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Dive into the research topics where Jacques Gielen is active.

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Featured researches published by Jacques Gielen.


Oncogene | 2003

NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells

Mohamed Bentires-Alj; Veronique Barbu; Marianne Fillet; Alain Chariot; Biserka Relic; Nathalie Jacobs; Jacques Gielen; Marie-Paule Merville; Vincent Bours

The ubiquitous NF-κB 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-κB or P-glycoprotein inhibition in the HCT15 colon cancer cells led to increased apoptotic cell death in response to daunomycin treatment. Interestingly, NF-κB inhibition through transfection of a plasmid coding for a mutated IκB-α inhibitor increased daunomycin cell uptake. Indeed, the inhibition of NF-κB reduced mdr1 mRNA and P-glycoprotein expression in HCT15 cells. We identified a consensus NF-κB binding site in the first intron of the human mdr1 gene and demonstrated that NF-κB complexes could bind with this intronic site. Moreover, NF-κB transactivates an mdr1 promoter luciferase construct. Our data thus demonstrate a role for NF-κB in the regulation of the mdr1 gene expression in cancer cells and in drug resistance.


Oncogene | 1999

Regulation of NF-kappaB activity by I kappaB-related proteins in adenocarcinoma cells.

Emmanuel Dejardin; Vale rie Deregowski; Muriel Chapelier; Nathalie Jacobs; Jacques Gielen; Marie-Paule Merville; Vincent Bours

Constitutive NF-κB activity varies widely among cancer cell lines. In this report, we studied the expression and the role of different IκB inhibitors in adenocarcinoma cell lines. High constitutive NF-κB activity and low IκB-α 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-α or other NF-κB activating agents induced only weakly nuclear NF-κB activity without significant p100 processing and led to a very weak transcription of NF-κB-dependent reporter gene. Induction of NF-κB 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-κB induction and NF-κB-dependent gene transcription following TNF-α stimulation. As a consequence of a competition between IκB-α and p100, cells expressing high levels of p100 respond poorly to NF-κB activating stimuli as TNF-α.


Journal of Molecular Biology | 1974

Globin gene expression in cultured erythroleukemic cells

Jeffrey Ross; Jacques Gielen; S. Packman; Yoji Ikawa; Philip Leder

Abstract A cultured, murine erythroleukemic cell line, which initially contains no detectable hemoglobin, can be induced to synthesize hemoglobin in quantities comparable to those found in normal red blood cells. In order to distinguish between several molecular mechanisms which might explain this induction, radioactive DNA complementary to mouse globin messenger RNA was used as a hybridization probe to measure globin genes and mRNA quantitatively during this form of differentiation. The results indicate that the number of globin genes does not change as these cells accumulate hemoglobin and that there are less than five copies of the globin genes per haploid genome. On the other hand, differentiated cells accumulate, on the average, 7000 to 8000 molecules of globin mRNA per cell, compared with less than ten in each undifferentiated cell. The accumulation of globin mRNA ceases in the presence of actinomycin D, suggesting that it is dependent on de novo RNA synthesis. It is also inhibited by cycloheximide and puromycin, suggesting a requirement for continued protein synthesis. Although a mechanism involving the post-transcriptional stabilization of newly synthesized globin mRNA can not be ruled out, these results are most simply explained on the basis of transcriptional activation of globin genes. Further data suggest that the globin mRNA synthesized in these erythroleukemic cells is relatively stable (chemical half-life more than 10 h) and is indistinguishable from authentic reticulocyte globin mRNA. The amount of globin mRNA, synthesized at the rate of approximately 20 nucleotides per second, has been measured and found comparable to the amount in mouse reticulocytes.


Oncogene | 1999

CBP and histone deacetylase inhibition enhance the transactivation potential of the HOXB7 homeodomain-containing protein

Alain Chariot; Carine Van Lint; Muriel Chapelier; Jacques Gielen; Marie-Paule Merville; Vincent Bours

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.


Biochemical Pharmacology | 2000

Pharmacological Modulation of the Bystander Effect in the Herpes Simplex Virus Thymidine Kinase/Ganciclovir Gene Therapy System: Effects of Dibutyryl Adenosine 3',5'-Cyclic Monophosphate, Alpha-Glycyrrhetinic Acid, and Cytosine Arabinoside

Pierre Robe; Frédéric Princen; Didier Martin; Brigitte Malgrange; Achille Stevenaert; Gustave Moonen; Jacques Gielen; Marie-Paule Merville; Vincent Bours

The herpes simplex virus type 1 thymidine kinase (HSV1-tk) suicide gene/ganciclovir system was first applied to the treatment of glioblastoma tumors, but was hampered by the low gene transfection yield. Fortunately, the gap junction-dependent diffusion of phosphorylated ganciclovir metabolites from transfected cells to their neighbors proved to enhance the overall benefit of this strategy. However, as tumor cells are often gap junction-deficient, we sought to restore this property pharmacologically and hence to improve the efficacy of the treatment. We demonstrated that this approach was feasible in glioblastoma cells using dibutyryl adenosine 3,5-cyclic monophosphate (cAMP) (100 microM) as a pharmacological inducer of gap junctions. alpha-Glycyrrhetinic acid (25 microM), on the other hand, strongly inhibited both gap junction-mediated intercellular communication and the bystander effect, thus confirming the role of gap junctions in HSV-tk-mediated bystander killing. Using cytosine arabinoside as a growth inhibitor, we underlined the role of tumor cell proliferation in the sensitivity of HSV-tk-transfected cells to ganciclovir and demonstrated its correlation with the importance of the bystander effect.


Oncogene | 2000

Additive effect between NF-kappaB subunits and p53 protein for transcriptional activation of human p53 promoter.

Valérie Benoit; Anne-Cécile Hellin; Sandra Huygen; Jacques Gielen; Vincent Bours; Marie-Paule Merville

The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-specific manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported. In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identified in the human p53 promoter a novel potential p53-responsive element that binds wild-type p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-κB binding site, we demonstrated an additive effect when NF-κB subunits and p53 protein combined to transactivate the human p53 promoter.


Biochemical Pharmacology | 2000

Chemotherapy and metabolic inhibitorsPharmacological modulation of the bystander effect in the herpes simplex virus thymidine kinase/ganciclovir gene therapy system: Effects of dibutyryl adenosine 3′,5′-cyclic monophosphate, α-glycyrrhetinic acid, and cytosine arabinoside

Pierre Robe; Frédéric Princen; Didier Martin; Brigitte Malgrange; Achille Stevenaert; Gustave Moonen; Jacques Gielen; Marie-Paule Merville; Vincent Bours

The herpes simplex virus type 1 thymidine kinase (HSV1-tk) suicide gene/ganciclovir system was first applied to the treatment of glioblastoma tumors, but was hampered by the low gene transfection yield. Fortunately, the gap junction-dependent diffusion of phosphorylated ganciclovir metabolites from transfected cells to their neighbors proved to enhance the overall benefit of this strategy. However, as tumor cells are often gap junction-deficient, we sought to restore this property pharmacologically and hence to improve the efficacy of the treatment. We demonstrated that this approach was feasible in glioblastoma cells using dibutyryl adenosine 3,5-cyclic monophosphate (cAMP) (100 microM) as a pharmacological inducer of gap junctions. alpha-Glycyrrhetinic acid (25 microM), on the other hand, strongly inhibited both gap junction-mediated intercellular communication and the bystander effect, thus confirming the role of gap junctions in HSV-tk-mediated bystander killing. Using cytosine arabinoside as a growth inhibitor, we underlined the role of tumor cell proliferation in the sensitivity of HSV-tk-transfected cells to ganciclovir and demonstrated its correlation with the importance of the bystander effect.


