Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1992 Dec;66(12):6969–6978. doi: 10.1128/jvi.66.12.6969-6978.1992

Down-regulation of the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells is accompanied by an increase in factor binding.

R Ge 1, A Kralli 1, R Weinmann 1, R P Ricciardi 1
PMCID: PMC240338  PMID: 1433502

Abstract

In transformed cells, the E1A gene of adenovirus type 12 (Ad12) represses transcription of class I genes of the major histocompatibility complex. The tumorigenic potential of Ad12-transformed cells correlates with this diminished class I expression. In contrast, the E1A gene of the nontumorigenic Ad5 does not affect class I expression. We show here that a transfected reporter chloramphenicol acetyltransferase plasmid driven by an H-2K promoter (-1049 bp) was expressed at much lower levels in Ad12- than in Ad5-transformed mouse cells. Analysis of mutant constructs revealed that only 83 bp of H-2 DNA, consisting of the enhancer juxtaposed to the basal promoter, was sufficient for this differential expression. Whereas the H-2 basal promoter alone was somewhat less active in Ad12-transformed cells, the H-2 TATA box itself did not appear to be important. The H-2 enhancer proved to be the principal element in Ad12 E1A-mediated repression, since (i) substitution of the H-2 enhancer by simian virus 40 enhancers overcame the repression, and (ii) when juxtaposed to either its native or heterologous basal promoters, the H-2 enhancer was functional in Ad5- but not Ad12-transformed cells. Mobility shift assays showed that there is a DNA-binding activity to the 5' site (R2 element) of the enhancer that is significantly higher in Ad12- than in Ad5-transformed cells. These results suggest that decreased class I enhancer activity in Ad12-transformed cells may, at least in part, be due to the higher levels of an enhancer-specific factor, possibly acting as a repressor.

