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See detailThe homeodomain-containing proteins: an update on their interacting partners
Chariot, Alain ULg; Gielen, Jacques; Merville, Marie-Paule ULg et al

in Biochemical Pharmacology (1999), 58

Homeodomain-containing proteins are transcription regulators controlling the coordinated expression of genes involved in development, differentiation, and cellular transformation. They share a highly ... [more ▼]

Homeodomain-containing proteins are transcription regulators controlling the coordinated expression of genes involved in development, differentiation, and cellular transformation. They share a highly conserved 60-amino-acid region (the "homeodomain"), which allows them to bind DNA and modulate the expression of multiple target genes, whose identities remain largely unknown. Although each HOX gene product exhibits in vivo specificity, they harbor very similar DNA-binding affinities in vitro, suggesting that other mechanisms such as protein-protein interactions are critical to modulate their function. In this commentary, we describe the proteins that can interact with the HOX gene products, including newly identified partners such as CREB binding protein and the NF-kappaB/IkappaB-alpha proteins. We also outline the molecular programs that are regulated by the transcriptional complexes involving the HOX gene products and where new pharmacological tools could find interesting targets. [less ▲]

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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 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 detailLes tumeurs malignes d'origine indéterminée
Rezaei Kalantari, Hassan ULg; Jerusalem, Guy ULg; Bours, Vincent ULg et al

in Revue Médicale de Liège (1999), 54(1), 39-42

Cancers of unknown origin form a specific clinical entity. The diagnostic procedure has to be guided by the therapeutical possibilities and requires a biopsy. Immunohistology, electron microscopy and ... [more ▼]

Cancers of unknown origin form a specific clinical entity. The diagnostic procedure has to be guided by the therapeutical possibilities and requires a biopsy. Immunohistology, electron microscopy and cytogenetics are informative for carcinomas and poorly differentiated adenocarcinomas. The clinical status and the histology allow the definition of groups of patients who can benefit from a specific therapy and have a better prognosis. For the other patients, the prognosis is severe and there is no efficient therapy available. Such tumors are usually characterized by a very aggressive behaviour. [less ▲]

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See detailPeripheral blood progenitor cell collections in cancer patients: analysis of factors affecting the yields.
Sautois, Brieuc ULg; Fraipont, V.; Baudoux, Etienne ULg et al

in Haematologica (1999), 84(4), 342-9

BACKGROUND AND OBJECTIVE: Peripheral blood progenitor cells (PBPC) are now widely used to restore hematopoiesis following high dose chemotherapy in patients with malignancies. We sought to identify ... [more ▼]

BACKGROUND AND OBJECTIVE: Peripheral blood progenitor cells (PBPC) are now widely used to restore hematopoiesis following high dose chemotherapy in patients with malignancies. We sought to identify parameters that could predict the yield of PBPC after mobilization with chemotherapy (CT) with or without granulocyte colony-stimulating factor (G-CSF) in cancer patients. DESIGN AND METHODS: One hundred and fifty patients underwent 627 PBPC collections during the recovery phase following CT with (n = 469) or without (n = 142) G-CSF. Hemogram, CFC-assays and CD34+ cell count were performed on peripheral blood and leukaphereses products. After log transformation of the data, differences between groups were assessed with the unpaired t-test or one-way analysis of variance. RESULTS: Seventeen and two patients required 2 and 3 mobilization cycles respectively to reach our target of 15x10(4) CFU-GM/kg. In patients with lymphoma but not in those with leukemia, the yields of both CFU-GM and CD34+ cells/kg were dramatically increased when G-CSF was added to CT for mobilization. In collections primed with CT and G-CSF, better yields were obtained in patients with breast cancer or small-cell lung carcinoma (SCLC) as opposed to other solid tumors and leukemia. Among potential predictive factors of CT- and G-CSF-primed harvests, we found that the CD34+ cell count in peripheral blood (PB) was strongly correlated with both the CFU-GM and CD34+ cell yields. Except in leukemia patients, more than 1x10(6) CD34+ cells/kg were harvested when the CD34+ cell count in blood was above 20x10(6)/L. Similarly, better results were obtained in collections performed when the percentage of myeloid progenitors in blood on the day of apheresis was above 5 % or when the leukocyte count in blood was above 5x10(9)/L. INTERPRETATION AND CONCLUSIONS: A diagnosis of breast cancer or SCLC, a leukocyte count in PB of more than 5x10(9)/L, more than 5% myeloid progenitors or more than 20x10(6) CD34+ cells/L in PB were associated with higher yields of PBPC in collections mobilized with CT+G-CSF. [less ▲]

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See detailActualités thérapeutiques dans le traitement du cancer colorectal
Jerusalem, Guy ULg; Bours, Vincent ULg; Fillet, Georges ULg

in Médecine et Hygiène (1999), 57

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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 detailSustained NF-kB activity after removal of the etiologic agent in an animal model of asthma
Bureau, Fabrice ULg; Bonizzi, G.; Kirschvink, Nathalie et al

in Proceedings: 1999 International Conference of the American Thoracic Society (1999)

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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 detailPharma-clinics. Comment je traite... II. Approche thérapeutique du cancer colorectal métastatique
Jerusalem, Guy ULg; Bours, Vincent ULg; Fillet, Georges ULg

in Revue Médicale de Liège (1998), 53(6), 318-21

Since its introduction in 1953, 5-fluorouracil based chemotherapy remained the standard treatment in advanced colorectal cancer. Continuous infusion or biochemical modulation by folinic acid enhanced the ... [more ▼]

Since its introduction in 1953, 5-fluorouracil based chemotherapy remained the standard treatment in advanced colorectal cancer. Continuous infusion or biochemical modulation by folinic acid enhanced the therapeutic efficacy of this agent. Quality of life is limited by the toxicity of these regimens as well as by the frequent visits to the hospital during each cycle. Raltitrexed, a thymidylate synthase inhibitor, offers similar antitumoral activity together with a tolerability in comparison to standard 5-fluorouracil based chemotherapy and its simple dosage schedule also contributes to better quality of life. New chemotherapeutic agents are currently in development for the treatment of patients refractory to 5-fluorouracil. Irinotecan and oxaliplatin demonstrate promising activity. [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 detailTraitement du cancer colorectal. Aspects pharmaco-économiques
Jerusalem, Guy ULg; Bours, Vincent ULg; Fillet, Georges ULg

in Revue Médicale de Liège (1998), 53(5), 276-8

Cancer patients care is mainly based on scientific studies, but sometimes approaches are empiric. Rapid growth of health care expenses force the physician to take pharmacoeconomic aspects into ... [more ▼]

Cancer patients care is mainly based on scientific studies, but sometimes approaches are empiric. Rapid growth of health care expenses force the physician to take pharmacoeconomic aspects into consideration. New clinical studies have to analyse clinical benefits but also cost-effectiveness. We will review the various aspects of colorectal cancer from primary prevention to post-treatment follow-up. Scientific data are integrated in a pharmacoeconomic analysis. [less ▲]

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See detailComment je traite ... Le cancer colorectal: I. Prévention et traitement adjuvant
Bours, Vincent ULg; Jerusalem, Guy ULg; Fillet, Georges ULg

in Revue Médicale de Liège (1998), 53(4), 167-70

Colorectal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Belgium and in other western countries. Prevention implies a modification of alimentation and maybe a chronic uptake ... [more ▼]

Colorectal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Belgium and in other western countries. Prevention implies a modification of alimentation and maybe a chronic uptake of acetylsalicylic acid. Treatment of colorectal cancers is based on surgery and the prognosis is determined by the locoregional or metastatic tumor spread. Complete resection of any Astler Coller stage C colorectal malignant tumor has to be followed by a 5-fluorouracil-based adjuvant chemotherapy. In these protocols, 5-fluorouracil is administered together with folinic acid or levamisole. The administration of an adjuvant chemotherapy could also be considered for stage BII diseases. As rectal cancers are characterized by high local relapse rates, their treatment should associate radiotherapy, given either post-surgery or preferentially pre-surgery, with resection and chemotherapy. Appropriate treatment of colorectal cancers thus requires a concerted multidisciplinary approach. [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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