References of "Piette, Jacques"
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See detailMolecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells
Buytaert, E.; Matroule, J. Y.; Durinck, S. et al

in Oncogene (2008)

Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O(2), cytotoxic reactive oxygen species, which cause ... [more ▼]

Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O(2), cytotoxic reactive oxygen species, which cause tumor ablation. Given that the photosensitizer hypericin is under consideration for PDT treatment of bladder cancer we used oligonucleotide microarrays in the T24 bladder cancer cell line to identify differentially expressed genes with therapeutic potential. This study reveals that the expression of several genes involved in various metabolic processes, stress-induced cell death, autophagy, proliferation, inflammation and carcinogenesis is strongly affected by PDT and pinpoints the coordinated induction of a cluster of genes involved in the unfolded protein response pathway after endoplasmic reticulum stress and in antioxidant response. Analysis of PDT-treated cells after p38(MAPK) inhibition or silencing unraveled that the induction of an important subset of differentially expressed genes regulating growth and invasion, as well as adaptive mechanisms against oxidative stress, is governed by this stress-activated kinase. Moreover, p38(MAPK) inhibition blocked autonomous regrowth and migration of cancer cells escaping PDT-induced cell death. This analysis identifies new molecular effectors of the cancer cell response to PDT opening attractive avenues to improve the therapeutic efficacy of hypericin-based PDT of bladder cancer. [less ▲]

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See detailGeldanamycin inhibits tyrosine phosphorylation-dependent NF-kB activation
Crèvecoeur, Julie ULg; Piette, Jacques ULg; Gloire, Geoffrey ULg

in Biochemical Pharmacology (2008), 75(11), 2183-2191

Hsp90 is a protein chaperone regulating the stability and activity of many signalling molecules. The requirement of Hsp90 activity in the NF-κB pathway has been recently reported by several authors using ... [more ▼]

Hsp90 is a protein chaperone regulating the stability and activity of many signalling molecules. The requirement of Hsp90 activity in the NF-κB pathway has been recently reported by several authors using the Hsp90 ATPase inhibitor Geldanamycin (GA), an anti-tumour drug. Hsp90 inhibition blocks the synthesis and activation of the IKK complex, the major kinases complex responsible for IκBα phosphorylation on serine 32 and 36, a key step for its degradation and the nuclear translocation of NF-κB. However, the effect of GA on other IκBα kinases, including tyrosine kinases, is unknown. In the present study, we investigated the effect of GA on NF-κB activation induced by sodium pervanadate (PV), a tyrosine phosphatase inhibitor triggering c-Src-mediated tyrosine phosphorylation of IκBα. We reporte for the first time that GA inhibits PV-induced IκBα tyrosine phosphorylation and degradation. Using an in vitro kinase assay, we demonstrated that GA inhibits the activity of c-Src as an IκBα tyrosine kinase, but not its cellular expression. As a result, GA blocked PV-induced NF-κB DNA binding activity on an exogenous κB element and on the endogenous iκbα promoter, thereby inhibiting IκBα transcription. Finally, we demonstrated that, despite NF-κB inhibition, pre-treatment with GA does not potentiate PV-induced apoptosis. We conclude that c-Src requires Hsp90 for its tyrosine kinase activity, and its inhibition by GA blocks c-Src-dependent signalling pathways, such as NF-κB activation induced by sodium pervanadate. The effect of GA on PV-induced apoptosis is discussed in the light of recent publications in the literature. [less ▲]

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See detailActin cytoskeleton differentially modulates NF-κB-mediated IL-8 expression in myelomonocytic cells
Kustermans, Gaëlle ULg; El Mjiyad, Nadia ULg; Horion, Julie ULg et al

in Biochemical Pharmacology (2008), 76(10)

Many physiopathological events such as phagocytosis, pathogen invasion, cellular adhesion and chemotaxis governed by actin-based cytoskeleton are often accompanied by nuclear factor kB (NF-kB) activation ... [more ▼]

Many physiopathological events such as phagocytosis, pathogen invasion, cellular adhesion and chemotaxis governed by actin-based cytoskeleton are often accompanied by nuclear factor kB (NF-kB) activation and expression of pro-inflammatory genes. In the present study, we demonstrated that reorganization of actin cytoskeleton induced by Cytochalasin D (CytD), an actin-polymerization inhibitor, enhanced il-8 gene expression induced by TNFa and LPS in HL-60 monocyte-like cells. Both transcriptional and post-transcriptional mechanisms were involved. CytD potentiated NF-kB-mediated transcription induced by both TNFa and LPS but via different mechanisms. In the case of LPS, the perturbation of actin dynamics increased the TLR4 levels at the cell membrane and consequently enhanced the IKK complex activation and NF-kB nuclear translocation. However, the canonical pathway involving the IKK complex and leading to the NF-kB translocation into the nucleus was not affected by actin remodelling in the case of TNFa. Interestingly, actin disruption primed p65 phosphorylation induced by TNFa and LPS, on Ser276 and Ser536, respectively, which suggested actin cytoskeleton could also modulate p65 transactivating activity. [less ▲]

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See detailAre the IKKs and IKK-related kinases TBK1 and IKK-ε similarly activated ?
Chau, Tieu-Lan ULg; Gioia, Romain ULg; Gatot, Jean-Stéphane et al

in Trends in Biochemical Sciences - Regular Edition (2008), 33

The IKKs, IKKa and IKKb, and the IKK-related kinases TBK1 and IKKe, play essential roles in innate immunity through signal-induced activation of NF-κB and IRF3/7, respectively. Although the signaling ... [more ▼]

The IKKs, IKKa and IKKb, and the IKK-related kinases TBK1 and IKKe, play essential roles in innate immunity through signal-induced activation of NF-κB and IRF3/7, respectively. Although the signaling events within these pathways have been extensively studied, the mechanisms of IKK and IKK-related complex assembly and activation remain poorly defined. Recent data provide insight into the requirement for scaffold proteins in complex assembly; NEMO coordinates some IKK complexes, whereas TANK, NAP1 or SINTBAD assemble TBK1 and IKKe complexes. The different scaffold proteins undergo similar post-translational modifications, including phosphorylation and non-degradative polyubiquitylation. Moreover, increasing evidence suggests that distinct scaffold proteins assemble IKK and potentially TBK1 and IKKε sub-complexes in a stimulus-specific manner, which might be a mechanism to achieve specificity. [less ▲]

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See detailRegulation of CD95/APO-1/Fas-induced apoptosis by protein phosphatases.
Gloire, Geoffrey ULg; Charlier, Edith ULg; Piette, Jacques ULg

in Biochemical Pharmacology (2008)

Triggering the CD95/APO-1/Fas receptor by CD95-L induces the assembly of the death-inducing signaling complex (DISC), which permits initiator caspases activation and progression of a signaling cascade ... [more ▼]

Triggering the CD95/APO-1/Fas receptor by CD95-L induces the assembly of the death-inducing signaling complex (DISC), which permits initiator caspases activation and progression of a signaling cascade that culminates in cellular apoptosis. Despite the CD95 receptor does not exhibit any kinase activity by itself, phosphorylation/dephosphorylation events seem important to regulate many aspects of CD95-mediated apoptosis. Here, we try to highlight particularly the importance of protein phosphatases in the modulation of the CD95 system. [less ▲]

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See detailLipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKK epsilon-dependent lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF
Gatot, Jean-Stéphane; Gioia, Romain ULg; Chau, Tieu-Lan ULg et al

in Journal of Biological Chemistry (2007), 282(43), 31131-31146

Type I interferon gene induction relies on IKK-related kinase TBK1 and IKK epsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins ... [more ▼]

Type I interferon gene induction relies on IKK-related kinase TBK1 and IKK epsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKK epsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKK epsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKK epsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKK epsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKK epsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys63-linked polyubiquitination of their scaffold protein, TANK. [less ▲]

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See detailThe varicella-zoster virus immediate-early 63 protein affects chromatin-controlled gene transcription in a cell-type dependent manner.
Habran, Lionel ULg; El Mjiyad, Nadia ULg; Di Valentin, Emmanuel ULg et al

in BMC Molecular Biology (2007), 8

Varicella Zoster Virus Immediate Early 63 protein (IE63) has been shown to be essential for VZV replication, and critical for latency establishment. The activity of the protein as a transcriptional ... [more ▼]

