References of "Merville, Marie-Paule"
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See detailA Cell Type-Specific and Gap Junction-Independent Mechanism for the Herpes Simplex Virus-1 Thymidine Kinase Gene/Ganciclovir-Mediated Bystander Effect
Princen, Frederic; Robe, Pierre ULg; Lechanteur, Chantal ULg et al

in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (1999), 5(11), 3639-44

Tumor cells expressing the herpes simplex virus type 1 thymidine kinase (HSV-tk) gene are killed by nucleoside analogues such as ganciclovir (GCV). GCV affects not only the cells expressing HSV-tk but ... [more ▼]

Tumor cells expressing the herpes simplex virus type 1 thymidine kinase (HSV-tk) gene are killed by nucleoside analogues such as ganciclovir (GCV). GCV affects not only the cells expressing HSV-tk but also neighboring cells that do not express the gene; this phenomenon commonly is called "bystander effect." GCV metabolites transfer via gap junctional intercellular communication (GJIC) accounts for the bystander effect in different cell lines, but other mechanisms have also been described. In this study, we analyzed the mechanisms of the bystander effect in two cell lines exhibiting different capacities of communication (DHD/K12 and 9L). The 9L cells exhibited a very good bystander effect, which was completely blocked by a long-term inhibitor of GJIC, 18 alpha-glycyrrhetinic acid. DHD/K12 cells exhibited a moderate bystander effect that was not abolished by 18 alpha-glycyrrhetinic acid or 1-octanol, another strong inhibitor of GJIC. Interestingly, we also observed a bystander effect in cultures where HSV-tk-expressing DHD/K12 cells were physically separated from their untransfected counterparts but grown in the same medium. Moreover, the transfer of filtered conditioned medium from GCV-treated HSV-tk-expressing DHD/K12 cells to DHD/K12 parental cells induced a decrease of survival in a concentration-dependent manner, suggesting that the bystander effect in this cell line was mediated by a soluble factor. [less ▲]

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See detailRole of Nuclear Factor-Kappa B in Colon Cancer Cell Apoptosis Mediated by Aminopyropheophorbide Photosensitization
Matroule, J. Y.; Hellin, A. C.; Morliere, P. et al

in Photochemistry & Photobiology (1999), 70(4), 540-8

Aminopyropheophorbide (APP) is a second generation of photosensitizer for photodynamic therapy (PDT). We demonstrated that APP strongly absorbed red light and, after being taken up by colon cancer cells ... [more ▼]

Aminopyropheophorbide (APP) is a second generation of photosensitizer for photodynamic therapy (PDT). We demonstrated that APP strongly absorbed red light and, after being taken up by colon cancer cells (HCT-116 cells), was localized in cytoplasmic and internal membranes but not in mitochondria. The APP-mediated photosensitization was cytotoxic for HCT-116 cells through an induction of apoptosis. Indeed, DNA fragmentation (DNA laddering and terminal deoxyuridine nick-end labeling) and chromatin condensation (4',6-diamidine-2'-phenylindole staining) could be visualized soon after photosensitization. Because nuclear factor (NF)-kappa B is involved in the response to many photosensitizers, we also demonstrated its nuclear translocation in two waves: a rapid and transient one, followed by a slow and sustained phase. The NF-kappa B turned out to be involved in an antiapoptotic response to APP-mediated photosensitization because the HCT-116 cell line expressing the dominant negative mutant of inhibitor-kappa B alpha was more sensitive to apoptosis as measured by DNA fragmentation and caspase activation. These data unambiguously show that a membrane-located photosensitizer can lead to effective apoptosis, reinforcing the idea that PDT can be an effective means to eradicate colon cancer cells. [less ▲]

