References of "Merville, Marie-Paule"
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See detailGSK3-Mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity
Viatour, Patrick ULg; Dejardin, Emmanuel ULg; Warnier, Michael et al

in Molecular Cell (2004), 16(1), 35-45

The oncoprotein BCL-3 is a nuclear transcription factor that activates NF-kappaB target genes through formation of heterocomplexes with p50 or p52. BCL-3 is phosphorylated in vivo, but specific BCL-3 ... [more ▼]

The oncoprotein BCL-3 is a nuclear transcription factor that activates NF-kappaB target genes through formation of heterocomplexes with p50 or p52. BCL-3 is phosphorylated in vivo, but specific BCL-3 kinases have not been identified so far. In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with HDAC1, -3, and -6 and attenuates its oncogenicity by selectively controlling the expression of a subset of newly identified target genes such as SLPI and CxcI1. Our results therefore suggest that constitutive BCL-3 phosphorylation by GSK3 regulates BCL-3 turnover and transcriptional activity. [less ▲]

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See detailDiscovery of new rheumatoid arthritis biomarkers using SELDI-TOF-MS ProteinChip approach
de Seny, D. M.; Fillet, Marianne ULg; Meuwis, Marie-Alice ULg et al

in Arthritis and Rheumatism (2004, September), 50(9, Suppl. S), 124

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See detailRegulation of HER-2 oncogene expression by cyclooxygenase-2 and prostaglandin E2
Benoit, Valérie; Relic, Biserka ULg; de Leval, Laurence ULg et al

in Oncogene (2004), 23(8), 1631-1635

The oncoprotein HER-2/neu is a prosurvival factor and its overexpression has been correlated with adverse prognosis in breast cancers. High levels of the cyclooxygenase-2 (COX-2), a proinflammatory and ... [more ▼]

The oncoprotein HER-2/neu is a prosurvival factor and its overexpression has been correlated with adverse prognosis in breast cancers. High levels of the cyclooxygenase-2 (COX-2), a proinflammatory and antiapoptotic enzyme, were detected in HER-2-positive tumors and this observation was linked to an HER-2-mediated induction of COX-2 gene transcription. Here, we report that COX-2 expression, and synthesis of its major enzymatic product, PGE2, leads in turn to an enhanced HER-2 expression. Moreover, COX-2 enzymatic inhibition dramatically reduced HER-2 protein levels, efficiently increased the cancer cells sensitility to chemotherapeutic treatment and acted in synergy with HER-2 inhibitor, trastuzumab. Therefore, we propose an original model where HER-2 and COX-2 transcriptionally regulate each other in a positive loop. [less ▲]

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See detailCaspase-8-dependent HER-2 cleavage in response to tumor necrosis factor alpha stimulation is counteracted by nuclear factor kappa B through c-FLIP-L expression
Benoit, Valérie; Chariot, Alain ULg; Delacroix, Laurence ULg et al

in Cancer Research (2004), 64(8), 2684-2691

The oncoprotein HER-2/neu is a prosurvival factor, and its overexpression has been correlated with poor prognosis in patients with breast cancer. We report that HER-2 is a new substrate for caspase-8 and ... [more ▼]

The oncoprotein HER-2/neu is a prosurvival factor, and its overexpression has been correlated with poor prognosis in patients with breast cancer. We report that HER-2 is a new substrate for caspase-8 and that tumor necrosis factor alpha (TNF-alpha) stimulation leads to an early caspase-8-dependent HER-2 cleavage in MCF7 A/Z breast adenocarcinoma cells defective for nuclear factor kappaB (NFkappaB) activation. We show that the antiapoptotic transcription factor NFkappaB counteracts this cleavage through induction of the caspase-8 inhibitor c-FLIP. Our results also demonstrate that this HER-2 cleavage contributes to the TNF-alpha-induced apoptosis pathway because ectopic expression of an uncleavable HER-2 protects NFkappaB-defective cells against TNF-alpha-mediated cell death. Therefore, we propose an original model in which NFkappaB exerts a new antiapoptotic function by counteracting TNF-alpha-triggered cleavage of the HER-2 survival factor. [less ▲]

