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Mol Cell Biol. 1993 June; 13(6): 3557–3566.
PMCID: PMC359825

The bcl-3 proto-oncogene encodes a nuclear I kappa B-like molecule that preferentially interacts with NF-kappa B p50 and p52 in a phosphorylation-dependent manner.

Abstract

The product of the putative proto-oncogene bcl-3 is an I kappa B-like molecule with novel binding properties specific for a subset of the rel family of transcriptional regulators. In vitro, Bcl-3 protein specifically inhibited the DNA binding of both the homodimeric NF-kappa B p50 subunit and a closely related homolog, p52 (previously p49), to immunoglobulin kappa NF-kappa B DNA motifs. Bcl-3 could catalyze the removal of these proteins from DNA. At concentrations that significantly inhibited DNA binding by homodimeric p50, Bcl-3 did not inhibit binding of reconstituted heterodimeric NF-kappa B (p50:p65), a DNA-binding homodimeric form of p65, or homodimers of c-Rel. Phosphatase treatment of Bcl-3 partially inactivated its inhibitory properties, implicating a role for phosphorylation in the regulation of Bcl-3 activity. Bcl-3, like p50, localizes to the cell nucleus. In cells cotransduced with Bcl-3 and p50, both molecules could be found in the nucleus of the same cells. Interestingly, coexpression of Bcl-3 with a p50 mutant deleted for its nuclear-localizing signal resulted in the relocalization of Bcl-3 to the cytoplasm, showing that the proteins interact in the cell. These properties contrast Bcl-3 to classically defined I kappa B, which maintains heterodimeric NF-kappa B p50:p65 in the cytoplasm through specific interactions with the p65 subunit. Bcl-3 appears to be a nuclear, I kappa B-related molecule that regulates the activity of homodimeric nuclear p50 and its homolog p52.

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  • Aves SJ, Durkacz BW, Carr A, Nurse P. Cloning, sequencing and transcriptional control of the Schizosaccharomyces pombe cdc10 'start' gene. EMBO J. 1985 Feb;4(2):457–463. [PubMed]
  • Baeuerle PA, Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science. 1988 Oct 28;242(4878):540–546. [PubMed]
  • Beg AA, Ruben SM, Scheinman RI, Haskill S, Rosen CA, Baldwin AS., Jr I kappa B interacts with the nuclear localization sequences of the subunits of NF-kappa B: a mechanism for cytoplasmic retention. Genes Dev. 1992 Oct;6(10):1899–1913. [PubMed]
  • Blank V, Kourilsky P, Israël A. Cytoplasmic retention, DNA binding and processing of the NF-kappa B p50 precursor are controlled by a small region in its C-terminus. EMBO J. 1991 Dec;10(13):4159–4167. [PubMed]
  • Breeden L, Nasmyth K. Similarity between cell-cycle genes of budding yeast and fission yeast and the Notch gene of Drosophila. Nature. 1987 Oct 15;329(6140):651–654. [PubMed]
  • Coffman C, Harris W, Kintner C. Xotch, the Xenopus homolog of Drosophila notch. Science. 1990 Sep 21;249(4975):1438–1441. [PubMed]
  • Davis N, Ghosh S, Simmons DL, Tempst P, Liou HC, Baltimore D, Bose HR., Jr Rel-associated pp40: an inhibitor of the rel family of transcription factors. Science. 1991 Sep 13;253(5025):1268–1271. [PubMed]
  • Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991 Aug 23;66(4):649–661. [PubMed]
  • Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K, Siebenlist U. The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition. Nature. 1992 Sep 24;359(6393):339–342. [PubMed]
  • Fujita T, Nolan GP, Ghosh S, Baltimore D. Independent modes of transcriptional activation by the p50 and p65 subunits of NF-kappa B. Genes Dev. 1992 May;6(5):775–787. [PubMed]
  • Ghosh S, Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature. 1990 Apr 12;344(6267):678–682. [PubMed]
  • Ghosh S, Gifford AM, Riviere LR, Tempst P, Nolan GP, Baltimore D. Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal. Cell. 1990 Sep 7;62(5):1019–1029. [PubMed]
  • Gilmore TD. Malignant transformation by mutant Rel proteins. Trends Genet. 1991 Oct;7(10):318–322. [PubMed]
  • Goebl M, Yanagida M. The TPR snap helix: a novel protein repeat motif from mitosis to transcription. Trends Biochem Sci. 1991 May;16(5):173–177. [PubMed]
  • Haskill S, Beg AA, Tompkins SM, Morris JS, Yurochko AD, Sampson-Johannes A, Mondal K, Ralph P, Baldwin AS., Jr Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell. 1991 Jun 28;65(7):1281–1289. [PubMed]
  • Henkel T, Zabel U, van Zee K, Müller JM, Fanning E, Baeuerle PA. Intramolecular masking of the nuclear location signal and dimerization domain in the precursor for the p50 NF-kappa B subunit. Cell. 1992 Mar 20;68(6):1121–1133. [PubMed]
  • Inoue J, Kerr LD, Kakizuka A, Verma IM. I kappa B gamma, a 70 kd protein identical to the C-terminal half of p110 NF-kappa B: a new member of the I kappa B family. Cell. 1992 Mar 20;68(6):1109–1120. [PubMed]
  • Israël A, Kimura A, Kieran M, Yano O, Kanellopoulos J, Le Bail O, Kourilsky P. A common positive trans-acting factor binds to enhancer sequences in the promoters of mouse H-2 and beta 2-microglobulin genes. Proc Natl Acad Sci U S A. 1987 May;84(9):2653–2657. [PubMed]
  • Kang SM, Tran AC, Grilli M, Lenardo MJ. NF-kappa B subunit regulation in nontransformed CD4+ T lymphocytes. Science. 1992 Jun 5;256(5062):1452–1456. [PubMed]
  • Kerr LD, Inoue J, Davis N, Link E, Baeuerle PA, Bose HR, Jr, Verma IM. The rel-associated pp40 protein prevents DNA binding of Rel and NF-kappa B: relationship with I kappa B beta and regulation by phosphorylation. Genes Dev. 1991 Aug;5(8):1464–1476. [PubMed]
  • Kerr LD, Duckett CS, Wamsley P, Zhang Q, Chiao P, Nabel G, McKeithan TW, Baeuerle PA, Verma IM. The proto-oncogene bcl-3 encodes an I kappa B protein. Genes Dev. 1992 Dec;6(12A):2352–2363. [PubMed]
  • Kidd S. Characterization of the Drosophila cactus locus and analysis of interactions between cactus and dorsal proteins. Cell. 1992 Nov 13;71(4):623–635. [PubMed]
  • Kieran M, Blank V, Logeat F, Vandekerckhove J, Lottspeich F, Le Bail O, Urban MB, Kourilsky P, Baeuerle PA, Israël A. The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell. 1990 Sep 7;62(5):1007–1018. [PubMed]
  • Lenardo MJ, Fan CM, Maniatis T, Baltimore D. The involvement of NF-kappa B in beta-interferon gene regulation reveals its role as widely inducible mediator of signal transduction. Cell. 1989 Apr 21;57(2):287–294. [PubMed]
  • Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol. 1990 May;10(5):2327–2334. [PMC free article] [PubMed]
  • Liou HC, Nolan GP, Ghosh S, Fujita T, Baltimore D. The NF-kappa B p50 precursor, p105, contains an internal I kappa B-like inhibitor that preferentially inhibits p50. EMBO J. 1992 Aug;11(8):3003–3009. [PubMed]
  • Lux SE, John KM, Bennett V. Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue-differentiation and cell-cycle control proteins. Nature. 1990 Mar 1;344(6261):36–42. [PubMed]
  • Nabel G, Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. [PubMed]
  • Neri A, Chang CC, Lombardi L, Salina M, Corradini P, Maiolo AT, Chaganti RS, Dalla-Favera R. B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell. 1991 Dec 20;67(6):1075–1087. [PubMed]
  • Nolan GP, Baltimore D. The inhibitory ankyrin and activator Rel proteins. Curr Opin Genet Dev. 1992 Apr;2(2):211–220. [PubMed]
  • Nolan GP, Ghosh S, Liou HC, Tempst P, Baltimore D. DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell. 1991 Mar 8;64(5):961–969. [PubMed]
  • Ohno H, Takimoto G, McKeithan TW. The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell. 1990 Mar 23;60(6):991–997. [PubMed]
  • Schmid RM, Perkins ND, Duckett CS, Andrews PC, Nabel GJ. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature. 1991 Aug 22;352(6337):733–736. [PubMed]
  • Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986 Dec 26;47(6):921–928. [PubMed]
  • Shinnick TM, Lerner RA, Sutcliffe JG. Nucleotide sequence of Moloney murine leukaemia virus. Nature. 1981 Oct 15;293(5833):543–548. [PubMed]
  • Stall AM, Fariñas MC, Tarlinton DM, Lalor PA, Herzenberg LA, Strober S, Herzenberg LA. Ly-1 B-cell clones similar to human chronic lymphocytic leukemias routinely develop in older normal mice and young autoimmune (New Zealand Black-related) animals. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7312–7316. [PubMed]
  • Ten RM, Paya CV, Israël N, Le Bail O, Mattei MG, Virelizier JL, Kourilsky P, Israël A. The characterization of the promoter of the gene encoding the p50 subunit of NF-kappa B indicates that it participates in its own regulation. EMBO J. 1992 Jan;11(1):195–203. [PubMed]
  • Tewari M, Dobrzanski P, Mohn KL, Cressman DE, Hsu JC, Bravo R, Taub R. Rapid induction in regenerating liver of RL/IF-1 (an I kappa B that inhibits NF-kappa B, RelB-p50, and c-Rel-p50) and PHF, a novel kappa B site-binding complex. Mol Cell Biol. 1992 Jun;12(6):2898–2908. [PMC free article] [PubMed]
  • Urban MB, Baeuerle PA. The 65-kD subunit of NF-kappa B is a receptor for I kappa B and a modulator of DNA-binding specificity. Genes Dev. 1990 Nov;4(11):1975–1984. [PubMed]
  • Van Etten RA, Jackson P, Baltimore D. The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization. Cell. 1989 Aug 25;58(4):669–678. [PubMed]
  • Weinmaster G, Roberts VJ, Lemke G. A homolog of Drosophila Notch expressed during mammalian development. Development. 1991 Sep;113(1):199–205. [PubMed]
  • Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell. 1985 Dec;43(3 Pt 2):567–581. [PubMed]
  • Wulczyn FG, Naumann M, Scheidereit C. Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B. Nature. 1992 Aug 13;358(6387):597–599. [PubMed]
  • Yochem J, Greenwald I. glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins. Cell. 1989 Aug 11;58(3):553–563. [PubMed]
  • Zabel U, Baeuerle PA. Purified human I kappa B can rapidly dissociate the complex of the NF-kappa B transcription factor with its cognate DNA. Cell. 1990 Apr 20;61(2):255–265. [PubMed]

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