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See detailNf- Kappa B and Chemoresistance: Could Nf- Kappa B Be an Antitumor Target?
Bentires-Alj, Mohamed; Merville, Marie-Paule ULg; Bours, Vincent ULg

in Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy (1999), 2(4), 274-276

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See detailRegulation of Nf-Kappab Activity by I Kappab-Related Proteins in Adenocarcinoma Cells
Dejardin, Emmanuel ULg; Deregowski, Valérie; Chapelier, Muriel et al

in Oncogene (1999), 18(16), 2567-77

Constitutive NF-kappaB activity varies widely among cancer cell lines. In this report, we studied the expression and the role of different I kappaB inhibitors in adenocarcinoma cell lines. High ... [more ▼]

Constitutive NF-kappaB activity varies widely among cancer cell lines. In this report, we studied the expression and the role of different I kappaB inhibitors in adenocarcinoma cell lines. High constitutive NF-kappaB activity and low I kappaB-alpha expression was found in a number of these cell lines. Moreover, some of these cells showed a high p100 expression, responsible for the cytoplasmic sequestration of most of p65 complexes. Treatment of these cells with TNF-alpha or other NF-kappaB activating agents induced only weakly nuclear NF-kappaB activity without significant p100 processing and led to a very weak transcription of NF-kappaB-dependent reporter gene. Induction of NF-kappaB activity can be restored by expression of the Tax protein or by treatment with antisense p100 oligonucleotides. In MCF7 A/Z cells stably transfected with a p100 expression vector, p65 complexes were sequestered in the cytoplasm by p100. These cells showed a reduced nuclear NF-kappaB induction and NF-kappaB-dependent gene transcription following TNF-alpha stimulation. As a consequence of a competition between I kappaB-alpha and p100, cells expressing high levels of p100 respond poorly to NF-kappaB activating stimuli as TNF-alpha. [less ▲]

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See detailRole of the Protein Kinase C Lambda/Iota Isoform in Nuclear Factor-Kappab Activation by Interleukin-1beta or Tumor Necrosis Factor-Alpha: Cell Type Specificities
Bonizzi, G.; Piette, Jacques ULg; Haterte, Stéphanie ULg et al

in Biochemical Pharmacology (1999), 57(6), 713-20

It has previously been reported that distinct signaling pathways can lead to nuclear factor (NF)-kappaB activation following stimulation of different cell types with inflammatory cytokines. As the role of ... [more ▼]

It has previously been reported that distinct signaling pathways can lead to nuclear factor (NF)-kappaB activation following stimulation of different cell types with inflammatory cytokines. As the role of atypical protein kinase C (PKC) isoforms in NF-kappaB activation remains a matter of controversy, we investigated whether this role might be cell type-dependent. Immunoblots detected atypical PKC expression in all the analyzed cell lines. The PKC inhibitor calphostin C inhibited NF-kappaB activation by tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta in Jurkat or NIH3T3 cells but not in MCF7 A/Z cells. Cell transfections with a PKC lambda/iota dominant negative mutant abolished TNF-alpha-induced NF-kappaB-dependent transcription in NIH3T3 and Jurkat cells but not in MCF7 A/Z cells. Similarly, the same mutant blocked NF-kappaB-dependent transactivation after IL-1beta stimulation of NIH3T3 cells, but was ineffective after IL-1beta treatment of MCF7 A/Z cells. In MCF7 A/Z cells, however, the PKC lambda/iota dominant negative mutant could abolish transactivation of an AP-1-dependent reporter plasmid after stimulation with TNF-alpha but not with IL-1beta. These data thus confirm that transduction pathways for NF-kappaB activation after cell stimulation with TNF-alpha or IL-1beta are cell-type specific and that atypical PKC isoforms participate in this pathway in NIH3T3 and Jurkat cells. [less ▲]

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See detailReactive Oxygen Intermediate-Dependent Nf-Kappab Activation by Interleukin-1beta Requires 5-Lipoxygenase or Nadph Oxidase Activity
Bonizzi, Giuseppina; Piette, Jacques ULg; Haterte, Stéphanie ULg et al

in Molecular & Cellular Biology (1999), 19(3), 1950-60

We previously reported that the role of reactive oxygen intermediates (ROIs) in NF-kappaB activation by proinflammatory cytokines was cell specific. However, the sources for ROIs in various cell types are ... [more ▼]

