg)
Full Text
Peer Reviewed
See detailNF-kappa B activation by double-strand breaks
Habraken, Yvette ULg; Piette, Jacques ULg

in Biochemical Pharmacology (2006), 72(9), 1132-1141

Cellular response to DNA damage is complex and relies on the simultaneous activation of different networks. It involves DNA damage recognition, repair, and induction of signalling cascades leading to cell ... [more ▼]

Cellular response to DNA damage is complex and relies on the simultaneous activation of different networks. It involves DNA damage recognition, repair, and induction of signalling cascades leading to cell cycle checkpoint activation, apoptosis, and stress related responses. The fate of damaged cells depends on the balance between pro- and antiapoptotic signals. in this decisive life or death choice, the transcription factor NF-kappa B has emerged as a prosurvival actor in most cell types. As corollary, it appears to be associated with tumorigenic process and resistance to therapeutic strategies as it protects cancerous cells from death. in this review, we will focus on NF-kappa B activation by double-strand breaks inducing agents, such as ionizing radiation and DNA topoisomerase I and II inhibitors routinely used in cancer therapy. Coinciding with the 20th anniversary of the NF-kappa B discovery, major steps of the DSB-triggered cascade have been recently identified. Two parallel cascades are necessary for NF-kappa B activation. The first one depends on ATM (activated by double-strand breaks) and the second on PIDD (activated by an unknown stress signal). The phosphorylation of NEMO by ATM is the point of convergence of these two cascades. The identification of ATM/NEMO complex as the long searched "nuclear to cytoplasm" signal leading to IKK activation is also a major piece of the puzzle. The knowledge of the precise steps leading to DSB-initiated NF kappa B activation will allow the development of specific blocking compounds reducing its prosurvival function. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

Detailed reference viewed: 21 (1 ULg)