Skip to main content
PMC home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1993 Mar 11;21(5):1179–1185. doi: 10.1093/nar/21.5.1179

Downregulation of HLA class I expression by c-myc in human melanoma is independent of enhancer A.

L T Peltenburg 1, R Dee 1, P I Schrier 1
PMCID: PMC309279  PMID: 8464702

Abstract

High constitutive expression of the c-myc oncogene in human melanoma leads to downregulation of expression of HLA Class I genes. The genes at the HLA-B locus are preferentially affected. To investigate the mechanism of downregulation, the activity of the main HLA Class I enhancer, enhancer A-region I, was compared in a panel of c-myc transfectants with increasing myc expression. Gel retardation experiments demonstrated in all tested cell lines binding of the transcription factors KBF1 and NF-kappa B to the enhancer. However, no correlation between the levels of HLA Class I expression and binding to the enhancer could be established. Strikingly, the cell line with the highest c-myc expression showed more binding of KBF1 and NF-kappa B than the parental cell line. By using CAT reporter plasmids in transient transfection assays we investigated the in vivo function of enhancer A-region I in the c-myc transfectant panel. Again, c-myc expression had no effect at all on the activity of enhancer A. This study shows that HLA Class I expression is regulated by the c-myc oncogene at the level of transcription, but that the main HLA Class I enhancer is not involved in this process.

Full text

PDF
1184

Images in this article

1181Image
on p.1181
1181Image
on p.1181
1182Image
on p.1182
1183Image
on p.1183

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baldwin A. S., Jr, Sharp P. A. Binding of a nuclear factor to a regulatory sequence in the promoter of the mouse H-2Kb class I major histocompatibility gene. Mol Cell Biol. 1987 Jan;7(1):305–313. doi: 10.1128/mcb.7.1.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baldwin A. S., Jr, Sharp P. A. Two transcription factors, NF-kappa B and H2TF1, interact with a single regulatory sequence in the class I major histocompatibility complex promoter. Proc Natl Acad Sci U S A. 1988 Feb;85(3):723–727. doi: 10.1073/pnas.85.3.723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernards R., Dessain S. K., Weinberg R. A. N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell. 1986 Dec 5;47(5):667–674. doi: 10.1016/0092-8674(86)90509-x. [DOI] [PubMed] [Google Scholar]
  4. Bernards R. N-myc disrupts protein kinase C-mediated signal transduction in neuroblastoma. EMBO J. 1991 May;10(5):1119–1125. doi: 10.1002/j.1460-2075.1991.tb08052.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bernards R., Schrier P. I., Houweling A., Bos J. L., van der Eb A. J., Zijlstra M., Melief C. J. Tumorigenicity of cells transformed by adenovirus type 12 by evasion of T-cell immunity. 1983 Oct 27-Nov 2Nature. 305(5937):776–779. doi: 10.1038/305776a0. [DOI] [PubMed] [Google Scholar]
  6. Blackwell T. K., Kretzner L., Blackwood E. M., Eisenman R. N., Weintraub H. Sequence-specific DNA binding by the c-Myc protein. Science. 1990 Nov 23;250(4984):1149–1151. doi: 10.1126/science.2251503. [DOI] [PubMed] [Google Scholar]
  7. Blackwood E. M., Eisenman R. N. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science. 1991 Mar 8;251(4998):1211–1217. doi: 10.1126/science.2006410. [DOI] [PubMed] [Google Scholar]
  8. Blanchet O., Bourge J. F., Zinszner H., Israel A., Kourilsky P., Dausset J., Degos L., Paul P. Altered binding of regulatory factors to HLA class I enhancer sequence in human tumor cell lines lacking class I antigen expression. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3488–3492. doi: 10.1073/pnas.89.8.3488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brands J. H., Maassen J. A., van Hemert F. J., Amons R., Möller W. The primary structure of the alpha subunit of human elongation factor 1. Structural aspects of guanine-nucleotide-binding sites. Eur J Biochem. 1986 Feb 17;155(1):167–171. doi: 10.1111/j.1432-1033.1986.tb09472.x. [DOI] [PubMed] [Google Scholar]
  10. Chertkoff L. P., Herrera M., Fainboim L., Satz M. L. Complete nucleotide sequence of a genomic clone encoding HLA-B35 isolated from a Caucasian individual of Hispanic origin. Identification of a new variant of HLA-B35. Hum Immunol. 1991 Jul;31(3):153–158. doi: 10.1016/0198-8859(91)90020-a. [DOI] [PubMed] [Google Scholar]
  11. David-Watine B., Israël A., Kourilsky P. The regulation and expression of MHC class I genes. Immunol Today. 1990 Aug;11(8):286–292. doi: 10.1016/0167-5699(90)90114-o. [DOI] [PubMed] [Google Scholar]
  12. Evan G. I., Lewis G. K., Ramsay G., Bishop J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. doi: 10.1128/mcb.5.12.3610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ganguly S., Vasavada H. A., Weissman S. M. Multiple enhancer-like sequences in the HLA-B7 gene. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5247–5251. doi: 10.1073/pnas.86.14.5247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ghosh S., Gifford A. M., Riviere L. R., Tempst P., Nolan G. P., 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. doi: 10.1016/0092-8674(90)90276-k. [DOI] [PubMed] [Google Scholar]
  15. Girdlestone J. Nucleotide sequence of an HLA-A1 gene. Nucleic Acids Res. 1990 Nov 25;18(22):6701–6701. doi: 10.1093/nar/18.22.6701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Güssow D., Rein R. S., Meijer I., de Hoog W., Seemann G. H., Hochstenbach F. M., Ploegh H. L. Isolation, expression, and the primary structure of HLA-Cw1 and HLA-Cw2 genes: evolutionary aspects. Immunogenetics. 1987;25(5):313–322. doi: 10.1007/BF00404424. [DOI] [PubMed] [Google Scholar]
  17. Hakem R., Le Bouteiller P., Barad M., Trujillo M., Mercier P., Wietzerbin J., Lemonnier F. A. IFN-mediated differential regulation of the expression of HLA-B7 and HLA-A3 class I genes. J Immunol. 1989 Jan 1;142(1):297–305. [PubMed] [Google Scholar]
  18. Henseling U., Schmidt W., Schöler H. R., Gruss P., 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. 1990 Aug;10(8):4100–4109. doi: 10.1128/mcb.10.8.4100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Isamat M., Girdlestone J., Milstein C. Nucleotide sequence of an HLA-Bw57 gene. Nucleic Acids Res. 1990 Nov 25;18(22):6702–6702. doi: 10.1093/nar/18.22.6702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kieran M., Blank V., Logeat F., Vandekerckhove J., Lottspeich F., Le Bail O., Urban M. B., Kourilsky P., Baeuerle P. A., 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. doi: 10.1016/0092-8674(90)90275-j. [DOI] [PubMed] [Google Scholar]
  21. Kimura A., Israël A., Le Bail O., Kourilsky P. Detailed analysis of the mouse H-2Kb promoter: enhancer-like sequences and their role in the regulation of class I gene expression. Cell. 1986 Jan 31;44(2):261–272. doi: 10.1016/0092-8674(86)90760-9. [DOI] [PubMed] [Google Scholar]
  22. Koller B. H., Orr H. T. Cloning and complete sequence of an HLA-A2 gene: analysis of two HLA-A alleles at the nucleotide level. J Immunol. 1985 Apr;134(4):2727–2733. [PubMed] [Google Scholar]
  23. Kretzner L., Blackwood E. M., Eisenman R. N. Myc and Max proteins possess distinct transcriptional activities. Nature. 1992 Oct 1;359(6394):426–429. doi: 10.1038/359426a0. [DOI] [PubMed] [Google Scholar]
  24. Lenardo M., Rustgi A. K., Schievella A. R., Bernards R. Suppression of MHC class I gene expression by N-myc through enhancer inactivation. EMBO J. 1989 Nov;8(11):3351–3355. doi: 10.1002/j.1460-2075.1989.tb08497.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ljunggren H. G., Kärre K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today. 1990 Jul;11(7):237–244. doi: 10.1016/0167-5699(90)90097-s. [DOI] [PubMed] [Google Scholar]
  26. Meijer I., Boot A. J., Mahabir G., Zantema A., van der Eb A. J. Reduced binding activity of transcription factor NF-kappa B accounts for MHC class I repression in adenovirus type 12 E 1-transformed cells. Cell Immunol. 1992 Nov;145(1):56–65. doi: 10.1016/0008-8749(92)90312-d. [DOI] [PubMed] [Google Scholar]
  27. Miyazaki J., Appella E., Ozato K. Negative regulation of the major histocompatibility class I gene in undifferentiated embryonal carcinoma cells. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9537–9541. doi: 10.1073/pnas.83.24.9537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Monaco J. J. A molecular model of MHC class-I-restricted antigen processing. Immunol Today. 1992 May;13(5):173–179. doi: 10.1016/0167-5699(92)90122-N. [DOI] [PubMed] [Google Scholar]
  29. N'Guyen C., Sodoyer R., Trucy J., Strachan T., Jordan B. R. The HLA-AW24 gene: sequence, surroundings and comparison with the HLA-A2 and HLA-A3 genes. Immunogenetics. 1985;21(5):479–489. doi: 10.1007/BF00430931. [DOI] [PubMed] [Google Scholar]
  30. Nielsch U., Zimmer S. G., Babiss L. E. Changes in NF-kappa B and ISGF3 DNA binding activities are responsible for differences in MHC and beta-IFN gene expression in Ad5- versus Ad12-transformed cells. EMBO J. 1991 Dec;10(13):4169–4175. doi: 10.1002/j.1460-2075.1991.tb04995.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Peltenburg L. T., Steegenga W. T., Krüse K. M., Schrier P. I. c-myc-induced natural killer cell sensitivity of human melanoma cells is reversed by HLA-B27 transfection. Eur J Immunol. 1992 Oct;22(10):2737–2740. doi: 10.1002/eji.1830221040. [DOI] [PubMed] [Google Scholar]
  32. Rustgi A. K., Van 't Veer L. J., Bernards R. Two genes encode factors with NF-kappa B- and H2TF1-like DNA-binding properties. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8707–8710. doi: 10.1073/pnas.87.22.8707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schepart B. S., Takahashi H., Cozad K. M., Murray R., Ozato K., Appella E., Frelinger J. A. The nucleotide sequence and comparative analysis of the H-2Dp class I H-2 gene. J Immunol. 1986 May 1;136(9):3489–3495. [PubMed] [Google Scholar]
  34. Schrier P. I., Bernards R., Vaessen R. T., Houweling A., van der Eb A. J. Expression of class I major histocompatibility antigens switched off by highly oncogenic adenovirus 12 in transformed rat cells. 1983 Oct 27-Nov 2Nature. 305(5937):771–775. doi: 10.1038/305771a0. [DOI] [PubMed] [Google Scholar]
