Interleukin-1 Beta Induces Nuclear Factor Kappa B in Epithelial Cells Independently of the Production of Reactive Oxygen Intermediates
; Dejardin, Emmanuel ; 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 ▲]Detailed reference viewed: 37 (0 ULg)
Rétinoïdes et leucémie aigue promyelocytaire. Une révolution thérapeutique
; Tassin, Françoise ; Bours, Vincent et al
in Revue Médicale de Liège (1996), 51(3), 217-23Detailed reference viewed: 45 (2 ULg)
Activation of the human immunodeficiency virus long terminal repeat by varicella-zoster virus ORF4 encoded protein involves binding sites for nuclear factor kappa B
; ; Merville, Marie-Paule et al
Conference (1996)Detailed reference viewed: 10 (0 ULg)
Intérêt de l'acide rétinoïque "tous trans" dans le traitement de la leucémie aiguë promyélocytaire
; ; Bours, Vincent et al
in Médecine et Hygiène (1996), 54Detailed reference viewed: 36 (0 ULg)
Highly-Expressed P100/P52 (Nfkb2) Sequesters Other Nf-Kappa B-Related Proteins in the Cytoplasm of Human Breast Cancer Cells
Dejardin, Emmanuel ; ; Bellahcene, Akeila et al
in Oncogene (1995), 11(9), 1835-41
Several observations have suggested that NF-kappa B transcription factors could be involved in carcinogenesis. To investigate the possibility that members of the NF-kappa B family participate in the ... [more ▼]
Several observations have suggested that NF-kappa B transcription factors could be involved in carcinogenesis. To investigate the possibility that members of the NF-kappa B family participate in the molecular control of the transformed phenotype, we examined the expression of these proteins in human breast cancer cell lines as well as in primary tumors. Western Immunoblots demonstrated high expression of the p52 precursor p100 (NFKB2) in several breast cancer cell lines while human mammary epithelial cells express this protein only faintly. Eighteen primary breast tumors out of 24 displayed significant expression of the p100/p52 protein. In MDA-MB-435 cells, overexpressed p100 and p52 are predominantly cytoplasmic and coimmunoprecipitation experiments demonstrated that p100 sequesters the heterodimer p50/p65 in the cytoplasm. We demonstrate that most p65 protein is complexed with p100 in these cells while it is complexed predominantly with I kappa B-alpha in cell lines expressing less p100. Our data strengthen the hypothesis that NF-kappa B could be involved in carcinogenesis and suggest that the p100/p52 NF-kappa B subunit could play a role in the development of human breast cancers, possibly by sequestering other NF-kappa B-related proteins in the cytoplasm. [less ▲]Detailed reference viewed: 52 (4 ULg)
Transcription factor NF-kB is activated by photosensitization generating oxidative DNA damages
Legrand-Poels, Sylvie ; Bours, Vincent ; et al
in Journal of Biological Chemistry (1995), 270(12), 6925-6934
Reactive oxygen intermediates like hydrogen peroxide (H2O2) have been shown to serve as messengers in the induction of NF-kappa B and, then, in the activation and replication of human immunodeficiency ... [more ▼]
Reactive oxygen intermediates like hydrogen peroxide (H2O2) have been shown to serve as messengers in the induction of NF-kappa B and, then, in the activation and replication of human immunodeficiency virus (HIV)-1 in human cells. Because H2O2 can be converted into the highly reactive OH. at various locations inside the cells, we started to investigate the generation of Reactive oxygen intermediates by photosensitization. This technique is based on the use of a photosensitizer which is a molecule absorbing visible light and which can be located at various sites inside the cell depending on its physicochemical properties. In this work, we used proflavine (PF), a cationic molecule having a high affinity for DNA, capable of intercalating between DNA base pairs. Upon visible light irradiation, intercalated PF molecules oxidize guanine residues and generate DNA single-strand breaks. In lymphocytes or monocytes latently infected with HIV-1 (ACH-2 or U1, respectively), this photosensitizing treatment induced a cytotoxicity, an induction of NF-kappa B, and a reactivation of HIV-1 in cells surviving the treatment. NF-kappa B induction by PF-mediated photosensitization was not affected by the presence of N-acetyl-L-cysteine while strong inhibition was recorded when the induction was triggered by H2O2 or by phorbol 12-myristate 13-acetate. Another transcription factor like AP-1 is less activated by this photosensitizing treatment. In comparison with other inducing treatments, such as phorbol 12-myristate 13-acetate or tumor necrosis factor alpha, the activation of NF-kappa B is slow, being optimal 120 min after treatment. These kinetic data were obtained by following, on the same samples, both the appearance of NF-kappa B in the nucleus and the disappearance of I kappa B-alpha in cytoplasmic extracts. These data allow us to postulate that signaling events, initiated by DNA oxidative damages, are transmitted into the cytoplasm where the inactive NF-kappa B factor is resident and allow the translocation of p50/p65 subunits of NF-kappa B to the nucleus leading to HIV-1 gene expression. [less ▲]Detailed reference viewed: 9 (1 ULg)
Simulation of Human B-Lymphocyte Proliferation by Agm-1470, a Potent Inhibitor of Angiogenesis
Antoine, Nadine ; Bours, Vincent ; Heinen, Ernst et al
in Journal of the National Cancer Institute (1995), 87(2), 136-9Detailed reference viewed: 11 (1 ULg)
Approche thérapeutique du cancer épithélial de l'ovaire au CHU Sart Tilman : Conclusions de la réunion interdisciplinaire du 22 mars 1995
Jerusalem, Guy ; Detroz, Bernard ; Herman, Philippe et al
in Revue Médicale de Liège (1995), 50
Notre but est de définir une approche multidisciplinaire permettant d'offrir les meilleures chances de guérison ou de survie prolongée aux patientes. Nous nous sommes basés sur notre expérience ... [more ▼]
Notre but est de définir une approche multidisciplinaire permettant d'offrir les meilleures chances de guérison ou de survie prolongée aux patientes. Nous nous sommes basés sur notre expérience personnelle et les données actuelles de la littérature, tout en intégrant les approches innovatrices (ex : chimiothérapie intrapéritonéale précoce). Pour certaines patientes, le pronostic reste trop sombre avec un traitement standard et il nous semble important de leur proposer un traitement potentiellement plus efficace. [less ▲]Detailed reference viewed: 39 (3 ULg)
NF kappa B and interferon regulatory factor 1 physically interact and synergistically induce major histocompatibility class I gene expression.
; ; et al
in Journal of Interferon & Cytokine Research (1995), 15(12), 1037-45
Major histocompatibility (MHC) class I gene expression is synergistically induced by the cytokines TNF-alpha and IFN-gamma. However, the mechanism that results in synergistic activation of these genes has ... [more ▼]
Major histocompatibility (MHC) class I gene expression is synergistically induced by the cytokines TNF-alpha and IFN-gamma. However, the mechanism that results in synergistic activation of these genes has remained unclear. We demonstrated here that TNF-alpha induced binding of NF kappa B p50 and p65 to the NF kappa B-like element of the MHC class I promoter termed region I and IFN-gamma induced binding of IRF-1 to the adjacent interferon consensus sequence (ICS). We further demonstrated that NF kappa B and IRF-1 physically interacted with each other and cooperatively induced MHC class I gene expression when cotransfected into CHP-126 neuroblastomas. These results provide a molecular mechanism by which TNF-alpha and IFN-gamma synergistically induce the expression of a variety of genes involved in immune responses, including MHC class I. [less ▲]Detailed reference viewed: 15 (1 ULg)
The Nf-Kappa B Transcription Factor and Cancer: High Expression of Nf-Kappa B- and I Kappa B-Related Proteins in Tumor Cell Lines
Bours, Vincent ; Dejardin, Emmanuel ; et al
in Biochemical Pharmacology (1994), 47(1), 145-9
NF-kappa B is a pleiotropic transcription factor which controls the expression of many genes and viruses. To date, there is good evidence, but no definitive proof, for its role in tumor formation and ... [more ▼]
NF-kappa B is a pleiotropic transcription factor which controls the expression of many genes and viruses. To date, there is good evidence, but no definitive proof, for its role in tumor formation and development of metastasis. To investigate the possibility that members of the NF-kappa B family could participate in the molecular control of the transformed and invasive phenotype, we examined the expression of these proteins in a variety of human tumor cell lines. The expression of p50, p65, p52 and I kappa B was quantified at the protein level using western immunoblot and mobility shift assay and at the RNA level by northern blot. We observed high expression of the NF-kappa B inhibitor I kappa B in the ovarian carcinoma cell line OVCAR-3 together with constitutive nuclear NF-kappa B activity. We also studied the colon carcinoma cell line HT-29 and its metastatic counterpart HTM-29 and we observed specific expression of the p52 NF-kappa B-related protein in the metastatic cells. Our data confirm that NF-kappa B could be involved in the genesis of a variety of cancers including solid tumors and provide us with interesting models to explore the exact role of these transcription factors in cancer. [less ▲]Detailed reference viewed: 28 (1 ULg)
Human RelB (I-Rel) functions as a kappa B site-dependent transactivating member of the family of Rel-related proteins.
Bours, Vincent ; ; Dejardin, Emmanuel et al
in Oncogene (1994), 9(6), 1699-702
RelB belongs to the family of Rel-related proteins, dimers of which determine NF-kappa B activity. The murine RelB protein has been reported to be a dimerizing partner in kappa B-binding complexes which ... [more ▼]
RelB belongs to the family of Rel-related proteins, dimers of which determine NF-kappa B activity. The murine RelB protein has been reported to be a dimerizing partner in kappa B-binding complexes which are capable of transactivation. On the other hand, the I-Rel protein, the presumed human homolog of RelB, was proposed to be an inhibitor whose presence in dimeric complexes interfered with their kappa B binding and therefore interfered also with transactivation. We demonstrate that human RelB (I-Rel) forms with p50 and p52 (p50B) kappa B-binding heterodimeric complexes which potently transactivate kappa B-dependent constructs in transfection studies. It is concluded that human RelB (I-Rel) and murine RelB can both function as transactivators and that no significant species-specific differences exist. [less ▲]Detailed reference viewed: 11 (0 ULg)
Chemically selected subclones of the CEM cell line demonstrate resistance to HIV-1 infection resulting from a selective loss of NF-kappa B DNA binding proteins.
; Bours, Vincent ; et al
in Journal of Immunology (1994), 152(8), 4183-91
To delineate cellular genes that are required for optimal HIV-1 infection, CEM cells were subjected to treatment with the chemical mutagen ethylmethanesulfonate (EMS) and subclones were selected based on ... [more ▼]
To delineate cellular genes that are required for optimal HIV-1 infection, CEM cells were subjected to treatment with the chemical mutagen ethylmethanesulfonate (EMS) and subclones were selected based on their increased resistance to HIV-1 infection and reduced syncytium formation, despite relatively normal CD4 expression (20,000 to 25,000 receptors/cell). Two subclones with this phenotype demonstrated a diminished capacity of HIV-1 long terminal repeat-chloramphenicol acetyl transferase expression either after treatment with the protein kinase C activator PMA, or through Tat-mediated transactivation. In this study, we show that the cellular levels of the NF-kappa B DNA binding proteins (but not AP1 or SP1) are markedly reduced in these cell mutants both at the mRNA and protein levels, resulting in reduced nuclear localization of p50/p65 after PMA induction or treatment with the lymphokine TNF-alpha. Transient reconstitution with a plasmid expressing p50 resulted in partial recovery of PMA-inducible LTR-chloramphenicol acetyl transferase expression. These data suggest that, at least in the CEM T cell line, a selective reduction in the NF-kappa B DNA binding proteins is sufficient to curtail HIV-1 infection. [less ▲]Detailed reference viewed: 9 (0 ULg)
The NF-kappaB transcription factor: structure, function and interaction with the oncoprotein Bcl-3.
Thèse d’agrégation de l’enseignement supérieur (1994)Detailed reference viewed: 5 (0 ULg)
Retinoic acid induction of major histocompatibility complex class I genes in NTera-2 embryonal carcinoma cells involves induction of NF-kappa B (p50-p65) and retinoic acid receptor beta-retinoid X receptor beta heterodimers.
; ; Bours, Vincent et al
in Molecular & Cellular Biology (1993), 13(10), 6157-69
Retinoic acid (RA) treatment of human embryonal carcinoma (EC) NTera-2 (NT2) cells induces expression of major histocompatibility complex (MHC) class I and beta-2 microglobulin surface molecules. We found ... [more ▼]
Retinoic acid (RA) treatment of human embryonal carcinoma (EC) NTera-2 (NT2) cells induces expression of major histocompatibility complex (MHC) class I and beta-2 microglobulin surface molecules. We found that this induction was accompanied by increased levels of MHC class I mRNA, which was attributable to the activation of the two conserved upstream enhancers, region I (NF-kappa B like) and region II. This activation coincided with the induction of nuclear factor binding activities specific for the two enhancers. Region I binding activity was not present in undifferentiated NT2 cells, but binding of an NF-kappa B heterodimer, p50-p65, was induced following RA treatment. The p50-p65 heterodimer was produced as a result of de novo induction of p50 and p65 mRNAs. Region II binding activity was present in undifferentiated cells at low levels but was greatly augmented by RA treatment because of activation of a nuclear hormone receptor heterodimer composed of the retinoid X receptor (RXR beta) and the RA receptor (RAR beta). The RXR beta-RAR beta heterodimer also bound RA responsive elements present in other genes which are likely to be involved in RA triggering of EC cell differentiation. Furthermore, transfection of p50 and p65 into undifferentiated NT2 cells synergistically activated region I-dependent MHC class I reporter activity. A similar increase in MHC class I reporter activity was demonstrated by cotransfection of RXR beta and RAR beta. These data show that following RA treatment, heterodimers of two transcription factor families are induced to bind to the MHC enhancers, which at least partly accounts for RA induction of MHC class I expression in NT2 EC cells. [less ▲]Detailed reference viewed: 3 (0 ULg)
The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites.
; Bours, Vincent ; et al
in EMBO Journal (1993), 12(10), 3893-901
Previously we have proposed a role for Bcl-3 in facilitating transactivation through kappa B sites by counteracting the inhibitory effects of bound, non-transactivating homodimers of the p50 subunit of NF ... [more ▼]
Previously we have proposed a role for Bcl-3 in facilitating transactivation through kappa B sites by counteracting the inhibitory effects of bound, non-transactivating homodimers of the p50 subunit of NF-kappa B. Such homodimers are abundant for example in nuclei of unstimulated primary T cells. Here we extend the model and provide new evidence which fulfills a number of predictions. (i) Bcl-3 preferentially targets p50 homodimers over NF-kappa B heterodimers since the homodimers are completely dissociated from kappa B sites at concentrations of Bcl-3 which do not affect NF-kappa B. (ii) Select kappa B sites associate very strongly and stably with p50 homodimers, completely preventing binding by NF-kappa B. Such kappa B sites are likely candidates for regulation by p50 homodimers and Bcl-3. (iii) Bcl-3 and p50 can be co-localized in the nucleus, a requirement for active removal of homodimers from their binding sites in vivo. (iv) The ankyrin repeat domain of Bcl-3 is sufficient for the reversal of p50 homodimer-mediated inhibition, correlating with the ability of this domain alone to inhibit p50 binding to kappa B sites in vitro. Our data support the model that induction of nuclear Bcl-3 may be required during cellular stimulation to actively remove stably bound p50 homodimers from certain kappa B sites in order to allow transactivating NF-kappa B complexes to engage. This exact mechanism is demonstrated with in vitro experiments. [less ▲]Detailed reference viewed: 5 (0 ULg)
Mutational analysis of the p50 subunit of NF-kappa B and inhibition of NF-kappa B activity by trans-dominant p50 mutants.
; ; et al
in Journal of Virology (1993), 67(1), 288-93
The NF-kappa B family of DNA-binding proteins regulates the expression of many cellular and viral genes. Each of these proteins has an N-terminal region that is homologous to the c-Rel proto-oncogene ... [more ▼]
The NF-kappa B family of DNA-binding proteins regulates the expression of many cellular and viral genes. Each of these proteins has an N-terminal region that is homologous to the c-Rel proto-oncogene product, and this Rel homology region defines both DNA binding and protein dimerization properties of the individual proteins. Most of the NF-kappa B family members have been shown to associate with themselves or with each other to form homodimers or heterodimers, and previous studies have shown that dimerization of NF-kappa B factors is necessary to provide a functional DNA binding domain. We have used site-directed mutagenesis to identify regions in the Rel homology domain of the p50/NF-kappa B protein that are important for DNA binding and protein dimerization. Our studies have identified mutations of p50 that interfere with DNA binding only and those that interfere with protein dimerization. Mutations of p50 which disrupt only DNA binding were still able to associate with other members of the NF-kappa B protein family. We demonstrate that such heterodimeric complexes inhibit transcriptional activation mediated in trans through a cis-acting kappa B motif; therefore, we have identified trans-dominant negative mutants of p50. [less ▲]Detailed reference viewed: 2 (0 ULg)
The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers.
Bours, Vincent ; ; et al
in Cell (1993), 72(5), 729-39
Bcl-3 is an I kappa B-related protein with ankyrin repeat motifs. Its gene is located at a site of recurrent translocations in a subset of B cell chronic lymphocytic leukemias. Bcl-3 associates tightly ... [more ▼]
Bcl-3 is an I kappa B-related protein with ankyrin repeat motifs. Its gene is located at a site of recurrent translocations in a subset of B cell chronic lymphocytic leukemias. Bcl-3 associates tightly with p50B (NFKB2, p52) homodimers in cells, and together these proteins form a ternary complex with DNA at kappa B sites. Such an association functionally leads to a novel and potent form of transactivation through the kappa B motif: the tethering of Bcl-3 to DNA via the p50B homodimers allows Bcl-3 to transactivate directly, while p50B homodimers alone cannot. Transactivation mediated by Bcl-3 requires two cooperating domains located amino- and carboxy-terminal to the ankyrin domain. Bcl-3 is localized to the nucleus, and a Bcl-3-p50B complex is detected in certain lymphoid cells. Our data reveal a novel role for Bcl-3, distinct from that of the inhibitor I kappa B. The results have implications for tumorigenesis. [less ▲]Detailed reference viewed: 8 (5 ULg)
The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition.
; Bours, Vincent ; et al
in Nature (1992), 359(6393), 339-42
The candidate oncogene bcl-3 was discovered as a translocation into the immunoglobulin alpha-locus in some cases of B-cell chronic lymphocytic leukaemias. The protein Bcl-3 contains seven so-called ... [more ▼]
The candidate oncogene bcl-3 was discovered as a translocation into the immunoglobulin alpha-locus in some cases of B-cell chronic lymphocytic leukaemias. The protein Bcl-3 contains seven so-called ankyrin repeats. Similar repeat motifs are found in a number of diverse regulatory proteins but the motifs of Bcl-3 are most closely related to those found in I kappa B proteins in which the ankyrin repeat domain is thought to be directly involved in inhibition of NF-kappa B activity. No biological function has yet been described for Bcl-3, but it was noted recently that Bcl-3 interferes with DNA-binding of the p50 subunit of NF-kappa B in vitro. Here we demonstrate that Bcl-3 can aid kappa B site-dependent transcription in vivo by counteracting the inhibitory effects of p50/NF-kappa B homodimers. Bcl-3 may therefore aid activation of select NF-kappa B-regulated genes, including those of the human immunodeficiency virus. [less ▲]Detailed reference viewed: 4 (0 ULg)
Lymphocyte activation and the family of NF-kappa B transcription factor complexes.
Bours, Vincent ; ; et al
in Current Topics in Microbiology and Immunology (1992), 182Detailed reference viewed: 6 (2 ULg)
A novel mitogen-inducible gene product related to p50/p105-NF-kappa B participates in transactivation through a kappa B site.
Bours, Vincent ; ; et al
in Molecular & Cellular Biology (1992), 12(2), 685-95
A Rel-related, mitogen-inducible, kappa B-binding protein has been cloned as an immediate-early activation gene of human peripheral blood T cells. The cDNA has an open reading frame of 900 amino acids ... [more ▼]
A Rel-related, mitogen-inducible, kappa B-binding protein has been cloned as an immediate-early activation gene of human peripheral blood T cells. The cDNA has an open reading frame of 900 amino acids capable of encoding a 97-kDa protein. This protein is most similar to the 105-kDa precursor polypeptide of p50-NF-kappa B. Like the 105-kDa precursor, it contains an amino-terminal Rel-related domain of about 300 amino acids and a carboxy-terminal domain containing six full cell cycle or ankyrin repeats. In vitro-translated proteins, truncated downstream of the Rel domain and excluding the repeats, bind kappa B sites. We refer to the kappa B-binding, truncated protein as p50B by analogy with p50-NF-kappa B and to the full-length protein as p97. p50B is able to form heteromeric kappa B-binding complexes with RelB, as well as with p65 and p50, the two subunits of NF-kappa B. Transient-transfection experiments in embryonal carcinoma cells demonstrate a functional cooperation between p50B and RelB or p65 in transactivation of a reporter plasmid dependent on a kappa B site. The data imply the existence of a complex family of NF-kappa B-like transcription factors. [less ▲]Detailed reference viewed: 3 (1 ULg)