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An HLA-B regulatory element binds a factor immunologically related to the upstream stimulation factor

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Abstract

HLA-A and-B are expressed by most cell types, and their levels can be increased by treatment with interferons (IFNs). The relative basal levels of HLA-A and-B expression can vary, and HLA-B loci are induced much more strongly by IFNs. Constitutive activity is dependent on an upstream enhancer (ENH) which contains a rel (KBF, NFκB) binding motif, and induction is mediated by an interferon response element (IRE) which binds members of the IRF family. Reported here is the identification of a regulatory element, ‘R’, which overlaps the IRE of HLA-B loci, but which is absent from the equivalent region of HLA-A or H2 class I genes. The core of the element, CACGAG, is bound by a nuclear factor which is recognized by an antiserum raised against the upstream stimulation factor (USF), a member of the helix-loop-helix/leucine zipper family. The use of reporter gene constructs shows that mutation of the R element results in increased induction by IFNα in some cell lines, which appears to be due to competitive binding of USF with IRF proteins.

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References

  • Baldwin, Jr, A. S., LeClair, K. P., Singh, H., and Sharp, P. A. A large protein containing zinc finger domains binds to related sequence elements in the enhancers of the class I major histocompatibility complex and kappa immunoglobulin genes. Mol Cell Biol 10: 1406–1414, 1990

    Google Scholar 

  • Beckman, H., Su, L.-K, and Kadesch, T. TFE3: A helix-loop-helix protein that activates transcription through the immunoglobulin enhancer μE3 motif. Genes Dev 4: 167–179, 1990

    Google Scholar 

  • Benezra, R., Davis, R. L., Lockshon, D., Turne, D. L., and Wientraub, H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 61: 49–59, 1990

    Google Scholar 

  • Bengal, E., Ransone, L., Scharfmann, R., Dwarki, V. J., Tapscott, S. J., Weintraub, H., and Verma, I. M. Functional antagonism between c-Jun and MyoD proteins: a direct physical interaction. Cell 68: 507–519, 1992

    Google Scholar 

  • Bernards, R., Dessain, S. K., and Weinberg, R. A. N-myc amplification causes down-regulation of MHC class I antigen expression in neuroblastoma. Cell 47: 667–674, 1986

    Google Scholar 

  • Blanchet, O., Bourge, J.-F., Zinszner, H., Israel, A., Kourilsky, P., Dausset, J., Degos, L., and Paul, P. Altered binding of regulatory factors to HLA class I enhancer sequence inhuman tumor cell lines lacking class I antigen expression. Proc Nat Acad Sci USA 89: 3488–3492, 1992

    Google Scholar 

  • Briggs, M. R., Kadonaga, J. T., Bell, S. P., and Tjian, R. Purification and biochemical characterization of the promoter-specific transcription factor, SP1. Science 234: 47–52, 1986

    Google Scholar 

  • Burrone, O. R., Kefford, R. F., Gilmore, D., and Milstein, C. Stimulation of HLA-A, B, C by IFN-alpha. The derivation of Molt4 variants and the differential expression of HLA-A, B, C subsets. EMBO J 4: 2855–2860, 1985

    Google Scholar 

  • Burrone, O. R. and Milstein, C. Control of HLA-A, B, C synthesis and expression in Interferon-treated cells. EMBO J 1: 345–349, 1982

    Google Scholar 

  • Carthew, R. W., Chodosh, L. A., and Sharp, P. A. An RNA polymerase II transcription factor binds to an upstream element in the adenovirus major late promoter. Cell 43: 439–448, 1985

    Google Scholar 

  • David-Watine, B., Israel, A., and Kourilsky, P. The regulation and expression of MHC class I genes. Immunol Today 11: 286–292, 1990

    Google Scholar 

  • Dignam, J. D., Lebovitz, R. M., and Roeder, R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11: 1475–1489, 1983

    Google Scholar 

  • Driggers, P. H., Ennist, D. L., Gleason, S. L., Mak, W.-H., Marks, M. S., B-Z., L., Flanagan, J. R., Apella, E., and Ozato, K. An interferon γ-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc Nat Acad Sci USA 87: 3743–3747, 1990

    Google Scholar 

  • Eager, K. B., Pfizenmaier, K., and Ricciardi, R. P. Modulation of major histocompatibility complex (MHC) class I genes in adenovirus 12 transformed cells: Interferon-γ increases class I expression by a mechanism that circumvents E1A induced-repression and tumor necrosis factor enhances the effect of interferon-γ. Oncogene 4: 39–44, 1989

    Google Scholar 

  • Eager, K. B., Williams, J., Breiding, D., Pan, S., Knowles, B., Appella, E., and Ricciardi, R. P. Expression of histocompatibility antigens H-2K,-D, and-L is reduced in adenovirus-12-transformed mouse cells and is restored by interferon γ. Proc Nat Acad Sci USA 82: 5525–5529, 1985

    Google Scholar 

  • Ephrussi, A., Church, G. M., Tonegawa, S., and Gilbert, W. B. Lineage specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science 227: 134–140, 1985

    Google Scholar 

  • Fisher, D. E., Parent, L. A., and Sharp, P. A. Myc/Max and other helix-loop-helix/leucine zipper proteins bend DNA toward the minor groove. Proc Nat Acad Sci USA 89: 11779–11783, 1992

    Google Scholar 

  • Fisher, F. and Goding,C. R. Single amino acid substitutions alter helix-loop-helix protein specificity from bases flanking the core CANNTG motif. EMBO J 11: 4103–4109, 1992

    Google Scholar 

  • Flanagan, J. R., Murata, M., Burke, P. A., Shirayoshi, Y., Appella, E., Sharp, P. A., and Ozato, K. Negative regulation of the major histocompatibility complex class I promoter in embryonal carcinoma cells. Proc Nat Acad Sci USA 88: 3145–3149, 1991

    Google Scholar 

  • Friedman, R. L., and Stark, G. R. Alpha interferon induces transcription of HLA and metallothionein genes which have homologous upstream sequences. Nature 314: 637–639, 1985

    Google Scholar 

  • Giacca, M., Gutierrez, M. I., Menzo, S., di Fagagna, F. D., and Falaschi, A. A human binding site for transcription factor USF/MLTF mimics the negative regulatory element of human immunodeficiency virus type 1. Virology 186: 133–147, 1992

    Google Scholar 

  • Girdlestone, J. Nucleotide sequence of an HLA-A1 gene. Nucleic Acids Res 18: 6701, 1990

    Google Scholar 

  • Girdlestone, J. and Milstein, C. Differential expression and interferon response of HLA class I genes in thymocyte lines and response variants. Eur J Immunol 18: 139–143, 1988

    Google Scholar 

  • Gussow, D., Rein, R. S., Meijer, I., de Hoog, W., Seemann, G. H. A., Hochstenbach, F.M., Ploegh, H. L Isolation expression and primary structure of HLA-Cw1 and-Cw2 genes: evolutionary aspects. Immunogenetics 25: 313–322, 1987

    Google Scholar 

  • Hakem, R., le Bouteiller, P., Jezo-Bremond, A., Harper, K., Campese, D., and Lemonnier, F. A. Differential regulation of HLA-A3 and HLA-B7 class I genes by IFN is due to two nucleotide differences in their IFN response sequences. J Immunol 147: 2384–2390, 1991

    Google Scholar 

  • Harada, H., Fujita, T., Miyamoto, M., Kimura, Y., Maruyama, M., Furia, A., Miyata, T., and Taniguchi, T. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell 58: 729–739, 1989

    Google Scholar 

  • Henseling, U., Schmidt, W., Scholer, H. R., Gruss, P., and Hatzopoulos, A. K. A transcription factor interacting with the class I gene enhancer is inactive in tumorigenic cell lines which suppress major histocompatibility complex class I genes. Mol Cell Biol 10: 4100–4109, 1990

    Google Scholar 

  • Isamat, M., Girdlestone, J., and Milstein, C. Nucleotide sequence of an HLA-Bw57 gene. Nucleic Acids Res 18: 6702, 1990

    Google Scholar 

  • Israël, A., Kimura, A., Fournier, A., Fellous, M., and Kourilsky, P. Interferon response sequence potentiates activity of an enhancer in the promoter region of a mouse H-2 gene. Nature 322: 743–746, 1986

    Google Scholar 

  • Israel, A., Le Bail, O., Hatat, D., Piette, J., Kieran, M., Logeat, F., Wallach, D., Fellous, M., and Kourilsky, P. TNF stimulates expression of mouse MHC class I genes by inducing an NFκB-like enhancer binding activity which displaces constitutive factors. EMBO J 8: 3793–3800, 1989

    Google Scholar 

  • Jiang, J. and Levine, M. Binding affinities and cooperative interactions with bHLH activators delimit threshold responses to the dorsal gradient morphogen. Cell 72: 741–752, 1993

    Google Scholar 

  • Johnson, D. R. and Pober, J. S. Tumor necrosis factor and immune interferon synergistically increase transcription of HLA class I heavy-and light-chain genes in vascular endothelium. Proc Nat Acad Sci USA 87: 5183–5187, 1990

    Google Scholar 

  • Kadesch, T. Helix-loop-helix proteins in the regulation of immunoglobulin gene transcription. Immunol Today 13: 31–36, 1992

    Google Scholar 

  • Kaklamanis, L., Gatter, K. C., Hill, A. B., Mortenson, N., Harris, A. L., Krausa, P., McMichael, A., Bodmer, J. G., and Bodmer, W. F. Loss of HLA class I alleles, heavy chains and β2-microglobulin in colorectal cancer. Int J Cancer 51: 379–385, 1992

    Google Scholar 

  • Kieran, M., Blank, V., Logeat, F., Vandekerckhove, J., Lottspeich, F., Le Bail, O., Urban, M. B., Kourilsky, P., Baeuerle, P. A., and Israël, A. The DNA binding subunit of NF-κB is identical to factor KBF1 and homologous to the rel oncogene product. Cell 62: 1007–1018, 1990

    Google Scholar 

  • Kimura, A., Israël, A., Le Bail, O., and Kourilsky, P. Detailed analysis of the mouse H-2K b promoter: enhancer-like sequences and their role in the regulation of class I gene expression. Cell 41: 261–272, 1986

    Google Scholar 

  • Kingsley, C. and Winoto, A. Cloning of GT box-binding proteins: a novel Sp1 multigene family regulating T-cell receptor gene expression. Mol Cell Biol 12: 4251–4261, 1992

    Google Scholar 

  • Koller, B. H. and Orr, H. T. Cloning and complete sequence of an HLA-A2 gene: analysis of two HLA-A alleles at the nucleotide level. J Immunol 134: 2727–2733, 1985

    Google Scholar 

  • Lassam, N. and Jay, G. Suppression of MHC class I RNA in highly oncogenic cells occurs at the level of transcription initiation. J Immunol 143: 3792–3797, 1989

    Google Scholar 

  • Lenardo, M., Rustgi, A. K., Schievella, R., and Bernards, R. Suppression of MHC class I gene expression by N-Myc through enhancer inactivation. EMBO J 8: 3351–3355, 1989

    Google Scholar 

  • Li, L., Zhou, J., James, G., Heller-Harrison, R., Czech, M. P., and Olson, E. N. FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains. Cell 71: 1181–1194, 1992

    Google Scholar 

  • Littlewood, T. D., Amati, B., Land, H., and Evan, G. I. Max and c-Myc/Max DNA-binding activities in cell extracts. Oncogene 7: 1783–1792, 1992

    Google Scholar 

  • Lu, Y., Touzjian, N., Stenzel, M., Dorfman, T., Sodroski, J. G., and Haseltine, W. A. Identification of cis-acting repressive sequences within the negative regulatory element of human immunodeficiency virus type 1. J Virol 64: 5226–5229, 1990

    Google Scholar 

  • Luscher, B., Mitchell, P. J., Williams, T., and Tjian, R. Regulation of transcriptional factor AP-2 by the morphogen retinoic acid and by second messengers. Genes Dev 3: 1507–1517, 1989

    Google Scholar 

  • Maschek, U., Pulm, W., Segal, S., and Hammerling, G. J. Major histocompatibility complex class I genes in murine fibrosarcoma IC9 are down regulated at the level of the chromatin structure. Mol Cell Biol 9: 3136–3142, 1989

    Google Scholar 

  • Miyamoto, M., Fujita, T., Kimura, Y., Maruyama, M., Harada, H., Sudo, Y., Miyata, T., and Taniguchi, T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell 54: 903–913, 1988

    Google Scholar 

  • Momburg, F., Ziegler, A., Harpprecht, J., Moller, P., Moldenhauer, G., and Hammerling, G. J. Selective loss of HLA-A or HLA-B antigen expression in colon carcinoma. J Immunol 142: 352–358, 1989

    Google Scholar 

  • Moore, J. P., Hancock, D. C., Littlewood, T. D., and Evan, G. I. A sensitive and quantitative enzyme-linked immunosorbence assay for the c-Myc and N-Myc oncoproteins. Oncogene Res 2: 65–80, 1987

    Google Scholar 

  • N'Guyen, C., Sodoyer, R., Trucy, J., Strachan, T., Jordan, B. R. The HLA-Aw24 gene: sequence, surroundings and comparison with HLA-A2 and-A3. Immunogenetics 21: 479–489, 1985

    Google Scholar 

  • Opelz, G. Effect of HLA matching and transplant survival. Transplant Proc XIX: 641–646, 1987

    Google Scholar 

  • Parham, P., Lawlor, D. A., Lomen, C. E., and Ennis, P. D. Diversity and diversification of HLA-A, B, C alleles. J Immunol 142: 3937–3950, 1989

    Google Scholar 

  • Perkins, N. D., Schmid, R. M., Duckett, C. S., Leung, K., Rice, N. R., and Nabel, G. J. Distinct combinations of NFκB subunits determine the specificity of transcriptional activation. Proc Nat Acad Sci USA 89: 1529–1533, 1992

    Google Scholar 

  • Pognonec, P., and Roeder, R. G. Recombinant 43-kDa USF binds to DNA and activates transcription in a manner indistiguishable from that of natural 43/44-kDa USF. Mol Cell Biol 11: 5125–5136, 1991

    Google Scholar 

  • Roy, A. L., Meisterernst, M., Pognonec, P., and Roeder, R. G. Cooperative interaction of an initiator-binding transcription initiation factor and the helix-loop-helix activator USF. Nature 354: 245–248, 1991

    Google Scholar 

  • Severinsson, L. and Peterson, P. A. Abrogation of cell surface expression of human class I transplantation antigens by an adenovirus protein in Xenopus laevis oocytes. J Cell Biol 101: 540–547, 1985

    Google Scholar 

  • Sugita, K., Miyazaki, J.-I., Appella, E., and Ozato, K. Interferons increase transcription of a major histocompatibility class I gene via a 5′ interferon consensus sequence. Mol Cell Biol 7: 2625–2630, 1987

    Google Scholar 

  • Tanaka, K., Isselbacher, K. J., Khoury, G., and Jay, G. Reversal of oncogenesis by the expression of a major histocompatibility complex class I gene. Science 228: 26–30, 1985

    Google Scholar 

  • Thorogood, J., Persijn, G. G., Schreuder, G. M. T., D'Amaro, J., Zantvoort, F. A., van Houwelingen, J. C., and van Rood, J. J. The effect of HLA matching on kidney graft survival in separate posttransplantation intervals. Transplantation 50: 146–150, 1990

    Google Scholar 

  • Vaessen, R. T. M. J., Houweling, A., and van der Eb, A. J. Post-transcriptional control of class I MHC mRNA expression in adenovirus 12-transformed cells. Science 235: 1486–1488, 1987

    Google Scholar 

  • Versteeg, R., Kruse-Wolters, K. M., Plomp, A. C., van Leeuwen, A., Stam, N. J., Ploegh, H. L., Ruiter, D. J., and Schrier, P. I. Suppression of class I human histocompatibility leukocyte antigen by c-myc is locus specific. J Exp Med 170: 621–635, 1989

    Google Scholar 

  • Versteeg, R., Noordermeer, I. A., Kruse-Wolters, M., Ruiter, D. J., and Schrier, P. I. c-myc down-regulates class I HLA expression in human melanomas. EMBO J 7: 1023–1029, 1988

    Google Scholar 

  • Wallich, R., Bulbuc, N., Hämmerling, G. J., Katzav, S., Segal, S., and Feldman, M. Abrogation of metastatic properties of tumour cells by de novo expression of H-2K antigens following H-2 gene transfection. Nature 315: 301–305, 1985

    Google Scholar 

  • Watts, S., Vogel, J. M., Harriman, W. D., Itoh, T., Stauss, H. J., and Goodenow, R. S. DNA sequence analysis of the C3H H-2K k and H-2D k loci. J Immunol 139: 3878–3885, 1987

    Google Scholar 

  • Weiss, E. H., Kuon, W., Dorner, C., Lang, M., Reithmuller, G. Organization, sequence, and expression of the HLA-B27 gene: a molecular approach to analyze HLA and disease associations. Immunobiology 170: 367–380, 1985

    Google Scholar 

  • Wilson, L. D., Flyer, D. C., and Faller, D. V. Murine retroviruses control class I major histocompatibility antigen gene expression via a trans effect at the transcriptional level. Mol Cell Biol 7: 2406–2415, 1987

    Google Scholar 

  • Xiao, J. H., Davidson, I., Ferrandon, D., Rosales, R., Vigneron, M., Macchi, M., Ruffenach, F., and Chambon, P. One cell-specific and three ubiquitous nuclear proteins bind in vitro to overlapping motifs in the domain B1 of the SV40 enhancer. EMBO J 6: 3005–3013, 1987

    Google Scholar 

  • Zinkernagel, R. M., and Doherty, P. C. MHC restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T cell restriction-specificity, function and responsiveness. Adv Immunol 26: 51–142, 1979

    Google Scholar 

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    John Girdlestone

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Girdlestone, J. An HLA-B regulatory element binds a factor immunologically related to the upstream stimulation factor. Immunogenetics 38, 430–436 (1993). https://doi.org/10.1007/BF00184523

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