Varicella Zoster Virus Immediate Early 63 protein (IE63) has been shown to be essential for VZV replication, and critical for latency establishment. The activity of the protein as a transcriptional regulator is not fully clear yet. Using transient transfection assays, IE63 has been shown to repress viral and cellular promoters containing typical TATA boxes by interacting with general transcription factors. In this paper, IE63 regulation properties on endogenous gene expression were evaluated using an oligonucleotide-based micro-array approach. We found that IE63 modulates the transcription of only a few genes in HeLa cells including genes implicated in transcription or immunity. Furthermore, we showed that this effect is mediated by a modification of RNA POL II binding on the promoters tested and that IE63 phosphorylation was essential for these effects. In MeWo cells, the number of genes whose transcription was modified by IE63 was somewhat higher, including genes implicated in signal transduction, transcription, immunity, and heat-shock signalling. While IE63 did not modify the basal expression of several NF-κB dependent genes such as IL-8, ICAM-1, and IκBα, it modulates transcription of these genes upon TNFα induction. This effect was obviously correlated with the amount of p65 binding to the promoter of these genes and with histone H3 acetylation and HDAC-3 removal. Conclusion While IE63 only affected transcription of a small number of cellular genes, it interfered with the TNF-inducibility of several NF-κB dependent genes by the accelerated resynthesis of the inhibitor IκBα. [less ▲]

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See detailFurther insights in the mechanisms of interleukin-1beta stimulation of osteoprotegerin in osteoblast-like cells
Lambert, Cécile ULg; Oury, Cécile ULg; Dejardin, Emmanuel ULg et al

in Journal of Bone and Mineral Research (2007), 22(9), 1350-1361

The mechanisms of IL-1beta stimulation of OPG were studied in more detail. Whereas p38 and ERK activation was confirmed to be needed, NF-kappaB was not necessary for this regulation. We also found that ... [more ▼]

The mechanisms of IL-1beta stimulation of OPG were studied in more detail. Whereas p38 and ERK activation was confirmed to be needed, NF-kappaB was not necessary for this regulation. We also found that OPG production after IL-1beta stimulation was not sufficient to block TRAIL-induced apoptosis in MG-63 cells. INTRODUCTION: Osteoprotegerin (OPG) plays a key role in the regulation of bone resorption and is stimulated by interleukin (IL)-1beta. Herein, we defined the mechanisms of IL-1beta stimulation of OPG focusing on the potential involvement of MAPK and NF-kappaB. We also examined whether OPG production in response to IL-1beta influences TRAIL-induced apoptosis in MG-63 cells. MATERIALS AND METHODS: OPG mRNA levels in MG-63 cells were quantified by real-time RT-PCR and protein levels of OPG and IL-6 by ELISA. Cell viability was assessed using the methyltetrazidium salt (MTS) reduction assay. The role of the MAPK pathway was studied by both Western blotting and the use of specific chemical inhibitors. NF-kappaB function was studied using BAY 11-7085 and by siRNA transfection to inhibit p65 synthesis. Transcription mechanisms were analyzed by transiently transfecting MG-63 cells with OPG promoter constructs. Post-transcriptional effects were examined by using cycloheximide and actinomycin D. RESULTS: MG-63 cells treatment with IL-1beta resulted in the phosphorylation of c-Jun NH(2)-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). The use of the specific inhibitors showed that p38 and ERK but not JNK were needed for IL-1beta-induced OPG production. In contrast, NF-kappaB was not essential for IL-1beta induction of OPG. We also showed a small transcriptional and a possible post-transcriptional or translational regulation of OPG by IL-1beta. Exogenous OPG blocked TRAIL-induced apoptosis, but IL-1beta induction of OPG did not influence TRAIL-induced cell death. CONCLUSIONS: IL-1beta stimulates OPG production by mechanisms dependent on p38 and ERK. In contrast, NF-kappaB was not essential for this regulation. Although the relevance of IL-1beta stimulation of OPG is still not fully understood, our data showed that IL-1beta stimulation of OPG does not modify TRAIL-induced cell death. [less ▲]

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See detailDoes propofol alter membrane fluidity at clinically relevant concentrations? An ESR spin label study
Bahri, Mohamed Ali ULg; Seret, Alain ULg; Hans, Pol ULg et al

in Biophysical Chemistry (2007), 129(1), 82-91

General anesthetics have been shown to perturb the membrane properties of excitable tissues. Due to their lipid solubility, anesthetics dissolve in every membrane, penetrate into organelles and interact ... [more ▼]

General anesthetics have been shown to perturb the membrane properties of excitable tissues. Due to their lipid solubility, anesthetics dissolve in every membrane, penetrate into organelles and interact with numerous cellular structures in multiple ways. Several studies indicate that anesthetics alter membrane fluidity and decrease the phase-transition temperature. However, the required concentrations to induce such effects on the properties of membrane lipids are by far higher than clinically relevant concentrations. In the present study, the fluidizing effect of the anesthetic agent propofol (2,6-diisopropyl phenol: PPF), a general anesthetic extensively used in clinical practice, has been investigated on liposome dimyristoyi-L-alpha phosphatidylcholine (DMPC) and cell (erythrocyte, Neuro-2a) membranes using electron spin resonance spectroscopy (ESR) of nitroxide labeled fatty acid probes (5-, 16-doxyl stearic acid). A clear effect of PPF at concentrations higher than the clinically relevant ones was quantified both in liposome and cell membranes, while no evident fluidity effect was measured at the clinical PPF doses. However, absorption spectroscopy of merocyanine 540 (MC540) clearly indicates a PPF fluidizing capacity in liposome membrane even at these clinical concentrations. PPF may locally influence the structure and dynamics of membrane domains, through the formation of small-scale lipid domains, which would explain the lack of ESR information at low PPF concentrations. (c) 2007 Elsevier B.V. All rights reserved. [less ▲]

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See detailPromoter-dependent effect of IKK alpha on NF-kappa B/p65 DNA binding
Gloire, Geoffrey ULg; Horion, Julie; El Mjiyad, Nadia ULg et al

in Journal of Biological Chemistry (2007), 282(29), 21308-21318

IKK alpha regulates many chromatin events in the nuclear phase of the NF-kappa B program, including phosphorylation of histone H3 and removal of co-repressors from NF-kappa B-dependent promoters. However ... [more ▼]

IKK alpha regulates many chromatin events in the nuclear phase of the NF-kappa B program, including phosphorylation of histone H3 and removal of co-repressors from NF-kappa B-dependent promoters. However, all of the nuclear functions of IKK alpha are not understood. In this study, using mouse embryonic fibroblasts IKK alpha knock-out and reexpressing IKK alpha after retroviral transduction, we demonstrate that IKK alpha contributes to NF-kappa B/p65 DNA binding activity on an exogenous kappa B element and on some, but not all, endogenous NF-kappa B-target promoters. Indeed, p65 chromatin immunoprecipitation assays revealed that IKK alpha is crucial for p65 binding on kappa B sites of icam-1 and mcp-1 promoters but not on i kappa b alpha promoter. The mutation of IKK alpha putative nuclear localization sequence, which prevents its nuclear translocation, or of crucial serines in the IKK alpha activation loop completely inhibits p65 binding on icam-1 and mcp-1 promoters and rather enhances p65 binding on the i kappa b alpha promoter. Further molecular studies demonstrated that the removal of chromatin-bound HDAC3, a histone deacetylase inhibiting p65 DNA binding, is differentially regulated by IKK alpha in a promoter-specific manner. Indeed, whereas the absence of IKK alpha induces HDAC3 recruitment and repression on the icam-1 promoter, it has an opposite effect on the i kappa b alpha promoter, where a better p65 binding occurs. We conclude that nuclear IKK alpha is required for p65 DNA binding in a gene-specific manner. [less ▲]

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See detailModulation of Nod2-dependent NF-kappa B signaling by the actin cytoskeleton
Legrand, Sylvie ULg; Kustermans, Gaëlle ULg; Bex, Françoise et al

in Journal of Cell Science (2007), 120(7), 1299-1310

Actin disruption by CytochalasinD (CytD) and LatrunculinB (LatB) induced NF-kappa B activation in myelomonocytic and intestinal epithelial cells. In an attempt to elucidate the mechanism by which actin ... [more ▼]

Actin disruption by CytochalasinD (CytD) and LatrunculinB (LatB) induced NF-kappa B activation in myelomonocytic and intestinal epithelial cells. In an attempt to elucidate the mechanism by which actin disruption induced IKK activation, we studied the human Nod2 protein, which was able to induce NF-kappa B activation and whose expression was restricted to myelomonocytic and intestinal epithelial cells. Nod2 is thought to play key roles in pathogen defence through sensing bacteria and generating an inflammatory immune response. We showed that actin disruption by CytD significantly and specifically increased Nod2-mediated NF-kappa B signaling. Nod2 was fully partitioned in the Triton-X-100-insoluble fraction but translocated into the soluble fraction after CytD treatment, demonstrating that the presence of Nod2 in the detergent-insoluble pellet was specific to actin cytoskeleton. Confocal analysis also revealed a Nod2 colocalization with membrane-associated F-actin. Colocalization and co-immunoprecipitation assays with endogenous Rac1 have shown that Nod2 associated with activated Rac1 in membrane ruffles through both its N-terminal caspase recruitment domains (CARD) and C-terminal leucine-rich repeats (LRRs). Membrane ruffle disruption by a Rac1 dominant negative form primed Nod2-dependent NF-kappa B signaling. The recruitment of Nod2 in Rac-induced dynamic cytoskeletal structures could be a strategy to both repress the Nod2-dependent NF-kappa B signaling in unstimulated cells and rapidly mobilize Nod2 during bacterial infection. [less ▲]