Full text

PDF
6970

Images in this article

6971Image
on p.6971
6975Image
on p.6975
6975Image
on p.6975
6976Image
on p.6976

Selected References

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

  1. Ackrill A. M., Blair G. E. Nuclear proteins binding to an enhancer element of the major histocompatibility class I promoter: differences between highly oncogenic and nononcogenic adenovirus-transformed rat cells. Virology. 1989 Oct;172(2):643–646. doi: 10.1016/0042-6822(89)90207-9. [DOI] [PubMed] [Google Scholar]
  2. Ackrill A. M., Blair G. E. Regulation of major histocompatibility class I gene expression at the level of transcription in highly oncogenic adenovirus transformed rat cells. Oncogene. 1988 Oct;3(4):483–487. [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. 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]
  6. Berk A. J. Adenovirus promoters and E1A transactivation. Annu Rev Genet. 1986;20:45–79. doi: 10.1146/annurev.ge.20.120186.000401. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Bernards R., Van der Eb A. J. Adenovirus: transformation and oncogenicity. Biochim Biophys Acta. 1984 Dec 14;783(3):187–204. doi: 10.1016/0167-4781(84)90029-0. [DOI] [PubMed] [Google Scholar]
  9. Borrelli E., Hen R., Chambon P. Adenovirus-2 E1A products repress enhancer-induced stimulation of transcription. Nature. 1984 Dec 13;312(5995):608–612. doi: 10.1038/312608a0. [DOI] [PubMed] [Google Scholar]
  10. Burke P. A., Hirschfeld S., Shirayoshi Y., Kasik J. W., Hamada K., Appella E., Ozato K. Developmental and tissue-specific expression of nuclear proteins that bind the regulatory element of the major histocompatibility complex class I gene. J Exp Med. 1989 Apr 1;169(4):1309–1321. doi: 10.1084/jem.169.4.1309. [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. Eager K. B., Pfizenmaier K., Ricciardi R. P. Modulation of major histocompatibility complex (MHC) class I genes in adenovirus 12 transformed cells: interferon-gamma increases class I expression by a mechanism that circumvents E1A induced-repression and tumor necrosis factor enhances the effect of interferon-gamma. Oncogene. 1989 Jan;4(1):39–44. [PubMed] [Google Scholar]
  13. Eager K. B., Williams J., Breiding D., Pan S., Knowles B., Appella E., 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 gamma. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5525–5529. doi: 10.1073/pnas.82.16.5525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Friedman D. J., Ricciardi R. P. Adenovirus type 12 E1A gene represses accumulation of MHC class I mRNAs at the level of transcription. Virology. 1988 Jul;165(1):303–305. doi: 10.1016/0042-6822(88)90689-7. [DOI] [PubMed] [Google Scholar]
  16. Frisch S. M., Reich R., Collier I. E., Genrich L. T., Martin G., Goldberg G. I. Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. Oncogene. 1990 Jan;5(1):75–83. [PubMed] [Google Scholar]
  17. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Hamada K., Gleason S. L., Levi B. Z., Hirschfeld S., Appella E., Ozato K. H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8289–8293. doi: 10.1073/pnas.86.21.8289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hen R., Borrelli E., Chambon P. Repression of the immunoglobulin heavy chain enhancer by the adenovirus-2 E1A products. Science. 1985 Dec 20;230(4732):1391–1394. doi: 10.1126/science.2999984. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Horikoshi N., Maguire K., Kralli A., Maldonado E., Reinberg D., Weinmann R. Direct interaction between adenovirus E1A protein and the TATA box binding transcription factor IID. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5124–5128. doi: 10.1073/pnas.88.12.5124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Israel A., Yano O., Logeat F., Kieran M., Kourilsky P. Two purified factors bind to the same sequence in the enhancer of mouse MHC class I genes: one of them is a positive regulator induced upon differentiation of teratocarcinoma cells. Nucleic Acids Res. 1989 Jul 11;17(13):5245–5257. doi: 10.1093/nar/17.13.5245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Katoh S., Ozawa K., Kondoh S., Soeda E., Israel A., Shiroki K., Fujinaga K., Itakura K., Gachelin G., Yokoyama K. Identification of sequences responsible for positive and negative regulation by E1A in the promoter of H-2Kbm1 class I MHC gene. EMBO J. 1990 Jan;9(1):127–135. doi: 10.1002/j.1460-2075.1990.tb08088.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Korber B., Mermod N., Hood L., Stroynowski I. Regulation of gene expression by interferons: control of H-2 promoter responses. Science. 1988 Mar 11;239(4845):1302–1306. doi: 10.1126/science.3125612. [DOI] [PubMed] [Google Scholar]