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See detail15-deoxy-delta12,14-prostaglandin J2 inhibits Bay 11-7085-induced sustained extracellular signal-regulated kinase phosphorylation and apoptosis in human articular chondrocytes and synovial fibroblasts
Relic, Biserka ULg; Benoit, Valerie; Franchimont, Nathalie et al

in Journal of Biological Chemistry (2004), 279(21), 399-403

We have previously shown that nuclear factor-kappaB inhibition by adenovirus expressing mutated IkappaB-alpha or by proteasome inhibitor increases human articular chondrocytes sensibility to apoptosis ... [more ▼]

We have previously shown that nuclear factor-kappaB inhibition by adenovirus expressing mutated IkappaB-alpha or by proteasome inhibitor increases human articular chondrocytes sensibility to apoptosis. Moreover, the nuclear factor-kappaB inhibitor BAY11-7085, a potent anti-inflammatory drug in rat adjuvant arthritis, is itself a proapoptotic agent for chondrocytes. In this work, we show that BAY 11-7085 but not the proteasome inhibitor MG-132 induced a rapid and sustained phosphorylation of extracellular signal-regulated kinases (ERK1/2) in human articular chondrocytes. The level of ERK1/2 phosphorylation correlated with BAY 11-7085 concentration and chondrocyte apoptosis. 15-Deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and its precursor prostaglandin (PG) D2 but not PGE2 and PGF2alpha rescued chondrocytes from BAY 11-7085-induced apoptosis. 15d-PGJ2 markedly inhibited BAY 11-7085-induced phosphorylation of ERK1/2. BAY 11-7085 also induced ERK1/2 phosphorylation and apoptosis in human synovial fibroblasts, and these reactions were down-regulated by 15d-PGJ2. Further analysis in synovial fibroblasts showed that only molecules that suppressed BAY 11-7085-induced phosphorylation of ERK1/2 (i.e. 15d-PGJ2, PGD2, and to a lesser extent, MEK1/2 inhibitor UO126, but not prostaglandins E2 and F2alpha or peroxisome proliferator-activated receptor-gamma agonist ciglitazone) were able protect cells from apoptosis. These results suggested that the antiapoptotic effect of 15d-PGJ2 on chondrocytes and synovial fibroblasts might involve inhibition of ERK1/2 phosphorylation. [less ▲]

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See detailEffect of non-steroidal anti-inflammatory drugs on amyloid-beta formation and macrophage activation after platelet phagocytosis.
Jans, Dominique ULg; Martinet, Wim; Fillet, Marianne ULg et al

in Journal of Cardiovascular Pharmacology (2004), 43(3), 462-70

Recently, we showed that platelet phagocytosis occurs in human atherosclerotic plaques and leads to foam cell formation. Platelet phagocytosis, resulting in macrophage activation and iNOS induction, was ... [more ▼]

Recently, we showed that platelet phagocytosis occurs in human atherosclerotic plaques and leads to foam cell formation. Platelet phagocytosis, resulting in macrophage activation and iNOS induction, was associated with the formation of amyloid-beta peptide (Abeta) via proteolytic cleavage of platelet-derived amyloid precursor protein (APP), possibly by secretases. To test the involvement of gamma-secretase in this process, we used indomethacin, ibuprofen, and sulindac sulfide, non-steroidal anti-inflammatory drugs (NSAIDs) known to alter the gamma-secretase cleaving site of APP, on their ability to inhibit macrophage activation evoked by platelet phagocytosis. J774 macrophages were incubated with human platelets or lipopolysaccharide (LPS) with or without NSAIDs. Nitrite was quantified as a measure for inducible nitric oxide synthase (iNOS) activity. Indomethacin, ibuprofen, sulindac sulfide, and meloxicam concentration-dependently reduced nitrite production by macrophages incubated with platelets, but did not alter LPS-induced iNOS activity or platelet uptake. However, acetylsalicylic acid and naproxen, two NSAIDs without effect on the gamma-secretase cleaving site of APP, did not affect nitrite production in either platelet- or LPS-stimulated macrophages. Surface-enhanced laser desorption/ionization time-of-flight mass-spectrometry demonstrated time-dependent formation of Abeta-containing peptides after platelet phagocytosis, which could be inhibited by indomethacin. In conclusion, these results point to the involvement of gamma-secretase in macrophage activation following platelet phagocytosis. [less ▲]

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See detailModulation of the HSV-TK/ganciclovir bystander effect by n-butyrate in glioblastoma: correlation with gap-junction intercellular communication.
Robe, Pierre ULg; Jolois, Olivier ULg; Nguyen Khac, Minh-Tuan ULg et al

in International Journal of Oncology (2004), 25(1), 187-92

The efficacy of HSV-TK/ganciclovir gene therapy largely relies on the bystander effect, i.e. the ability of transfected cells to kill the adjacent, untrasfected cells. This mechanism itself depends ... [more ▼]

The efficacy of HSV-TK/ganciclovir gene therapy largely relies on the bystander effect, i.e. the ability of transfected cells to kill the adjacent, untrasfected cells. This mechanism itself depends chiefly on the transfer via gap junctions of phosphorylated ganciclovir between cells, and is often deficient in glioblastomas. In this report, we demonstrate that n-butyrate markedly enhances the gap junction intercellular communication of GJIC-deficient glioma cells, and significantly increases the bystander effect in such cells. This effect of n-butyrate appears to be independent from its HDAC inhibitory effect, since trichostatin A does not reproduce it. [less ▲]

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See detailIn vitro and in vivo activity of the nuclear factor-kappa B inhibitor sulfasalazine in human glioblastomas.
Robe, Pierre ULg; Bentires-Alj, Mohamed; Bonif, Marianne et al

in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2004), 10(16), 5595-603

Glioblastomas, the most common primary brain cancers, respond poorly to current treatment modalities and carry a dismal prognosis. In this study, we demonstrated that the transcription factor nuclear ... [more ▼]

Glioblastomas, the most common primary brain cancers, respond poorly to current treatment modalities and carry a dismal prognosis. In this study, we demonstrated that the transcription factor nuclear factor (NF)-kappaB is constitutively activated in glioblastoma surgical samples, primary cultures, and cell lines and promotes their growth and survival. Sulfasalazine, an anti-inflammatory drug that specifically inhibits the activation of NF-kappaB, blocked the cell cycle and induced apoptosis in several glioblastoma cell lines and primary cultures, as did gene therapy with a vector encoding a super-repressor of NF-kappaB. In vivo, sulfasalazine also significantly inhibited the growth of experimental human glioblastomas in nude mice brains. Given the documented safety of sulfasalazine in humans, these results may lead the way to a new class of glioma treatment. [less ▲]

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See detailPharmacological evaluation of BM-573, a dual thromboxane A2 receptor antagonist and thromboxane synthase inhibitor, as potential anti-metastatic agent
De Leval, X.; Dassesse, T.; Benoît, V. et al

Poster (2003, December)

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See detailCytoplasmic I kappa B alpha increases NF-kappa B-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3
Viatour, Patrick ULg; Legrand-Poels, Sylvie; van Lint, Carine et al

in Journal of Biological Chemistry (2003), 278(47), 46541-46548

IkappaBalpha is an inhibitory molecule that sequesters NF-kappaB dimers in the cytoplasm of unstimulated cells. Upon stimulation, NF-kappaB moves to the nucleus and induces the expression of a variety of ... [more ▼]

IkappaBalpha is an inhibitory molecule that sequesters NF-kappaB dimers in the cytoplasm of unstimulated cells. Upon stimulation, NF-kappaB moves to the nucleus and induces the expression of a variety of genes including IkappaBalpha. This newly synthesized IkappaBalpha also translocates to the nucleus, removes activated NF-kappaB from its target genes, and brings it back to the cytoplasm to terminate the phase of NF-kappaB activation. We show here that IkappaBalpha enhances the transactivation potential of several homeodomain-containing proteins such as HOXB7 and Pit-1 through a NF-kappaB-independent association with histone deacetylase (HDAC) 1 and HDAC3 but not with HDAC2, -4, -5, and -6. IkappaBalpha bound both HDAC proteins through its ankyrin repeats, and this interaction was disrupted by p65. Immunofluorescence experiments demonstrated further that IkappaBalpha acts by partially redirecting HDAC3 to the cytoplasm. At the same time, an IkappaBalpha mutant, which lacked a functional nuclear localization sequence, interacted very efficiently with HDAC1 and -3 and intensively enhanced the transactivation potential of Pit-1. Our results support the hypothesis that the NF-kappaB inhibitor IkappaBalpha regulates the transcriptional activity of homeodomain-containing proteins positively through cytoplasmic sequestration of HDAC1 and HDAC3, a mechanism that would assign a new and unexpected role to IkappaBalpha. [less ▲]

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See detailPharmacological evaluation of BM-573, a dual thromboxane A(2) receptor antagonist and thromboxane synthase inhibitor, as potential anti-metastatic agent
de Leval, X. J.; Dassesse, T.; Benoit, V. et al

in Blood (2003, November 16), 102(11, Part 2), 72

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See detailRaloxifene protects Osteoblasts from apoptosis induced by sodium nitroprusside: Potential involvement of ceramide
Olivier, Sabine ULg; Fillet, Marianne ULg; Malaise, Michel ULg et al

in Journal of Bone and Mineral Research (2003, September), 18(Suppl. 2), 136

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See detailIdentification of the signalling pathways required for interleukin-1 beta stimulation of osteoprotegerin synthesis in osteoblastic cells
Lambert, Cecile; Ribbens, Clio ULg; Bours, Vincent ULg et al

in Journal of Bone and Mineral Research (2003, September), 18(Suppl. 2), 142

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See detailInterleukin-1beta and tumor necrosis factor-alpha enhance the shedding of Interleukin-6 receptor in osteoblastic cells: Involvement of tumor necrosis factor-alpha converting enzyme
Franchimont, N. M.; Lambert, Cecile; Ribbens, Clio ULg et al

in Arthritis and Rheumatism (2003, September), 48(9, Suppl. S), 482

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See detailNF-kappa B2/p100 induces Bcl-2 expression
Viatour, Patrick ULg; Bentires-Alj, Mohamed; Chariot, Alain ULg et al

in Leukemia (2003), 17(7), 1349-1356

The NF-kappaB2/p100 and bcl-3 genes are involved in chromosomal translocations described in chronic lymphocytic leukemias (CLL) and non-Hodgkin's lymphomas, and nuclear factor kappaB (NF-kappaB) protects ... [more ▼]

The NF-kappaB2/p100 and bcl-3 genes are involved in chromosomal translocations described in chronic lymphocytic leukemias (CLL) and non-Hodgkin's lymphomas, and nuclear factor kappaB (NF-kappaB) protects cancer cells against apoptosis. Therefore, we investigated whether this transcription factor could modulate the expression of the Bcl-2 antiapoptotic protein. Bcl-2 promoter analysis showed multiple putative NF-kappaB binding sites. Transfection assays of bcl-2 promoter constructs in HCT116 cells showed that NF-kappaB can indeed transactivate bcl-2. We identified a kappaB site located at position -180 that can only be bound and transactivated by p50 or p52 homodimers. As p50 and p52 homodimers are devoid of any transactivating domains, we showed that they can transactivate the bcl-2 promoter through association with Bcl-3. We also observed that stable overexpression of p100 and its processed product p52 can induce endogenous Bcl-2 expression in MCF7AZ breast cancer cells. Finally, we demonstrated that, in breast cancer and leukemic cells ( CLL), high NF-kappaB2/p100 expression was associated with high Bcl-2 expression. Our data suggest that Bcl-2 could be an in vivo target gene for NF-kappaB2/p100. [less ▲]

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See detailIsostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, induces cell cycle arrest and apoptosis in human colon cancer cells
Frederich, Michel ULg; Bentires-Alj, M.; Tits, Monique ULg et al

in Journal of Pharmacology and Experimental Therapeutics (2003), 304(3), 1103-1110

Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in the leaves of Strychnos usambarensis, a well known African shrub or little tree. The roots contain quaternary alkaloids ... [more ▼]

Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in the leaves of Strychnos usambarensis, a well known African shrub or little tree. The roots contain quaternary alkaloids, which are used to make a curare-like arrow poison. However, tertiary alkaloids isolated from the same plant possess cytotoxic activities against mammalian cells and protozoa. The effect of ISP has been investigated on the growth and viability of HCT-116 colon cancer cells during their exponentially growing phase. ISP induced apoptotic cell death as shown by the translocation of phosphatidylserine from the inner layer to the outer layer of the plasma membrane, chromatin condensation, DNA fragmentation, and caspase-3 and -9 activation. ISP provoked also cell cycle arrest in the G(2)-M phase. We also showed that the expression of p53 was not modified in ISP-treated cells, but that p21 was induced in a p53-independent manner. Finally, we demonstrated that ISP did not affect the catalytic activity of human topoisomerases I and II. In conclusion, ISP, which promotes cell death by a p53-independent apoptotic pathway, could be an interesting lead for cancer chemotherapy. [less ▲]

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See detailMechanisms involved in exogenous C2- and C6-ceramide-induced cancer cell toxicity.
Fillet, Marianne ULg; Bentires-Alj, Mohamed; Deregowski, Valérie et al

in Biochemical Pharmacology (2003), 65(10), 1633-42

Ceramides are important intracellular second messengers that play a role in the regulation of cell growth, differentiation, and programmed cell death. To determine whether ceramides can mediate the ... [more ▼]

Ceramides are important intracellular second messengers that play a role in the regulation of cell growth, differentiation, and programmed cell death. To determine whether ceramides can mediate the apoptosis of HCT116 and OVCAR-3 cancer cells, exogenous C2-, C6-, and C16-ceramides were used to mimic the endogenous lipid increase that follows a large variety of stresses. C2- and C6-ceramides (cell-permeable ceramide analogs), but not C16-ceramide, induced nuclear factor-kappaB (NF-kappaB) DNA-binding, caspase-3 activation, poly(ADP-ribose) polymerase degradation, and mitochondrial cytochrome c release, indicating that apoptosis occurs through the caspase cascade and the mitochondrial pathway. No difference in survival was observed between control cells and cells expressing mutated IkappaBalpha and treated with the permeable ceramides. This suggests that, at least in these cell lines, stable NF-kappaB inhibition did not modify the ceramide-induced cytotoxicity pathway. C6-ceramide also induced a double block in G1 and G2, thus emptying the S phase. [less ▲]

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See detailNF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells
Bentires-Alj, Mohamed; Barbu, Véronique; Fillet, Marianne ULg et al

in Oncogene (2003), 22

The ubiquitous NF-kappaB transcription factor has been reported to inhibit apoptosis and to induce drug resistance in cancer cells. Drug resistance is the major reason for cancer therapy failure and ... [more ▼]

The ubiquitous NF-kappaB transcription factor has been reported to inhibit apoptosis and to induce drug resistance in cancer cells. Drug resistance is the major reason for cancer therapy failure and neoplastic cells often develop multiple mechanisms of drug resistance during tumor progression. We observed that NF-kappaB or P-glycoprotein inhibition in the HCT15 colon cancer cells led to increased apoptotic cell death in response to daunomycin treatment. Interestingly, NF-kappaB inhibition through transfection of a plasmid coding for a mutated IkappaB-alpha inhibitor increased daunomycin cell uptake. Indeed, the inhibition of NF-kappaB reduced mdr1 mRNA and P-glycoprotein expression in HCT15 cells. We identified a consensus NF-kappaB binding site in the first intron of the human mdr1 gene and demonstrated that NF-kappaB complexes could bind with this intronic site. Moreover, NF-kappaB transactivates an mdr1 promoter luciferase construct. Our data thus demonstrate a role for NF-kappaB in the regulation of the mdr1 gene expression in cancer cells and in drug resistance. [less ▲]

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