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See detailThe role of SHIP1 in T-lymphocyte life and death
Gloire, Geoffrey ULg; Erneux, Christophe; Piette, Jacques ULg

in Biochemical Society Transactions (2007), 35(Pt 2), 277-280

SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase-1], an inositol 5-phosphatase expressed in haemopoietic cells, acts by hydrolysing the 5-phosphates from PtdIns(3,4,5)P(3) and Ins(1,3,4,5)P(4 ... [more ▼]

SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase-1], an inositol 5-phosphatase expressed in haemopoietic cells, acts by hydrolysing the 5-phosphates from PtdIns(3,4,5)P(3) and Ins(1,3,4,5)P(4), thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathway. SHIP1 plays a major role in inhibiting proliferation of myeloid cells. As a result, SHIP1(-/-) mice have an increased number of neutrophils and monocytes/macrophages due to enhanced survival and proliferation of their progenitors. Although SHIP1 contributes to PtdIns(3,4,5)P(3) metabolism in T-lymphocytes, its exact role in this cell type is much less explored. Jurkat cells have recently emerged as an interesting tool to study SHIP1 function in T-cells because they do not express SHIP1 at the protein level, thereby allowing reintroduction experiments in a relatively easy-to-use system. Data obtained from SHIP1 reintroduction have revealed that SHIP1 not only acts as a negative player in T-cell lines proliferation, but also regulates critical pathways, such as NF-kappaB (nuclear factor kappaB) activation, and also appears to remarkably inhibit T-cell apoptosis. On the other hand, experiments using primary T-cells from SHIP1(-/-) mice have highlighted a new role for SHIP1 in regulatory T-cell development, but also emphasize that this protein is not required for T-cell proliferation. In support of these results, SHIP1(-/-) mice are lymphopenic, suggesting that SHIP1 function in T-cells differs from its role in the myeloid lineage. [less ▲]

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See detailPolyubiquitination of the scaffold protein tank/I-traf: implications for the TLR-mediated signalling pathways
Gatot, J. S.; Gioia, R.; Chau, Tieu-Lan ULg et al

Poster (2007, March)

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See detailCaractérisation de la protéine 9p du virus de la varicelle et du zona (VZV)
Joris-Gerards, Aline; BONTEMS, Sébastien ULg; Di Valentin et al

Poster (2007)

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See detailHIV-1 protease inhibitors do not interfere with provirus transcription and host cell apoptosis induced by combined treatment TNF-alpha plus TSA
Vandergeeten, Claire ULg; Quivy, Vincent; Moutschen, Michel ULg et al

in Biochemical Pharmacology (2007), 73(11), 1738-1748

HIV-1 latency represents a major hurdle to the complete eradication of the virus from patients under highly active anti-retroviral therapy (HAART) regimens. One solution to this problem would be to ... [more ▼]

HIV-1 latency represents a major hurdle to the complete eradication of the virus from patients under highly active anti-retroviral therapy (HAART) regimens. One solution to this problem would be to eliminate the latently infected cellular reservoirs by forcing gene expression in presence of HAART to prevent spreading of the infection by the newly synthesized viruses. Many studies have reported that a combination of a histone deacetylase inhibitor (HDACi) (i.e. TSA, NaBut, Valproic acid,...) with a pro-inflammatory cytokine (i.e. TNF alpha, IL-1,...) reactivates in a synergistic manner HIV-1 transcription in latently infected cells. The aim of the present study was to determine whether HIV-1 protease inhibitors (PIs) used in HAART (such as Saquinavir, Indinavir, Nelfinavir, Lopinavir, Ritonavir and Amprenavir) could interfere with the potential purge of the cellular reservoirs induced by a combined treatment involving TSA and TNF alpha. We showed, in two HIV-1 latently infected cell lines (ACH-2 and U1) that all PIs efficiently inhibited release of mature viral particles but did neither affect cell apoptosis nor NF-kappa B induction and HIV-1 transcription activation following combined treatment with TNF alpha + TSA. This study is encouraging in the fight against HIV-1 and shows that PIs should be compatible with an inductive adjuvent therapy for latent reservoir reduction/elimination in association with efficient HAART regimens. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]

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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 ▲]

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