  28. Kralli A., Ge R., Graeven U., Ricciardi R. P., Weinmann R. Negative regulation of the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells via a retinoic acid response element. J Virol. 1992 Dec;66(12):6979–6988. doi: 10.1128/jvi.66.12.6979-6988.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Liu F., Green M. R. A specific member of the ATF transcription factor family can mediate transcription activation by the adenovirus E1a protein. Cell. 1990 Jun 29;61(7):1217–1224. doi: 10.1016/0092-8674(90)90686-9. [DOI] [PubMed] [Google Scholar]
  31. Mellor A. L., Golden L., Weiss E., Bullman H., Hurst J., Simpson E., James R. F., Townsend A. R., Taylor P. M., Schmidt W. Expression of murine H-2Kb histocompatibility antigen in cells transformed with cloned H-2 genes. Nature. 1982 Aug 5;298(5874):529–534. doi: 10.1038/298529a0. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Offringa R., Gebel S., van Dam H., Timmers M., Smits A., Zwart R., Stein B., Bos J. L., van der Eb A., Herrlich P. A novel function of the transforming domain of E1a: repression of AP-1 activity. Cell. 1990 Aug 10;62(3):527–538. doi: 10.1016/0092-8674(90)90017-9. [DOI] [PubMed] [Google Scholar]
  34. Ruley H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983 Aug 18;304(5927):602–606. doi: 10.1038/304602a0. [DOI] [PubMed] [Google Scholar]
  35. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Shapiro D. J., Sharp P. A., Wahli W. W., Keller M. J. A high-efficiency HeLa cell nuclear transcription extract. DNA. 1988 Jan-Feb;7(1):47–55. doi: 10.1089/dna.1988.7.47. [DOI] [PubMed] [Google Scholar]
  38. Shirayoshi Y., Miyazaki J., Burke P. A., Hamada K., Appella E., Ozato K. Binding of multiple nuclear factors to the 5' upstream regulatory element of the murine major histocompatibility class I gene. Mol Cell Biol. 1987 Dec;7(12):4542–4548. doi: 10.1128/mcb.7.12.4542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Simon M. C., Fisch T. M., Benecke B. J., Nevins J. R., Heintz N. Definition of multiple, functionally distinct TATA elements, one of which is a target in the hsp70 promoter for E1A regulation. Cell. 1988 Mar 11;52(5):723–729. doi: 10.1016/0092-8674(88)90410-2. [DOI] [PubMed] [Google Scholar]
  40. Tanaka K., Yoshioka T., Bieberich C., Jay G. Role of the major histocompatibility complex class I antigens in tumor growth and metastasis. Annu Rev Immunol. 1988;6:359–380. doi: 10.1146/annurev.iy.06.040188.002043. [DOI] [PubMed] [Google Scholar]
  41. Vaessen R. T., Houweling A., Israel A., Kourilsky P., van der Eb A. J. Adenovirus E1A-mediated regulation of class I MHC expression. EMBO J. 1986 Feb;5(2):335–341. doi: 10.1002/j.1460-2075.1986.tb04217.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Vasavada R., Eager K. B., Barbanti-Brodano G., Caputo A., Ricciardi R. P. Adenovirus type 12 early region 1A proteins repress class I HLA expression in transformed human cells. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5257–5261. doi: 10.1073/pnas.83.14.5257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Velcich A., Ziff E. Adenovirus E1a proteins repress transcription from the SV40 early promoter. Cell. 1985 Mar;40(3):705–716. doi: 10.1016/0092-8674(85)90219-3. [DOI] [PubMed] [Google Scholar]
  44. Vogel J., Kress M., Khoury G., Jay G. A transcriptional enhancer and an interferon-responsive sequence in major histocompatibility complex class I genes. Mol Cell Biol. 1986 Oct;6(10):3550–3554. doi: 10.1128/mcb.6.10.3550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Webster L. C., Ricciardi R. P. trans-dominant mutants of E1A provide genetic evidence that the zinc finger of the trans-activating domain binds a transcription factor. Mol Cell Biol. 1991 Sep;11(9):4287–4296. doi: 10.1128/mcb.11.9.4287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Whyte P., Williamson N. M., Harlow E. Cellular targets for transformation by the adenovirus E1A proteins. Cell. 1989 Jan 13;56(1):67–75. doi: 10.1016/0092-8674(89)90984-7. [DOI] [PubMed] [Google Scholar]
  47. Yewdell J. W., Bennink J. R., Eager K. B., Ricciardi R. P. CTL recognition of adenovirus-transformed cells infected with influenza virus: lysis by anti-influenza CTL parallels adenovirus-12-induced suppression of class I MHC molecules. Virology. 1988 Jan;162(1):236–238. doi: 10.1016/0042-6822(88)90413-8. [DOI] [PubMed] [Google Scholar]
  48. Zinkernagel R. M., Doherty P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701–702. doi: 10.1038/248701a0. [DOI] [PubMed] [Google Scholar]
  49. van Dam H., Offringa R., Meijer I., Stein B., Smits A. M., Herrlich P., Bos J. L., van der Eb A. J. Differential effects of the adenovirus E1A oncogene on members of the AP-1 transcription factor family. Mol Cell Biol. 1990 Nov;10(11):5857–5864. doi: 10.1128/mcb.10.11.5857. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES