Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1993 Jan;12(1):195–200. doi: 10.1002/j.1460-2075.1993.tb05645.x

N-myc suppresses major histocompatibility complex class I gene expression through down-regulation of the p50 subunit of NF-kappa B.

L J van 't Veer 1, R L Beijersbergen 1, R Bernards 1
PMCID: PMC413191  PMID: 8428579

Abstract

In neuroblastoma, N-myc suppresses the expression of major histocompatibility complex (MHC) Class I antigens by reducing the binding of a nuclear factor to the enhancer-A element in the MHC Class I gene promoter. We show here that the p50 subunit of NF-kappa B is part of this complex and that expression of p50 mRNA is suppressed by N-myc. Transfection of a p50 expression vector in neuroblastoma cells that express N-myc at a high level leads to restoration of factor binding to the MHC Class I gene enhancer, restores enhancer activity and leads to re-expression of MHC Class I antigens at the cell surface. These data indicate that the p50 subunit of NF-kappa B is involved in the regulation of MHC Class I antigen expression and that N-myc down-regulates MHC Class I gene expression primarily through suppression of p50 expression.

Full text

PDF

Images in this article

Selected References

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

  1. Baeuerle P. A. The inducible transcription activator NF-kappa B: regulation by distinct protein subunits. Biochim Biophys Acta. 1991 Apr 16;1072(1):63–80. doi: 10.1016/0304-419x(91)90007-8. [DOI] [PubMed] [Google Scholar]
  2. Baldwin A. S., Jr, LeClair K. P., Singh H., 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. 1990 Apr;10(4):1406–1414. doi: 10.1128/mcb.10.4.1406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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. doi: 10.1002/j.1460-2075.1991.tb04994.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Blank V., Kourilsky P., Israël A. NF-kappa B and related proteins: Rel/dorsal homologies meet ankyrin-like repeats. Trends Biochem Sci. 1992 Apr;17(4):135–140. doi: 10.1016/0968-0004(92)90321-y. [DOI] [PubMed] [Google Scholar]
  10. Bours V., Burd P. R., Brown K., Villalobos J., Park S., Ryseck R. P., Bravo R., Kelly K., Siebenlist U. A novel mitogen-inducible gene product related to p50/p105-NF-kappa B participates in transactivation through a kappa B site. Mol Cell Biol. 1992 Feb;12(2):685–695. doi: 10.1128/mcb.12.2.685. [DOI] [PMC free article] [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. Fan C. M., Maniatis T. A DNA-binding protein containing two widely separated zinc finger motifs that recognize the same DNA sequence. Genes Dev. 1990 Jan;4(1):29–42. doi: 10.1101/gad.4.1.29. [DOI] [PubMed] [Google Scholar]
  13. Fujita T., Nolan G. P., 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. doi: 10.1101/gad.6.5.775. [DOI] [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. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  16. Hall C. V., Jacob P. E., Ringold G. M., Lee F. Expression and regulation of Escherichia coli lacZ gene fusions in mammalian cells. J Mol Appl Genet. 1983;2(1):101–109. [PubMed] [Google Scholar]
  17. Henkel T., Zabel U., van Zee K., Müller J. M., Fanning E., Baeuerle P. A. 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. doi: 10.1016/0092-8674(92)90083-o. [DOI] [PubMed] [Google Scholar]
  18. Hémar A., Barrand P., Ferrer M., Cornet V., Buttin G., Dautry-Varsat A. Activity of the kappa B enhancer of the interleukin-2 receptor alpha chain in somatic cell hybrids is accompanied by the nuclear localization of NF-kappa B. New Biol. 1991 Nov;3(11):1097–1105. [PubMed] [Google Scholar]
  19. 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. doi: 10.1073/pnas.84.9.2653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Israël A., Le Bail O., Hatat D., Piette J., Kieran M., Logeat F., Wallach D., Fellous M., Kourilsky P. TNF stimulates expression of mouse MHC class I genes by inducing an NF kappa B-like enhancer binding activity which displaces constitutive factors. EMBO J. 1989 Dec 1;8(12):3793–3800. doi: 10.1002/j.1460-2075.1989.tb08556.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Lenardo M. J., Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. doi: 10.1016/0092-8674(89)90833-7. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Logeat F., Israël N., Ten R., Blank V., Le Bail O., Kourilsky P., Israël A. Inhibition of transcription factors belonging to the rel/NF-kappa B family by a transdominant negative mutant. EMBO J. 1991 Jul;10(7):1827–1832. doi: 10.1002/j.1460-2075.1991.tb07708.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Macchi M., Bornert J. M., Davidson I., Kanno M., Rosales R., Vigneron M., Xiao J. H., Fromental C., Chambon P. The SV40 TC-II(kappa B) enhanson binds ubiquitous and cell type specifically inducible nuclear proteins from lymphoid and non-lymphoid cell lines. EMBO J. 1989 Dec 20;8(13):4215–4227. doi: 10.1002/j.1460-2075.1989.tb08607.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nolan G. P., Ghosh S., Liou H. C., 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. doi: 10.1016/0092-8674(91)90320-x. [DOI] [PubMed] [Google Scholar]
  27. Pierce J. W., Lenardo M., Baltimore D. Oligonucleotide that binds nuclear factor NF-kappa B acts as a lymphoid-specific and inducible enhancer element. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1482–1486. doi: 10.1073/pnas.85.5.1482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Ryseck R. P., Bull P., Takamiya M., Bours V., Siebenlist U., Dobrzanski P., Bravo R. RelB, a new Rel family transcription activator that can interact with p50-NF-kappa B. Mol Cell Biol. 1992 Feb;12(2):674–684. doi: 10.1128/mcb.12.2.674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schmid R. M., Perkins N. D., Duckett C. S., Andrews P. C., Nabel G. J. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature. 1991 Aug 22;352(6337):733–736. doi: 10.1038/352733a0. [DOI] [PubMed] [Google Scholar]
  31. Schmitz M. L., Baeuerle P. A. The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J. 1991 Dec;10(12):3805–3817. doi: 10.1002/j.1460-2075.1991.tb04950.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. 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. doi: 10.1016/0092-8674(86)90807-x. [DOI] [PubMed] [Google Scholar]
  34. Urban M. B., Schreck R., Baeuerle P. A. NF-kappa B contacts DNA by a heterodimer of the p50 and p65 subunit. EMBO J. 1991 Jul;10(7):1817–1825. doi: 10.1002/j.1460-2075.1991.tb07707.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES