Skip to main content
SpringerLink
Log in

The transcription factor, Bright, and immunoglobulin heavy chain expression

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Bright, or B cell regulator of immunoglobulin heavy chain transcription, is a B lymphocyte-specific protein first discovered for its ability to increase immunoglobulin transcription three-to sevenfold in antigen-activated B cells. It interacts with DNA through an ARID, or A/T-rich interaction domain, and is the only member of a previously undescribed family of DNA-binding proteins for which target genes have been identified. The mechanisms(s) by which Bright facilitatestran scription are unknown. Several proteins that associate with Bright may shed light upon its function. These include the nuclear matrix proteins sp 100 and LYSp 100B, and suggest that Bright may affect chromatin configuration and nuclear sublocalization. Furthermore, Bruton's tyrosine kinase is required for Bright binding activity, suggesting links between Bright, cell signaling cascades, and X-linked immunodeficiency disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Georgopoulos K: Transcription factors required for lymphoid, lineage commitment. Curr Opin Immunol 1997;9(2):222–227.

    Article  PubMed  CAS  Google Scholar 

  2. Desiderio S: Transcription factors controlling B-cell development. Curr Biol 1995:5:605–608.

    Article  PubMed  CAS  Google Scholar 

  3. Shinkai Y, Rathbun G, Lam K-P et al.: RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 1992;68:855–867.

    Article  PubMed  CAS  Google Scholar 

  4. Spanopoulou E, Roman CAJ, Corcoran LM et al.: Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes & Dev 1994;8:1030–1042.

    Article  CAS  Google Scholar 

  5. Lam KP, Kühn R, Rajewsky K: In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 1997;90(6): 1073–1083.

    Article  PubMed  CAS  Google Scholar 

  6. Kerner JD, Appleby MW, Mohr RN et al.: Impaired expansion of mouse B cell progenitors lacking Btk. Immunity 1995;3:301–312.

    Article  PubMed  CAS  Google Scholar 

  7. Khan WN, Alt FW, Gerstein RM et al.: Defective B cell development and function in Btk-deficient mice. Immunity 1995;3: 283–299.

    Article  PubMed  CAS  Google Scholar 

  8. Leitges M, Schmedt C, Guinamard R et al.: Immunodeficiency in protein kinase Cβ-deficientmice. Science 1996;273:788–791.

    Article  PubMed  CAS  Google Scholar 

  9. Pappu R, Cheng AM, Li B et al.: Requirement for B cell linker protein (BLNK) in B cell development. Science 1999;286 (5446): 1949–1954.

    Article  PubMed  CAS  Google Scholar 

  10. Kurosaki T, Tsukada S: BLNK: Connecting Sykand Btk to calcium signals. Immunity 2000;12(1):1–5.

    Article  PubMed  CAS  Google Scholar 

  11. Petro JB, Rahman SMJ, Ballard DW, Khan WN: Bruton's tyrosine kinase is required for activation of 1kappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. Journal of Experimental Medicine 2000;191(10): 1745–1753.

    Article  PubMed  CAS  Google Scholar 

  12. Feldhaus AL, Klug CA, Arvin KL, Singh H: Targeted disruption of the Oct-2 locus in a B cell provides genetic evidence for two distinct cell type-specific pathways of octamer element-mediated gene activation. EMBO J 1993; 12: 2763–2772.

    PubMed  CAS  Google Scholar 

  13. Corcoran LM, Karvelas M, Nossal GJV, Ye Z-S, Jacks T, Baltimore D: Oct-2, although not required for early B-cell development, is critical for later B-cell maturation and for postnata 1 survival. Genes Dev 1993;7:570–582.

    Article  PubMed  CAS  Google Scholar 

  14. Kim U, Qin X-F, Gong S et al.: The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes. Nature 1996;383:542–547.

    Article  PubMed  CAS  Google Scholar 

  15. Schubart DB, Rolink A, Kosco-Vilbois MH, Botteri F, Matthias P: B-cell-specific coativator OB F-1/QCA-B/B ob 1 required for immune response and germinal centre formation. Nature 1996; 383:538–542.