  35. Schrier P. I., Peltenburg L. T. Relationship between myc oncogene activation and MHC class I expression. Adv Cancer Res. 1993;60:181–246. doi: 10.1016/s0065-230x(08)60826-x. [DOI] [PubMed] [Google Scholar]
  36. Seed B., Sheen J. Y. A simple phase-extraction assay for chloramphenicol acyltransferase activity. Gene. 1988 Jul 30;67(2):271–277. doi: 10.1016/0378-1119(88)90403-9. [DOI] [PubMed] [Google Scholar]
  37. Singh H., LeBowitz J. H., Baldwin A. S., Jr, Sharp P. A. Molecular cloning of an enhancer binding protein: isolation by screening of an expression library with a recognition site DNA. Cell. 1988 Feb 12;52(3):415–423. doi: 10.1016/s0092-8674(88)80034-5. [DOI] [PubMed] [Google Scholar]
  38. Soong T. W., Hui K. M. Locus-specific transcriptional control of HLA genes. J Immunol. 1992 Sep 15;149(6):2008–2020. [PubMed] [Google Scholar]
  39. Stein B., Rahmsdorf H. J., Steffen A., Litfin M., Herrlich P. UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein. Mol Cell Biol. 1989 Nov;9(11):5169–5181. doi: 10.1128/mcb.9.11.5169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Strachan T., Sodoyer R., Damotte M., Jordan B. R. Complete nucleotide sequence of a functional class I HLA gene, HLA-A3: implications for the evolution of HLA genes. EMBO J. 1984 Apr;3(4):887–894. doi: 10.1002/j.1460-2075.1984.tb01901.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tibensky D., Delovitch T. L. Promoter region of HLA-C genes: regulatory elements common to and different from those of HLA-A and HLA-B genes. Immunogenetics. 1990;32(3):210–213. doi: 10.1007/BF02114976. [DOI] [PubMed] [Google Scholar]
  42. Urban J. L., Schreiber H. Tumor antigens. Annu Rev Immunol. 1992;10:617–644. doi: 10.1146/annurev.iy.10.040192.003153. [DOI] [PubMed] [Google Scholar]
  43. Versteeg R., Krüse-Wolters K. M., Plomp A. C., van Leeuwen A., Stam N. J., Ploegh H. L., Ruiter D. J., Schrier P. I. Suppression of class I human histocompatibility leukocyte antigen by c-myc is locus specific. J Exp Med. 1989 Sep 1;170(3):621–635. doi: 10.1084/jem.170.3.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Versteeg R., Noordermeer I. A., Krüse-Wolters M., Ruiter D. J., Schrier P. I. c-myc down-regulates class I HLA expression in human melanomas. EMBO J. 1988 Apr;7(4):1023–1029. doi: 10.1002/j.1460-2075.1988.tb02909.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Watts S., Vogel J. M., Harriman W. D., Itoh T., Stauss H. J., Goodenow R. S. DNA sequence analysis of the C3H H-2Kk and H-2Dk loci. Evolutionary relationships to H-2 genes from four other mouse strains. J Immunol. 1987 Dec 1;139(11):3878–3885. [PubMed] [Google Scholar]
  46. Weiss E. H., Kuon W., Dörner C., Lang M., Riethmüller G. Organization, sequence and expression of the HLA-B27 gene: a molecular approach to analyze HLA and disease associations. Immunobiology. 1985 Dec;170(5):367–380. doi: 10.1016/S0171-2985(85)80061-9. [DOI] [PubMed] [Google Scholar]
  47. Wenzel A., Cziepluch C., Hamann U., Schürmann J., Schwab M. The N-Myc oncoprotein is associated in vivo with the phosphoprotein Max(p20/22) in human neuroblastoma cells. EMBO J. 1991 Dec;10(12):3703–3712. doi: 10.1002/j.1460-2075.1991.tb04938.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yano O., Kanellopoulos J., Kieran M., Le Bail O., Israël A., Kourilsky P. Purification of KBF1, a common factor binding to both H-2 and beta 2-microglobulin enhancers. EMBO J. 1987 Nov;6(11):3317–3324. doi: 10.1002/j.1460-2075.1987.tb02652.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. van 't Veer L. J., Beijersbergen R. L., Bernards R. N-myc suppresses major histocompatibility complex class I gene expression through down-regulation of the p50 subunit of NF-kappa B. EMBO J. 1993 Jan;12(1):195–200. doi: 10.1002/j.1460-2075.1993.tb05645.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. van 't Veer L. J., Lutz P. M., Isselbacher K. J., Bernards R. Structure and expression of major histocompatibility complex-binding protein 2, a 275-kDa zinc finger protein that binds to an enhancer of major histocompatibility complex class I genes. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):8971–8975. doi: 10.1073/pnas.89.19.8971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. van der Eb A. J., Graham F. L. Assay of transforming activity of tumor virus DNA. Methods Enzymol. 1980;65(1):826–839. doi: 10.1016/s0076-6879(80)65077-0. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES