[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine
Franzoso, G.
Azarenko, V.
Park, S.
Kanno, T.
Brown, K.
Siebenlist, U.
Language :
English
Title :
The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers.
Publication date :
1993
Journal title :
Cell
ISSN :
0092-8674
eISSN :
1097-4172
Publisher :
Cell Press, Cambridge, United States - Massachusetts
Baeuerle (1991) The inducible transcription activator NF-κB: regulation by distinct protein subunits. Biochim. Biophys. Acta 1072:63-80.
Baeuerle, Baltimore (1988) IκB: a specific inhibitor of the NF-κB transcription factor. Science 242:540-546.
Ballard, Walker, Doerre, Sista, Molitor, Dixon, Peffer, Hannink, Greene (1990) The v-rel oncogene encodes a κB enhancer binding protein that inhibits NF-κB function. Cell 63:803-814.
Ballard, Dixon, Peffer, Bogerd, Doerre, Stein, Greene (1992) The 65-kDa subunit of human NF-κB functions as a potent transcriptional activator and a target for v-Relmediated repression. Proc. Natl. Acad. Sci. USA 89:1875-1879.
Beg, Ruben, Scheinman, Haskill, Rosen, Baldwin (1992) IκB interacts with the nuclear localization sequences of the subunits of NF-κB: a mechanism for cytoplasmic retention. Genes Dev., 6:1899-1913.
Bhatia, Huppi, McKeithan, Siwarski, Mushinski, Magrath (1991) Mouse bcl-3: cDNA structure, mapping and stage-dependent expression in B lymphocytes. Oncogene 6:1569-1573.
Blank, Kourilsky, Israël (1991) Cytoplasmic retention, DNA binding and processing of the NF-κB p50 precursor are controlled by a small region in its C-terminus. EMBO J. 10:4159-4167.
Böhnlein, Lowenthal, Siekevitz, Ballard, Franza, Greene (1988) The same inducible nuclear protein(s) regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell 53:827-836.
Böhnlein, Ballard, Bogerd, Peffer, Lowenthal, Greene (1989) Induction of interleukin-2 receptor-α gene expression is regulated by post-translational activation of κB specific DNA binding proteins. J. Biol. Chem., 264:8475-8478.
Bours, Villalobos, Burd, Kelly, Siebenlist (1990) Cloning of a mitogen-inducible gene encoding a κB DNA-binding protein with homology to the rel oncogene and to cell-cycle motifs. Nature 348:76-80.
Bours, Burd, Brown, Villalobos, Park, Ryseck, Bravo, Kelly, Siebenlist (1992) A novel mitogen-inducible gene product related to p50-p105-NF-κB participates in transactivation through a κB site. Mol. Cell. Biol., 12:685-695.
Bressler, Brown, Timmer, Bours, Siebenlist, Fauci (1993) Mutational analysis of the p50 subunit of NF-κB and inhibition of NF-κB activity by trans-dominant p50 mutants. J. Virol., 67:288-293.
Brownell, Mittereder, Rice (1989) A human rel protooncogene cDNA containing an Alu fragment as a potential coding exon. Oncogene 4:935-942.
Cohen, Hiscott (1992) Heterodimerization and transcriptional activation in vitro by NF-κB proteins. J. Cell. Physiol., 152:10-18.
Davis, Ghosh, Simmons, Tempst, Liou, Baltimore, Bose (1992) Rel-associated pp40: an inhibitor of the rel family of transcription factors. Science 253:1268-1271.
Fan, Maniatis (1991) Generation of p50 subunit of NF-κB by processing of p105 through an ATP-dependent pathway. Nature 354:395-398.
Franzoso, Bours, Park, Tomita-Yamaguchi, Kelly, Siebenlist (1992) The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-κB-mediated inhibition. Nature 359:339-342.
Fujita, Nolan, Ghosh, Baltimore (1992) Independent modes of transcriptional activation by the p50 and p65 subunits of NF-κB. Genes Dev., 6:775-787.
Geisler, Bergmann, Hiromi, Nüsslein-Volhard (1992) cactus, a gene involved in dorsoventral pattern formation of Drosophila, is related to the IκB gene family of vertebrates. Cell 71:613-621.
Gelinas, Temin (1988) The v-rel oncogene encodes a cell-specific transcriptional activator of certain promoters. Oncogene 3:349-355.
Ghosh, Gifford, Rivière, Tempst, Nolan, Baltimore (1990) Cloning of the p50 DNA binding subunit of NF-κB: homology to rel and dorsal. Cell 62:1019-1029.
Gorman, Merlino, Willingham, Pastan, Howard (1982) The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. Proc. Natl. Acad. Sci. USA 79:6777-6781.
Gorman, Moffat, Howard (1982) Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol. Cell. Biol., 2:1044-1051.
Grilli, Chiu, Lenardo (1993) NF-κB and Rel participants in a multiform transcriptional regulatory system. Int. Rev. Cytol., 148:1-63.
Hannink, Temin (1989) Transactivation of gene expression by nuclear and cytoplasmic rel proteins. Mol. Cell. Biol., 9:4323-4336.
Haskill, Beg, Tompkins, Morris, Yurochko, Sampson-Johannes, Mondal, Ralph, Baldwin (1991) Characterization of an immediate-early gene induced in adherent monocytes that encodes IκB-like activity. Cell 65:1281-1289.
Hatada, Nieters, Wulczyn, Naumann, Meyer, Nucifora, McKeithan, Scheidereit (1992) The ankyrin repeat domains of the NF-κB precursor p105 and the protooncogene bcl-3 act as specific inhibitors of NF-κB DNA binding. Proc. Natl. Acad. Sci. USA 89:2489-2493.
Henkel, Zabel, van Zee, Müller, Fanning, Baeuerle (1992) Intramolecular masking of the nuclear location signal and dimerization domain in the precursor for the p50 NF-κB subunit. Cell 68:1121-1133.
Inoue, Kerr, Ransone, Bengal, Hunter, Verma (1991) c-rel activates but v-rel suppresses transcription from κB sites. Proc. Natl. Acad. Sci. USA 88:3715-3719.
Inoue, Kerr, Rashid, Davis, Bose, Verma (1992) Direct association of pp40/IκBB with rel/NF-κB transcription factors: role of ankyrin repeats in the inhibition of DNA binding activity. Proc. Natl. Acad. Sci. USA 89:4333-4337.
Inoue, Kerr, Kakizuka, Verma (1992) IκBα, a 70 kd protein identical to the C-terminal half of p110 NF-κB: a new member of the IκB family. Cell 68:1109-1120.
Israël, Kaufman (1989) Highly inducible expression from vectors containing multiple GRE's in CHO cells overexpressing the glucocorticoid receptor. Nucleic Acids Research 17:4589-4604.
Kamens, Richardson, Mosialos, Brent, Gilmore (1990) Oncogenic transformation by vRel requires an amino-terminal activation domain. Mol. Cell. Biol., 10:2840-2847.
Kang, Tran, Grilli, Lenardo (1992) NF-κB subunit regulation in nontransformed CD4+ T lymphocytes. Science 256:1452-1456.
Kerr, Inoue, Davis, Link, Baeuerle, Bose, Verma (1991) The Rel-associated pp40 protein prevents DNA binding of Rel and NF-κB: relationship with IκBβ and regulation by phosphorylation. Genes Dev., 5:1464-1476.
Kerr, Duckett, Wamsley, Zhang, Chiao, Nabel, McKeithan, Baeuerle, Verma (1992) The protooncogene BCL-3 encodes an IκB protein. Genes Dev., 6:2352-2363.
Kidd (1992) Characterization of the Drosophila catus locus and analysis of interactions between cactus and dorsal proteins. Cell 71:623-635.
Kieran, Blank, Logeat, Vandekerckhove, Lottspeich, Le Bail, Urban, Kourilsky, Baeuerle, Israël (1990) The DNA binding subunit of NF-κB is identical to factor KBF1 and homologous to the rel oncogene product. Cell 62:1007-1018.
Kretzschmar, Meisterernst, Scheidereit, Li, Roeder (1992) Transcriptional regulation of the HIV-1 promoter by NF-κB in vitro. Genes Dev., 6:761-774.
Kunsch, Ruben, Rosen (1992) Selection of optimal κB/Rel DNA-binding motifs: interaction of both subunits of NF-κB with DNA is required for transcriptional activation. Mol. Cell. Biol., 12:4412-4421.
Liou, Nolan, Ghosh, Fujita, Baltimore (1992) The NF-κB p50 precursor, p105, contains an internal IκB-like inhibitor that preferentially inhibits p50. EMBO J. 11:3003-3009.
Logeat, Israël, Ten, Blank, Le Bail, Kourilsky, Israël (1991) Inhibition of transcription factors belonging to the rel/NF-κB family by a transdominant negative mutant. EMBO J. 10:1827-1832.
Lu, Thompson, Gorski, Rice, Mayer, Yunis (1991) Alterations at the rel locus in human lymphoma. Oncogene 6:1235-1241.
Lux, John, Bennett (1990) Analysis of cDNA human erythrocyte ankyrin indicates a repeated structure with homology to tissue-differentiation and cell cycle control proteins. Nature 344:36-42.
Mercurio, Didonato, Rosette, Karin (1992) Molecular cloning and characterization of a novel Rel/NF-κB family member displaying structural and functional homology to NF-κB p50–p105. DNA Cell Biol., 11:523-537.
Meyer, Hatada, Hohmann, Haiker, Bartsch, Röthlisberger, Lahm, Schlaeger, van Loon, Scheidereit (1991) Cloning of the DNA-binding subunit of human nuclear factor κB: the level of its mRNA is strongly regulated by phorbol ester or tumor necrosis factor α. Proc. Natl. Acad. Sci. USA 88:966-970.
Moore, Bose (1988) Expression of the v-rel oncogene in reticuloendotheliosis virus-transformed fibroblasts. Virology 162:377-387.
Moore, Bose (1988) Transformation of avian lymphoid cells by reticuloendotheliosis virus. Mutat. Res., 195:79-80.
Morin, Gilmore (1992) The C terminus of the NF-κB p50 precursor and an IκB isoform contain transcription activation domains. Nucl. Acids Res., 20:2453-2458.
Nabel, Baltimore (1987) An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326:711-713.
Narayanan, Klement, Ruben, Higgins, Rosen (1992) Identification of a naturally occurring transforming variant of the p65 subunit of NF-κB. Science 256:367-370.
Neumann, Morency, Russian (1987) A novel rapid assay for chloramphenicol acetyltransferase gene expression. Biotechniques 5:444-447.
Nolan, Ghosh, Liou, Tempst, Baltimore (1991) DNA binding and IκB inhibition of the cloned p65 subunit of NF-κB, a rel-related polypeptide. Cell 64:961-969.
Ohno, Takimoto, McKeithan (1990) The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell 60:991-997.
Rice, MacKichan, Israël (1992) The precursor of NF-κB p50 has lκB-like functions. Cell 71:243-253.
Rivière, Blank, Kourilsky, Israël (1991) Processing of the precursor of NF-κB by the HIV-1 protease during acute infection. Nature 350:625-626.
Ruben, Dillon, Schreck, Henkel, Chen, Maher, Baeuerle, Rosen (1991) Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-κB. Science 251:1490-1493.
Ruben, Klement, Coleman, Maher, Chen, Rosen (1992) I-Rel: a novel rel-related protein that inhibits NF-κB transcriptional activity. Genes Dev., 6:745-760.
Ryseck, Bull, Takamiya, Bours, Siebenlist, Dobrzanski, Bravo (1992) RelB, a new rel family transcription activator that can interact with p50-NF-κB. Mol. Cell. Biol., 12:674-684.
Schmid, Perkins, Duckett, Andrews, Nabel (1991) Cloning of an NF-κB subunit which stimulates HIV transcription in synergy with p65. Nature 352:733-736.
Schmitz, Baeuerle (1991) The p65 subunit is responsible for the strong transcription activation potential of NF-κB. EMBO J. 10:3805-3817.
Sen, Baltimore (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46:705-716.
Shimizu, Mitomo, Watanabe, Okamoto, Yamamoto (1990) Involvement of a NF-κB-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol. Cell. Biol., 10:561-568.
Stephens, Rice, Hiebsch, Bose, Gilden (1983) Nucleotide sequence of v-rel: the oncogene of the reticuloendotheliosis virus. Proc. Natl. Acad. Sci. USA 80:6229-6232.
Steward (1987) Dorsal, an embryonic polarity gene in Drosophila, is homologous to the vertebrate proto-oncogene, c-rel. Science 238:692-694.
Sylla, Temin (1986) Activation of oncogenicity of the c-rel proto-oncogene. Mol. Cell. Biol., 6:4709-4716.
Tewari, Dobrzanski, Mohn, Cressman, Hsu, Bravo, Taub (1992) Rapid induction in regenerating liver of RL/IF-1 (an lκB that inhibits NF-κB, RelB-p50, and c-Rel-p50) and PHF, a novel κB site-binding complex. Mol. Cell. Biol., 12:2898-2908.
Thisse, Perrin-Schmitt, Stoetzel, Thisse (1991) Sequence-specific transactivation of the Drosophila twist gene by the dorsal gene product. Cell 65:1191-1201.
Urban, Baeuerle (1990) The 65-kD subunit of NF-κB is a receptor for lκB and a modulator of DNA-binding specificity. Genes Dev., 4:1975-1984.
Urban, Schreck, Baeuerle (1991) NF-κB contacts DNA by a heterodimer of the p50 and p65 subunit. EMBO J. 10:1817-1825.
van Krieken, McKeithan, Raghoebier, Medeiros, Kluin, Raffeld (1990) Chromosomal translocation t(4:19) as indicated by bcl-3 rearrangement is a rare phenomenon in non-Hodgkin's lymphoma and chronic lymphocytic leukemia: a molecular genetic analysis of 176 cases. Leukemia 4:811-812.
Walker, Stein, Ganchi, Hoffman, Kaufman, Ballard, Hannink, Greene (1992) The v-rel oncogene: insights into the mechanisms of transcriptional activation, repression, and transformation. J. Virol., 66:5018-5029.
Wilhelmsen, Eggleton, Temin (1984) Nucleic acid sequence of the oncogene v-rel in reticuloendotheliosis virus strain T and its cellular homolog, the protooncogene c-rel. J. Virol., 52:172-182.
Wulczyn, Naumann, Scheidereit (1992) Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-κB. Nature 358:597-599.
Zabel, Baeuerle (1990) Purified human lκB can rapidly dissociate the complex of the NF-κB transcription factor with its cognate DNA. Cell 61:255-265.
Zabel, Henkel, dos Santos Silva, Baeuerle (1993) Nuclear uptake control of NF-κB by MAD-3, an lκB protein present in the nucleus. EMBO J. 12:201-211.