    Article  PubMed  CAS  Google Scholar 

  16. Tumas-Brundage K, Manser T: The transcriptional promoter regulates hypermutation of the antibody heavy chain locus. J Exp Med 1997;185:239–250.

    Article  PubMed  CAS  Google Scholar 

  17. Webb CF, Smith EA, Medina KL, Buchanan KL, Smithson G, Dou S: Expression of Bright and two distinctstages of B lymphocyte development. J Immunol 1998;160: 4747–4754.

    PubMed  CAS  Google Scholar 

  18. Webb CF, Das C, Coffman RL, Tucker PW: Induction of immunoglobulin, μ mRNA in a B cell transfectant stimulated with interleukin-5 and a T-dependentantigen. J Immunol 1989;143:3934–3939.

    PubMed  CAS  Google Scholar 

  19. Webb CF, Das C, Eaton S, Calame K, Tucker PW: Novelprotein-DNA interactions associated with increased immunoglobulin transcription in response to antigen plus interleukin-5. Mol Cell Biol 1991;11:5197–5205.

    PubMed  CAS  Google Scholar 

  20. Herrscher RF, Kaplan MH, Lelsz DL, Das C, Scheuermann R, Tucker PW: The immunoglobulin heavy-chain matrix-associating regions are bound by Bright: a B cell-specific trans-activator that describesa new DNA-binding protein family. Genes Dev 1995;9: 3067–3082.

    Article  PubMed  CAS  Google Scholar 

  21. Malone CS, Patrone L, Buchanan KL, Webb C, Wall R: An upstream Oct-1 and Oct-2 binding silencer governs B 29, (Igβ) gene expression. J Immunol 2000;164: 2550–2556.

    PubMed  CAS  Google Scholar 

  22. Zong RT, Das C, Tucker PW: Regulation of matrix attachment region-dependent, lymphocyte-restricted transcription through differential localization within promyelocytic leukemia nuclear bodies. EMBO J 2000;19(15): 4123–4133.

    Article  PubMed  CAS  Google Scholar 

  23. Wang Z, Goldstein A, Zong R-T et al.: Cus/CDP homeoprotein is a component of NF-μNR and represses the immunoglobulin heavy chain intronic enhancer by antagonizing the Bright transcription activator. Mol Cell Biol 1999;19:284–295.

    PubMed  CAS  Google Scholar 

  24. Webb C, Zong R-T, Lin D et al.: Differential regulation of immunoglobulin gene transcription via nuclear matrix-associated regions. Cold Spring Harbor Symp Quant Biol 1999;LXIV:109.

    Article  Google Scholar 

  25. Gregory SL, Kortschak RD, Kalionis B, Saint R: Characterization of the dead ringer gene identifies a novel, highly conserved family of sequence-specific DNA-binding proteins. Mol Cell Biol 1996;16: 792–799.

    PubMed  CAS  Google Scholar 

  26. Kortschak RD, Reimann H, Zimmer M, Eyre HJ, Saint R, Jenne DE: The human dead ringer brighthomolog, DRILI: cDNA cloning, gene structure, and mapping to D19S886, a marker on 19pl 3.3 that is strictly linked to the Peutz-Jeghers syndrome. Genomics 1998;51(2):288–292.

    Article  PubMed  CAS  Google Scholar 

  27. Numata S, Claudio PP, Dean C, Giordano A, Croce CM: Bdp, a new member of a family of DNA-binding proteins, associates with the retinoblastoma gene product. Cancer Res 1999;59(15): 3741–3747.

    PubMed  CAS  Google Scholar 

  28. Iwahara J, Clubb RT: Bolution structure of the DNA binding domain from dead ringer, a sequence-specific AT-rich interaction domain (ARID). EMBO J 1999;18:6084–6094.

    Article  PubMed  CAS  Google Scholar 

  29. Webb CF, Das C, Eneff KL, Tucker PW: Identification of a matrix-associated region 5' of animmunoglobulin heavy chain variable region gene. Mol Cell Biol 1991; 11:5206–5211.

    PubMed  CAS  Google Scholar 

  30. Garrard WT: Chromosomal loop organtization, in eukaryotic genomes. Nucleic Acids & Mol Bio 19 A.D.; 4:1–28.

  31. Oancea AE, Berru M, Shulman MJ: Expression of the (recombinant) endogenous immunoglobulin heavy-chain locus requires the intronic matrix attachment regions. Mol Cell Biol 1997;17:2658–2668.

    PubMed  CAS  Google Scholar 

  32. Forrester WC, van Genderen C, Jenuwein T, Grosschedl R. Dependence of enhancer-mediated transcription of the immunoglobulin μ gene on nuclear matrix attachment regions. Science 1994;265: 1221–1225.

    Article  PubMed  CAS  Google Scholar 

  33. Jenuwein T, Forrester WC, Fernandez-Herrero LA, Laible G, Dull M, Grosschedl R: Extension of chromatin accessibility by nuclear matrix attachment regions. Nature 1997;385:269–272.

    Article  PubMed  CAS  Google Scholar 

  34. Serwe M, Sablitzky F: V(D)J recombination in B cells is impaired but not blocked by targeted deletion of the immunoglobulin heavy chain intron enhancer. EMBO J 1993;12:2321–2327.

    PubMed  CAS  Google Scholar 

  35. Sakai E, Bottaro A, Davidson L, Sleckman BP, Alt FW: Recombination and transcription of the endogenous Ig heavy chain locus is effected by the 1g heavy chain intronic enhancer core region in the absence of the matrix attachment regions. Proc Natl Acad Sci USA 1999;96(4):1526–1531.

    Article  PubMed  CAS  Google Scholar 

  36. Scheuermann RH, Garrard WT: MARs of antigen receptor and coreceptor genes. Critical Reviews in Eukaryotic Gene Expression 1999;9:295–310.

    PubMed  CAS  Google Scholar 

  37. Webb CF, Eneff KL, Drake FH: A topoisomerase 11-like protein is part of an inducible DNA-binding protein complex that binds 5′ of an immunoglobulin promoter. Nuc Acids Res 1993;21:4363–4368.

    Article  CAS  Google Scholar 

  38. Scheuermann RH, Chen U: A developmental-specific factor binds to supressor sites flanking the immunoglobulin heavy-chain enhancer. Genes Dev 1989;3: 1255–1266.

    Article  PubMed  CAS  Google Scholar 

  39. Dent AL, Yewdell J, Puvion-Dutilleul F, Koken MHM, de The H, Staudt LM: LYSP100-associated nuclear domains (LANDs): Description of a new class of subnuclear structures and their relationship to PML nuclear bodies. Blood 1996;88:1423–1436.

    PubMed  CAS  Google Scholar 

  40. Lipinski MM, Jacks T: The retinoblastoma gene family in differentiation and development. Oncogene 1999;18(55):7873–7882.

    Article  PubMed  CAS  Google Scholar 

  41. Webb CF, Yamashita, Y, Ayers N et al.: The transcription factor Bright associates with Bruton's tyrosine kinase, the defective protein in immunodeficiency disease. J Immunol 2000;165:6956–6965.

    PubMed  CAS  Google Scholar 

  42. Tsukada S, Saffran DC, Rawlings DJ et al.: Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993;72: 279–290.

    Article  PubMed  CAS  Google Scholar 

  43. Vetrie D, Vorechovsky I, Sideras P et al.: The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993;361:226–233.

    Article  PubMed  CAS  Google Scholar 

  44. Conley ME, Parolini O, Rohrer J, Campana D: X-linked agammaglobulinemia: New approaches to old questions based on the identification of the defective gene. Immunol Rev 1994;138:5–21.

    Article  PubMed  CAS  Google Scholar 

  45. Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J: Mutations in Btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet 1998;62(5): 1034–1043.

    Article  PubMed  CAS  Google Scholar 

  46. Rawlings DJ, Saffran DC, Tsukada S et al.: Mutation of the unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science 1993;261:358–361.

    Article  PubMed  CAS  Google Scholar 

  47. Thomas JD, Sideras P, Smith CIE, Vorechovsky I, Chapman V, Paul WE: Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 1993;261:355–358.

    Article  PubMed  CAS  Google Scholar 

  48. de Weers M, Verschuren MCM, Mensink RGJ, Schuunnan RKB, van Dongen JJM, Hendriks RW: The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. Eur J Immunol 1993;23:3109–3114.

    Article  PubMed  Google Scholar 

  49. Fukuda M, Kojima T, Kabayama H, Mikoshiba K: Mutation of the pleckstrin homology domain of Bruton's tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-tetrakisphosphate binding capacity. J Biol Chem 1996;271: 30303–30306.

    Article  PubMed  CAS  Google Scholar 

  50. Kojima T, Fukuda M, Watanabe Y, Hamazato F, Mikoshiba K: Characterization of the pleckstrin homology domain of Btk as an inositol polyphosphate and phosphoinositide binding domain. Biochem Biophys Res Commun 1997;236(2):333–339.

    Article  PubMed  CAS  Google Scholar 

  51. Hyvonen M, Saraste M: Structure of the PH domain and btk motif from Bruton's tyrosine kinase: molecular explanations for X-linked agammaglobulinemia. EMBO J 1997;16:3396–3404.

    Article  PubMed  CAS  Google Scholar 

  52. Yao L, Kawakami Y, Kawakami T: The pleckstrin homology domain of Bruton tyrosine kinase interacts with protein kinase C. Proc Natl Acad Sci USA 1994;91:9175–9179.

    Article  PubMed  CAS  Google Scholar 

  53. Tsukada S, Simon MI, Witte ON, Katz A: Binding of beta gamma subunits of heterotrimeric G proteins to the PH domain of Bruton tyrosine kinase. Proc Natl Acad Sci USA 1994;91:11256–11260.

    Article  PubMed  CAS  Google Scholar 

  54. Yang WY, Desiderio S: BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement. Proc Natl Acad Sci USA 1997;94:604–609.

    Article  PubMed  CAS  Google Scholar 

  55. Guinamard R, Fougereau M, Seckinger P: The SH3 domain of Bruton's tyrosine kinase interacts with Vav, Sam68 and EWS. Scandinavian Journal of Immunology 1997;45(6):587–595.

    Article  PubMed  CAS  Google Scholar 

  56. Cheng G, Ye Z-S, Baltimore D: Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction. Proc Natl Acad Sci USA 1994;91:8152–8155.

    Article  PubMed  CAS  Google Scholar 

  57. Yang W, Malek SN, Desiderio S: An SH3-binding site conserved in Bruton's tyrosine kinase and related tyrosine kinases mediates specific protein interactions in vitro and in vivo. J Biol Chem 1995;270:20832–20840.

    Article  PubMed  CAS  Google Scholar 

  58. Aoki Y, Isselbacher KJ, Pillai S: Bruton tyrosine kinase is tyrosine phosphorylated and activated in pre-B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci USA 1994;91:10606–10609.

    Article  PubMed  CAS  Google Scholar 

  59. Sato S, Katagiri T, Takaki S et al.: IL-5 receptor-mediated tyrosine phosphorylation of SH2/SH3-containing proteins and activation of Bruton's tyrosine and Janus 2 kinases. J Exp Med 1994;180: 2101–2111.

    Article  PubMed  CAS  Google Scholar 

  60. Vihinen M, Nore BF, Mattsson PT et al.: Missense mutations affecting a conserved cysteine pair in the TH domain of Btk. FEBS Lett 1997;413(2):205–210.

    Article  PubMed  CAS  Google Scholar 

  61. Mohamed AJ, Vargas L, Nore BF, Backesjo CM, Christensson B, Smith CI: Nucleocytoplasmic shuttling of Bruton's tyrosine kinase. J Biol Chem 2000; 275(51):40614–40619.

    Article  PubMed  CAS  Google Scholar 

  62. 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;58: 669–678.

    Article  PubMed  Google Scholar 

  63. Roy AL, Du H, Gregor PD, Novina CD, Martinez E, Roeder RG: Cloning of an Inr- and E-box-binding protein, TFII-1, that interacts physically and functionally with USF1. EMBO J 1997;16: 7091–7104.

    Article  PubMed  CAS  Google Scholar 

  64. Roy AL, Malik S, Meisterenst M, Roeder RG: An alternative pathway for transcription initiation involving TFII-1. Nature 1993;365: 355–359.

    Article  PubMed  CAS  Google Scholar 

  65. Manzano-Winkler B, Novina CD, Roy AL: TFII is required for transcription of the naturally TATA-less but initiator-containing VBeta promoter. J Biol Chem 1996;271: 12076–12081.

    Article  PubMed  CAS  Google Scholar 

  66. Cheriyath V, Novina CD, Roy AL: TFII-1 regulates Vβ promoter activity through an initiator element. Mol Cell Biol 1998;18:4444–4454.

    PubMed  CAS  Google Scholar 

  67. Novina CD, Cheriyath V, Roy AL: Regulation of TFII-1 activity by phosphorylation. J Biol Chem 1998;273(50):33443–33448.

    Article  PubMed  CAS  Google Scholar 

  68. Buchanan KL, Hodgetts SE, Byrnes J, Webb CF: Differential transcription efficiency of two Ig VH promoters in vitro. J Immunol 1995;155:4270–4277.

    PubMed  CAS  Google Scholar 

  69. Buchanan KL, Smith EA, Dou S, Corcoran LM, Webb CF: Family-specific differences in transcription efficiency of Ig heavy-chain promoters. J Immunol 1997;159: 1247–1254.

    PubMed  CAS  Google Scholar 

  70. Brown M, Stenzel-poore M, Rittenberg M: Immunologic memory to phosphocholine VII. Lack of T15V1 gene utilization in Xidanti-PC hybridomas. J Immunol 1985;135:3558–3563.

    PubMed  CAS  Google Scholar 

  71. Scher I: The CBA/N mouse strain: An experimental model illustrating the influence of the x-chromosome on immunity. Adv Immunol 1982;33:1–71.

    Article  PubMed  CAS  Google Scholar 

  72. Zhang K: Immunoglobulin class switch recombination machinery: Progress and challenges. Clin Immunol 2000;95(1 PT 1):1–8.

    Article  PubMed  CAS  Google Scholar 

  73. Roy AL, Meisterernst M, Pognonec P, Roeder RG: Cooperative interaction of an initiator-binding transcription initiation factor and the helix-loop-helix activator USF. Nature 1991;354:245–248.

    Article  PubMed  CAS  Google Scholar 

  74. Kim DW, Cheriyath V, Roy AL, Cochran BH: TFII-1 enhances activation of the c-fos promoter through interactions with upstream elements. Mol Cell Biol 1998; 18(6):3310–3320.

    PubMed  CAS  Google Scholar 

  75. Myung PS, Boerthe NJ, Koretzky GA: Adapter proteins in lymphocyte antigen-receptor signaling. Curr Opin Immunol 2000;12(3): 256–266.

    Article  PubMed  CAS  Google Scholar 

  76. Vihinen M, Brandau O, Brandén LJ et al.: BTK base, mutation database for X-linked agammaglobulinemia (XLA). Nuc Acids Res 1998;26(1):242–247

    Article  CAS  Google Scholar 

  77. Holinski-Feder E, Weiss M, Brandau O et al.: Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics 1998;101(2):276–284.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Carol F. Webb

    Present address: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 3104, Oklahoma City, Oklahoma

Authors and Affiliations

    Authors
    1. Carol F. Webb
      View author publications

      You can also search for this author in PubMed Google Scholar

    Rights and permissions

    Reprints and permissions

    About this article

    Cite this article

    Webb, C.F. The transcription factor, Bright, and immunoglobulin heavy chain expression. Immunol Res 24, 149–161 (2001). https://doi.org/10.1385/IR:24:2:149

    Download citation

    • Issue Date:

    • DOI: https://doi.org/10.1385/IR:24:2:149

    Key Words

    Search

    Navigation