We previously reported that the role of reactive oxygen intermediates (ROIs) in NF-kappaB activation by proinflammatory cytokines was cell specific. However, the sources for ROIs in various cell types are yet to be determined and might include 5-lipoxygenase (5-LOX) and NADPH oxidase. 5-LOX and 5-LOX activating protein (FLAP) are coexpressed in lymphoid cells but not in monocytic or epithelial cells. Stimulation of lymphoid cells with interleukin-1beta (IL-1beta) led to ROI production and NF-kappaB activation, which could both be blocked by antioxidants or FLAP inhibitors, confirming that 5-LOX was the source of ROIs and was required for NF-kappaB activation in these cells. IL-1beta stimulation of epithelial cells did not generate any ROIs and NF-kappaB induction was not influenced by 5-LOX inhibitors. However, reintroduction of a functional 5-LOX system in these cells allowed ROI production and 5-LOX-dependent NF-kappaB activation. In monocytic cells, IL-1beta treatment led to a production of ROIs which is independent of the 5-LOX enzyme but requires the NADPH oxidase activity. This pathway involves the Rac1 and Cdc42 GTPases, two enzymes which are not required for NF-kappaB activation by IL-1beta in epithelial cells. In conclusion, three different cell-specific pathways lead to NF-kappaB activation by IL-1beta: a pathway dependent on ROI production by 5-LOX in lymphoid cells, an ROI- and 5-LOX-independent pathway in epithelial cells, and a pathway requiring ROI production by NADPH oxidase in monocytic cells. [less ▲]

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See detailIkappab-Alpha Enhances Transactivation by the Hoxb7 Homeodomain-Containing Protein
Chariot, Alain ULg; Princen, Frédéric; Gielen, Jacques et al

in Journal of Biological Chemistry (1999), 274(9), 5318-25

Combinatorial interactions between distinct transcription factors generate specificity in the controlled expression of target genes. In this report, we demonstrated that the HOXB7 homeodomain-containing ... [more ▼]

Combinatorial interactions between distinct transcription factors generate specificity in the controlled expression of target genes. In this report, we demonstrated that the HOXB7 homeodomain-containing protein, which plays a key role in development and differentiation, physically interacted in vitro with IkappaB-alpha, an inhibitor of NF-kappaB activity. This interaction was mediated by the IkappaB-alpha ankyrin repeats and C-terminal domain as well as by the HOXB7 N-terminal domain. In transient transfection experiments, IkappaB-alpha markedly increased HOXB7-dependent transcription from a reporter plasmid containing a homeodomain consensus-binding sequence. This report therefore showed a novel function for IkappaB-alpha, namely a positive regulation of transcriptional activation by homeodomain-containing proteins. [less ▲]

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See detailStable Inhibition of Nuclear Factor Kappab in Cancer Cells Does Not Increase Sensitivity to Cytotoxic Drugs
Bentires-Alj, M.; Hellin, A. C.; Ameyar, M. et al

in Cancer Research (1999), 59(4), 811-5

Several reports indicated that nuclear factor kappaB (NF-kappaB) activation by cytokines, cytotoxic drugs, or ionizing radiation protects cells against apoptosis. Therefore, we investigated the ... [more ▼]

Several reports indicated that nuclear factor kappaB (NF-kappaB) activation by cytokines, cytotoxic drugs, or ionizing radiation protects cells against apoptosis. Therefore, we investigated the consequence of NF-kappaB inhibition on the efficiency of antineoplastic agents. HPB, HCT116, MCF7, and OVCAR-3 cells stably expressing a dominant negative IkappaBalpha inhibitor showed a decreased NF-kappaB activation following treatment with tumor necrosis factor a and various chemotherapeutic agents. However, there was no difference in survival between parental cells and cells expressing mutated IkappaBalpha. These studies suggest that, at least in these cell lines, stable NF-kappaB inhibition did not modify the response to cytotoxic drugs. [less ▲]

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See detailCBP and histone deacetylase inhibition enhance the transactivation potential of the HOXB7 homeodomain-containing protein
Chariot, Alain ULg; Van Lint, Carine; Chapelier, Muriel et al

in Oncogene (1999), 18

Homeodomain-containing proteins are transcription factors regulating the coordinated expression of multiple target genes involved in development, differentiation and cellular transformation. In this study ... [more ▼]

Homeodomain-containing proteins are transcription factors regulating the coordinated expression of multiple target genes involved in development, differentiation and cellular transformation. In this study, we demonstrated that HOXB7, one member of this family, behaved as a transactivator in breast cancer cells. Deletion of either the HOXB7 N-terminal domain or the C-terminal acidic tail abolished this transcriptional effect, suggesting a combination of distinct functional transactivating domains. HOXB7 physically interacted both in vitro and in vivo with the coactivator CREB-binding protein (CBP). This interaction led to an enhanced transactivating potential and required the N-terminal of HOXB7 as well as two domains located at the C-terminal part of CBP. Moreover, trichostatin A, a deacetylase inhibitor, strongly enhanced the transcriptional properties of HOXB7. Our data therefore indicate that HOX proteins can directly interact with CBP and that acetylation/deacetylation may regulate their transcriptional properties. [less ▲]

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See detailRepeated Cycles of Retrovirus-Mediated Hsvtk Gene Transfer Plus Ganciclovir Increase Survival of Rats with Peritoneal Carcinomatosis
Princen, Frédéric; Lechanteur, Chantal ULg; Lopez Y Cadenas, Miguel ULg et al

in Gene Therapy (1998), 5(8), 1054-60

Peritoneal carcinomatosis is a common clinical situation that requires novel therapeutic approaches. We investigated the efficiency of an HSVtk gene therapy for the treatment of peritoneal carcinomatosis ... [more ▼]

Peritoneal carcinomatosis is a common clinical situation that requires novel therapeutic approaches. We investigated the efficiency of an HSVtk gene therapy for the treatment of peritoneal carcinomatosis induced in syngeneic rats by DHD/K12 colon carcinoma cells. In this setting, the efficiency of two different retrovirus producing cell lines (GP+AmEnv12 and FLYA13) was compared. Rats treated with a single injection of retrovirus producing cells followed by a 5-day course of ganciclovir treatment showed an increased survival as compared with control animals. Animals treated with three injections of producing cells, each followed by a 4-5-day course of ganciclovir treatment, showed an increased survival as compared with control rats and with those treated with a single cycle of retrovirus producing cells plus ganciclovir. However, only a few animals remained tumor-free after day 180. There was no difference between the two producing cell lines in any of the experiments. RT-PCR demonstrated a faint expression of the tk transgene in the liver, spleen, epiploon, bowels and the lung of the animals injected with the HSVtk producing cells, reflecting most likely the transduction of only a limited number of cells. [less ▲]

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See detailActivation of the human immunodeficiency virus long terminal repeat by varicella-zoster virus IE4 protein requires nuclear factor-kB and involves both the amino-terminal and the carboxyl-terminal cysteine-rich region
Defechereux-Thibaut de Maisières, Patricia; Baudoux-Tebache, Laurence; Merville, Marie-Paule ULg et al

in Journal of Biological Chemistry (1998), 273(22), 13636-13644

Varicella-zoster virus open reading frame 4-encoded protein (IE4) possesses transactivating properties for varicella-zoster virus genes as well as for those of heterologous viruses such as the human ... [more ▼]

Varicella-zoster virus open reading frame 4-encoded protein (IE4) possesses transactivating properties for varicella-zoster virus genes as well as for those of heterologous viruses such as the human immunodeficiency virus type 1 (HIV-1). Mechanisms of HIV-1 LTR (long terminal repeat) transactivation were investigated in HeLa cells transiently transfected with an IE4 expression plasmid and a CAT reporter gene under the control of the HIV-1 LTR. These results demonstrated that IE4-mediated transactivation of the HIV-1 LTR in HeLa cells required transcription factor kappaB (NF-kappaB). Using the gel retardation assay, it was shown that transfection of the IE4 expression vector in HeLa cells was not associated with induction of NF-kappaB under the p50.p65 heterodimeric form and that no direct binding of IE4 to the kappaB sites could be detected. Both Western blot and immunofluorescence analyses suggested that the ability of IE4 to activate transcription through kappaB motives was not connected with its capacity to override the inhibitory activities of IkappaB-alpha or p105. Finally, in vitro protein-protein interactions involving IE4 and basal transcription factors such as TATA-binding protein and transcription factor IIB were carried out. A direct interaction between IE4 and TATA-binding protein or transcription factor IIB components of the basal complex of transcription was evidenced, as well as binding to the p50 and p65 NF-kappaB subunits. Mutagenesis analysis of IE4 indicated that the COOH-terminal cysteine-rich and arginine-rich regions (residues 82-182) were critical for transactivation, whereas the first 81 amino acids appeared dispensable. Moreover, the arginine-rich region is required for the in vitro binding activity, whereas the COOH-terminal end did not appear essential. [less ▲]

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See detailNuclear Factor - Kappab-Dependent Regulation of P53 Gene Expression Induced by Daunomycin Genotoxic Drug
Hellin, Anne-Cécile; Calmant, Philippe ULg; Bours, Vincent ULg et al

in Oncogene (1998), 16(9), 1187-95

Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological effect is still poorly understood. In the HCT116 colon carcinoma cell line ... [more ▼]

Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological effect is still poorly understood. In the HCT116 colon carcinoma cell line, which retains a wild-type inducible p53 gene, we show that the anthracycline daunomycin is a potent inducer of p53 and NF-kappaB transcription factors. Nuclear accumulation of p53 protein occurred because of increased protein stability and enhanced gene expression. In addition, daunomycin induced the p53 promoter through the binding of p50/p65 NF-kappaB heterodimers to the kappaB site in the p53 promoter. Under our conditions, the free radical scavengers NAC and PDTC were not able to block NF-kappaB activation or p53 induction, indicating that reactive oxygen intermediates were not involved in the cellular response to daunomycin stimulation. Overexpression of a stable unresponsive IkappaBalpha mutant in HCT116 cells resulted in a complete inhibition of the NF-kappaB activation but only a partial impairment of the p53 protein accumulation induced by daunomycin. We conclude that the p53-activating signal generated by daunomycin is partially regulated by NF-kappaB. [less ▲]

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See detailRegulation of major histocompatibility complex class I expression by NF-kB-related proteins in breast cancer cells
Dejardin, Emmanuel ULg; Deregowski, Valérie; GREIMERS, Roland ULg et al

in Oncogene (1998)

Downregulation of MHC Class I antigens has been observed in many cancers and usually results from a decreased gene transcription. A reporter CAT gene dependent on the MHC Class I kB site or on a longer ... [more ▼]

Downregulation of MHC Class I antigens has been observed in many cancers and usually results from a decreased gene transcription. A reporter CAT gene dependent on the MHC Class I kB site or on a longer promoter is transactivated by NF-kB complexes contain- ing p65 or RelB. p100 as well as IkB-a are potent inhibitors of this transcription and p100 sequesters RelB and p65 complexes in the cytoplasm of breast cancer cells. However, although p100 is highly expressed in a number of breast cancer cell lines, MHC Class I antigen expression was observed on all the cell lines we analysed and could be further induced by stimulation with the cytokines IFN-g or TNF-a. Stable transfection of a unresponsive mutated IkB-a Ser 32-36 expression vector showed that TNF-a induced MHC Cl I expression in an NF-kB-dependent way while IFN-g did it independently of any NF-kB activation. [less ▲]

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See detailHsv-1 Thymidine Kinase Gene Therapy for Peritoneal Carcinomatosis
Lechanteur, Chantal ULg; Princen, Frédéric; Lo Bue, S. et al

in Advances in Experimental Medicine and Biology (1998), 451

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See detailDistinct Signal Transduction Pathways Mediate Nuclear Factor-Kappab Induction by Il-1beta in Epithelial and Lymphoid Cells
Bonizzi, Giuseppina; Piette, Jacques ULg; Merville, Marie-Paule ULg et al

in Journal of Immunology (1997), 159(11), 5264-72

We previously demonstrated that IL-1beta-mediated induction of the nuclear factor-kappaB (NF-kappaB) transcription factor proceeds through the production of reactive oxygen intermediates in lymphoid cells ... [more ▼]

We previously demonstrated that IL-1beta-mediated induction of the nuclear factor-kappaB (NF-kappaB) transcription factor proceeds through the production of reactive oxygen intermediates in lymphoid cells, while it occurs independently of any oxidative stress in epithelial transformed cells. Indeed, inhibition of receptor internalization as well as NH4Cl and chloroquine blocked IL-1beta-mediated induction of NF-kappaB in OVCAR-3 and in other epithelial cell lines but not in lymphoid cells, indicating that distinct pathways are involved. Conversely, while we observed phospholipase A2 activity in both cell types following IL-1beta stimulation, specific inhibitors of this enzyme inhibited NF-kappaB induction only in lymphoid cells. Moreover, expression of the 5-lipoxygenase (5-LOX) enzyme was not detected in epithelial cells, and inhibition of this enzyme blocked NF-kappaB induction by IL-1beta only in lymphoid cells. This study thus indicates that the activation of NF-kappaB following IL-1beta treatment involves the activation of phospholipase A2 and 5-LOX and the production of reactive oxygen intermediates (ROIs) in lymphoid cells, while in epithelial cells, another pathway predominates and could involve the acid sphingomyelinase. Moreover, arachidonic acid could induce NF-kappaB in epithelial and lymphoid cells, but this activation involved the 5-LOX enzyme and the production of ROIs only in lymphoid cells. The inefficiency of the ROI pathway in epithelial cells is probably the consequence of both low ROI production due to undetectable expression of 5-LOX and rapid degradation of hydrogen peroxide due to high catalase activity. [less ▲]

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See detailMultiple Redox Regulation in Nf-Kappab Transcription Factor Activation
Piette, Jacques ULg; Piret, Bernard; Bonizzi, Giuseppina et al

in Biological Chemistry (1997), 378(11), 1237-45

The well-known Rel/NF-kappaB family of vertebrate transcription factors comprises a number of structurally related, interacting proteins that bind DNA as dimers and whose activity is regulated by ... [more ▼]

The well-known Rel/NF-kappaB family of vertebrate transcription factors comprises a number of structurally related, interacting proteins that bind DNA as dimers and whose activity is regulated by subcellular location. This family includes many members (p50, p52, RelA, RelB, c-Rel, ...), most of which can form DNA-binding homo- or hetero-dimers. All Rel proteins contain a highly conserved domain of approximately 300 amino-acids, called the Rel homology domain (RH), which contains sequences necessary for the formation of dimers, nuclear localization, DNA binding and IkappaB binding. Nuclear expression and consequent biological action of the eukaryotic NF-kappaB transcription factor complex are tightly regulated through its cytoplasmic retention by ankyrin-rich inhibitory proteins known as IkappaB. The IkappaB proteins include a group of related proteins that interact with Rel dimers and regulate their activities. The interaction of a given IkappaB protein with a Rel complex can affect the Rel complex in distinct ways. In the best characterized example, IkappaB-alpha interacts with a p50/RelA (NF-kappaB) heterodimer to retain the complex in the cytoplasm and inhibit its DNA-binding activity. The NF-kappaB/IkappaB-alpha complex is located in the cytoplasm of most resting cells, but can be rapidly induced to enter the cell nucleus. Upon receiving a variety of signals, many of which are probably mediated by the generation of reactive oxygen species (ROS), IkappaB-alpha undergoes phosphorylation at serine residues by a ubiquitin-dependent protein kinase, is then ubiquitinated at nearby lysine residues and finally degraded by the proteasome, probably while still complexed with NF-kappaB. Removal of IkappaB-alpha uncovers the nuclear localization signals on subunits of NF-kappaB, allowing the complex to enter the nucleus, bind to DNA and affect gene expression. Like proinflammatory cytokines (e.g. IL-1, TNF), various ROS (peroxides, singlet oxygen, ...) as well as UV (C to A) light are capable of mediating NF-kappaB nuclear translocation, while the sensor molecules which are sensitive to these agents and trigger IkappaB-alpha proteolysis are still unidentified. We also show that a ROS-independent mechanism is activated by IL-1beta in epithelial cells and seems to involve the acidic sphingomyelinase/ceramide transduction pathway. [less ▲]

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See detailHsv-1 Thymidine Kinase Gene Therapy for Colorectal Adenocarcinoma-Derived Peritoneal Carcinomatosis
Lechanteur, Chantal ULg; Princen, Frédéric; Lo Bue, S. et al

in Gene Therapy (1997), 4(11), 1189-94

Peritoneal carcinomatosis is a common clinical situation which, in most cases, cannot be eradicated by surgery or chemotherapy. The feasibility of an HSV-TK-based suicide gene therapy for peritoneal ... [more ▼]

Peritoneal carcinomatosis is a common clinical situation which, in most cases, cannot be eradicated by surgery or chemotherapy. The feasibility of an HSV-TK-based suicide gene therapy for peritoneal carcinomatosis induced by DHD/K12 colon carcinoma cells was investigated. DHD/K12 cells stably expressing the tk gene were killed in vitro in the presence of low concentrations of ganciclovir, they exhibited a 'bystander effect' when mixed with TK-negative cells. BD-IX rats injected intraperitoneally, either directly or after surgical peritoneal irritations, with DHD/K12 cells developed peritoneal carcinomatosis within 2 weeks. Ganciclovir treatment of animals injected with DHD/K12-TK cells allowed a significant reduction of the tumor volume as well as a prolonged survival. Of these animals 35-40% showed a long-term disease-free survival after ganciclovir therapy. Residual or relapsing tumors could be explained by a low expression of the transgene as demonstrated by RT-PCR. [less ▲]

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See detailInterleukin-1 Beta Induces Nuclear Factor Kappa B in Epithelial Cells Independently of the Production of Reactive Oxygen Intermediates
Bonizzi, Giuseppina; Dejardin, Emmanuel ULg; Piret, Bernard et al

in European Journal of Biochemistry (1996), 242(3), 544-9

A large body of work has been devoted to tumor necrosis factor alpha or interleukin-1 beta (IL-1 beta) signaling leading to the activation of the transcription factor nuclear factor-kappa B (NF-kappa B ... [more ▼]

A large body of work has been devoted to tumor necrosis factor alpha or interleukin-1 beta (IL-1 beta) signaling leading to the activation of the transcription factor nuclear factor-kappa B (NF-kappa B) in various cell types. Several studies have indicated that NF-kappa B activation depends strictly on the production of reactive oxygen intermediates. In this report, we first demonstrated that IL-1 beta is a potent activator of NF-kappa B in various epithelial transformed cell lines (OVCAR-3, SKOV-3, MCF7 A/Z). In these cells, IL-1 beta rapidly induces NF-kappa B through a complete degradation of I kappa B-alpha, while H2O2 activates NF-kappa B with slower kinetics through a partial degradation of I kappa B-alpha, p100 and p105. We showed that IL-1 beta-mediated induction of NF-kappa B in OVCAR-3 and in other epithelial cell lines does not proceed through the production of reactive oxygen intermediates, while the same cytokine activates NF-kappa B in lymphoid cells through the intracellular generation of H2O2. Our study demonstrated that several signaling pathways lead to the activation of NF-kappa B, following IL-1 beta treatment in different cell types. [less ▲]

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See detailLessons to be learned from varicella-zoster virus
Rentier, Bernard ULg; Piette, Jacques ULg; Baudoux, Laurence et al

in Veterinary Microbiology (1996), 53(1-2), 55-66

Varicella-zoster virus (VZV) is an alphaherpesvirus responsible for two human diseases: chicken pox and shingles. The virus has a respiratory port of entry. After two successive viremias, it reaches the ... [more ▼]

Varicella-zoster virus (VZV) is an alphaherpesvirus responsible for two human diseases: chicken pox and shingles. The virus has a respiratory port of entry. After two successive viremias, it reaches the skin where it causes typical lesions. There, it penetrates the peripheral nervous system and it remains latent in dorsal root ganglia. It is still debatable whether VZV persists in neurons or in satellite cells. During latency, VZV expresses a limited set of transcripts of its immediate early (IE) and early (E) genes but no protein has been detected. Mechanisms of reactivation from ganglia have not been identified. However, dysfunction of the cellular immune system appears to be involved in this process. The cell-associated nature of VZV has made it difficult to identify a temporal order of gene expression, but there appears to be a cascade mechanism as for HSV-1. The lack of high titre cell-free virions or recombination mutants has hindered so far the understanding of VZV gene functions. Five genes, ORFs 4, 10, 61, 62, and 63 that encode regulatory proteins could be involved in VZV latency. ORF4p activates gene promoters with basal activities. ORF10p seems to activate the ORF 62 promoter. ORF61p has trans-activating and trans-repressing activities. The major IE protein ORF62p, a virion component, has DNA-binding and regulatory functions, transactivates many VZV promoters and even regulates its own expression. ORF63p is a nuclear IE protein of yet unclear regulatory functions, abundantly expressed very early in infection. We have established an animal model of VZV latency in the rat nervous system, enabling us to study the expression of viral mRNA and protein expression during latency, and yielding results similar to those found in humans. This model is beginning to shed light on the molecular events in VZV persistent infection and on the regulatory mechanisms that maintain the virus in a latent stage in nerve cells. [less ▲]

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See detailEnhancement of Varicella-Zoster virus infection in cell lines expressing ORF4- or ORF62-encoded proteins
Schoonbroodt, Sonia; Piette, Jacques ULg; Baudoux, Laurence et al

in Journal of Medical Virology (1996), 49(4), 264-273

Varicella-Zoster virus (VZV) open reading frames 4 (ORF4) and 62 (ORF62) encode putative immediate-early proteins (ORF4p and ORF62p, respectively) which are strong transactivators of other VZV genes and ... [more ▼]

Varicella-Zoster virus (VZV) open reading frames 4 (ORF4) and 62 (ORF62) encode putative immediate-early proteins (ORF4p and ORF62p, respectively) which are strong transactivators of other VZV genes and are involved in the very early stages of viral infection. ORF4p and ORF62p transactivate immediate-early and early gene promoters but have little or no effect on late gene promoters. To investigate the effect of ORF4p or ORF62p overexpression on the viral replication cycle, we constructed Vero cell lines expressing those genes under the control of the human cytomegalovirus major immediate-early promoter. VZV OKA infection of these stably transformed cell lines was followed-up using VZV glycoprotein E (gE) antigen quantification and virus titration. Upon serial passaging of infection in these cell lines expressing functionally active ORF4p or ORF62p, a 5- to 10-fold increase in viral gE antigen production was observed. Viral titers also demonstrated a 2- to 5-fold increase in viral production in these transformed cell lines. These results emphasize the role that both ORF4p and ORF62p play in enhancing the VZV replicative cycle. (C) 1996 Wiley-Liss, Inc. [less ▲]

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