Journal of Biological Chemistry | 1999

IkappaB-alpha enhances transactivation by the HOXB7 homeodomain-containing protein.

Alain Chariot; Frédéric Princen; Jacques Gielen; Marie-Paule Merville; Guido Franzoso; Keith Brown; Ulrich Siebenlist; Vincent Bours

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 IκB-α, an inhibitor of NF-κB activity. This interaction was mediated by the IκB-α ankyrin repeats and C-terminal domain as well as by the HOXB7 N-terminal domain. In transient transfection experiments, IκB-α markedly increased HOXB7-dependent transcription from a reporter plasmid containing a homeodomain consensus-binding sequence. This report therefore showed a novel function for IκB-α, namely a positive regulation of transcriptional activation by homeodomain-containing proteins.


Archives of Biochemistry and Biophysics | 1974

Characteristics of rabbit globin mRNA purification by oligo(dT) cellulose chromatography

Jacques Gielen; H. Aviv; Philip Leder

Abstract We have purified rabbit globin mRNA using oligo(dT)-cellulose and sucrose gradient centrifugation. Both α- and β-globulin mRNA molecules behave heterogeneously with respect to their elution properties during chromatography on oligo(dT)-cellulose. Those fractions eluted at the lowest ionic strength are most active in directing cell-free globin biosynthesis. By making use of hybridization with synthetic [3H]DNA complementary to globin mRNA, we have shown that this technique can be used to quantitate the extent of mRNA purification. Thus, globin mRNA is approximately 90-fold purified from reticulocyte polysomal RNA and originally constituted slightly more than 1% of the polysomal RNA. Since more than 98% of the globin mRNA sequences are bound to oligo(dT)-cellulose, we suggest that most polysomal globin mRNAs contain a poly (A)-rich region and that this region is not of uniform length nor preponderately associated with either the α- or β-globin mRNAs. In addition, we observe that the 9S globin mRNA most resistant to dissociation from oligo (dT)-cellulose is most active in directing globin biosynthesis.


Cancer Gene Therapy | 2000

Antitumoral vaccination with granulocyte-macrophage colony-stimulating factor or interleukin-12-expressing DHD/K12 colon adenocarcinoma cells.

Chantal Lechanteur; Michel Moutschen; Frédéric Princen; M. Lopez; Elizabeth Franzen; Jacques Gielen; Vincent Bours; Marie-Paule Merville

Immunomodulating gene therapy for the treatment of malignant diseases is under extensive investigation. In this study, we induced an antitumoral immune response with murine interleukin-12 (mIL-12) and murine granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cells in a model of peritoneal carcinomatosis. Intraperitoneal injection of DHD/K12 tumoral cells engineered to produce IL-12 or GM-CSF did not generate any tumors, whereas untransduced DHD/K12 cells gave rise to peritoneal carcinomatosis. IL-12-expressing DHD/K12 cells also protected against tumors derived from coinjected parental cells. To test whether cytokine-producing cells could elicit a memory antitumoral immune response, animals received a challenge with parental DHD/K12 cells 35 days after the injection of proliferating or irradiated DHD/K12 engineered cells. Under our experimental conditions, irradiated tumor cells did not generate any antitumoral immunity. In contrast, tumor development was delayed and survival increased in the animals vaccinated with cytokine-secreting proliferating cells. A specific cytotoxic T-lymphocyte response against DHD/K12 parental cells was observed after vaccination with GM-CSF-expressing cells. Our results demonstrated that intraperitoneal vaccination with IL-12- or GM-CSF-expressing adenocarcinoma cells induced a systemic immune antitumoral response that may be useful as an adjuvant therapy after surgical resection of colorectal cancer.

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Daniel W. Nebert

University of Cincinnati Academic Health Center

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Jeffrey Ross

National Institutes of Health

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S. Packman

National Institutes of Health

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