Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Jul;71(7):5095–5101. doi: 10.1128/jvi.71.7.5095-5101.1997

Restoration of interferon responses of adenovirus E1A-expressing HT1080 cell lines by overexpression of p48 protein.

G T Leonard 1, G C Sen 1
PMCID: PMC191743  PMID: 9188575

Abstract

We have previously shown that both alpha interferon (IFN-alpha) and IFN-gamma signaling pathways are blocked in HeLa cells expressing the adenovirus E1A proteins (G. T. Leonard and G. C. Sen, Virology 224:25-33, 1996). Here, we report that in two other E1A-expressing cell lines derived from the HT1080 cells, neither IFN-alpha nor IFN-gamma could induce the transcription of genes containing the IFN-stimulated response element (ISRE). In contrast, IFN-gamma-mediated signaling to the gamma-activated sequence was unimpaired in these cells. This dichotomy was due to a lowered level of functional p48 protein but not of STAT1 protein in the E1A-expressing HT1080 cells. When p48 was overexpressed in those cells by stably transfecting a p48 expression vector, both types of IFN could effectively induce the transcription of ISRE-driven genes. Consequently, IFN-alpha was highly effective in inhibiting the replication of encephelomyocarditis virus in the E1A-expressing cells, which also overexpressed p48. These results reinforce the general conclusion that adenovirus E1A proteins block IFN signaling pathways by lowering the functional levels of one or more components of the trans-acting complexes that activate the transcription of IFN-stimulated genes.

Full Text

The Full Text of this article is available as a PDF (997.6 KB).

Selected References

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

  1. Ackrill A. M., Foster G. R., Laxton C. D., Flavell D. M., Stark G. R., Kerr I. M. Inhibition of the cellular response to interferons by products of the adenovirus type 5 E1A oncogene. Nucleic Acids Res. 1991 Aug 25;19(16):4387–4393. doi: 10.1093/nar/19.16.4387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson K. P., Fennie E. H. Adenovirus early region 1A modulation of interferon antiviral activity. J Virol. 1987 Mar;61(3):787–795. doi: 10.1128/jvi.61.3.787-795.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bandara L. R., La Thangue N. B. Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor. Nature. 1991 Jun 6;351(6326):494–497. doi: 10.1038/351494a0. [DOI] [PubMed] [Google Scholar]
  4. Bandyopadhyay S. K., Leonard G. T., Jr, Bandyopadhyay T., Stark G. R., Sen G. C. Transcriptional induction by double-stranded RNA is mediated by interferon-stimulated response elements without activation of interferon-stimulated gene factor 3. J Biol Chem. 1995 Aug 18;270(33):19624–19629. doi: 10.1074/jbc.270.33.19624. [DOI] [PubMed] [Google Scholar]
  5. Banerjee A. C., Recupero A. J., Mal A., Piotrkowski A. M., Wang D. M., Harter M. L. The adenovirus E1A 289R and 243R proteins inhibit the phosphorylation of p300. Oncogene. 1994 Jun;9(6):1733–1737. [PubMed] [Google Scholar]
  6. Biol M. C., Lenoir D., Hugueny I., Louisot P. Hormonal regulation of glycosylation process in rat small intestine: responsiveness of fucosyl-transferase activity to hydrocortisone during the suckling period, unresponsiveness after weaning. Biochim Biophys Acta. 1992 Jan 13;1133(2):206–212. doi: 10.1016/0167-4889(92)90070-r. [DOI] [PubMed] [Google Scholar]
  7. Bluyssen H. A., Muzaffar R., Vlieststra R. J., van der Made A. C., Leung S., Stark G. R., Kerr I. M., Trapman J., Levy D. E. Combinatorial association and abundance of components of interferon-stimulated gene factor 3 dictate the selectivity of interferon responses. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5645–5649. doi: 10.1073/pnas.92.12.5645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Braun T., Bober E., Arnold H. H. Inhibition of muscle differentiation by the adenovirus E1a protein: repression of the transcriptional activating function of the HLH protein Myf-5. Genes Dev. 1992 May;6(5):888–902. doi: 10.1101/gad.6.5.888. [DOI] [PubMed] [Google Scholar]
  9. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  10. Debbas M., White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev. 1993 Apr;7(4):546–554. doi: 10.1101/gad.7.4.546. [DOI] [PubMed] [Google Scholar]
  11. Dyson N., Howley P. M., Münger K., Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989 Feb 17;243(4893):934–937. doi: 10.1126/science.2537532. [DOI] [PubMed] [Google Scholar]
  12. Gutch M. J., Reich N. C. Repression of the interferon signal transduction pathway by the adenovirus E1A oncogene. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):7913–7917. doi: 10.1073/pnas.88.18.7913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Horikoshi N., Usheva A., Chen J., Levine A. J., Weinmann R., Shenk T. Two domains of p53 interact with the TATA-binding protein, and the adenovirus 13S E1A protein disrupts the association, relieving p53-mediated transcriptional repression. Mol Cell Biol. 1995 Jan;15(1):227–234. doi: 10.1128/mcb.15.1.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kalvakolanu D. V., Bandyopadhyay S. K., Harter M. L., Sen G. C. Inhibition of interferon-inducible gene expression by adenovirus E1A proteins: block in transcriptional complex formation. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7459–7463. doi: 10.1073/pnas.88.17.7459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kalvakolanu D. V., Sen G. C. Differentiation-dependent activation of interferon-stimulated gene factors and transcription factor NF-kappa B in mouse embryonal carcinoma cells. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3167–3171. doi: 10.1073/pnas.90.8.3167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Katze M. G., DeCorato D., Safer B., Galabru J., Hovanessian A. G. Adenovirus VAI RNA complexes with the 68 000 Mr protein kinase to regulate its autophosphorylation and activity. EMBO J. 1987 Mar;6(3):689–697. doi: 10.1002/j.1460-2075.1987.tb04809.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kimura T., Kadokawa Y., Harada H., Matsumoto M., Sato M., Kashiwazaki Y., Tarutani M., Tan R. S., Takasugi T., Matsuyama T. Essential and non-redundant roles of p48 (ISGF3 gamma) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies. Genes Cells. 1996 Jan;1(1):115–124. doi: 10.1046/j.1365-2443.1996.08008.x. [DOI] [PubMed] [Google Scholar]
  18. Kitajewski J., Schneider R. J., Safer B., Munemitsu S. M., Samuel C. E., Thimmappaya B., Shenk T. Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2 alpha kinase. Cell. 1986 Apr 25;45(2):195–200. doi: 10.1016/0092-8674(86)90383-1. [DOI] [PubMed] [Google Scholar]
  19. Leonard G. T., Sen G. C. Effects of adenovirus E1A protein on interferon-signaling. Virology. 1996 Oct 1;224(1):25–33. doi: 10.1006/viro.1996.0503. [DOI] [PubMed] [Google Scholar]
  20. Mathews M. B., Shenk T. Adenovirus virus-associated RNA and translation control. J Virol. 1991 Nov;65(11):5657–5662. doi: 10.1128/jvi.65.11.5657-5662.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Müller M., Laxton C., Briscoe J., Schindler C., Improta T., Darnell J. E., Jr, Stark G. R., Kerr I. M. Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-alpha and -gamma signal transduction pathways. EMBO J. 1993 Nov;12(11):4221–4228. doi: 10.1002/j.1460-2075.1993.tb06106.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nevins J. R. Adenovirus E1A: transcription regulation and alteration of cell growth control. Curr Top Microbiol Immunol. 1995;199(Pt 3):25–32. doi: 10.1007/978-3-642-79586-2_2. [DOI] [PubMed] [Google Scholar]
  23. Reid L. E., Brasnett A. H., Gilbert C. S., Porter A. C., Gewert D. R., Stark G. R., Kerr I. M. A single DNA response element can confer inducibility by both alpha- and gamma-interferons. Proc Natl Acad Sci U S A. 1989 Feb;86(3):840–844. doi: 10.1073/pnas.86.3.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sen G. C., Ransohoff R. M. Interferon-induced antiviral actions and their regulation. Adv Virus Res. 1993;42:57–102. doi: 10.1016/s0065-3527(08)60083-4. [DOI] [PubMed] [Google Scholar]
  25. Sims S. H., Cha Y., Romine M. F., Gao P. Q., Gottlieb K., Deisseroth A. B. A novel interferon-inducible domain: structural and functional analysis of the human interferon regulatory factor 1 gene promoter. Mol Cell Biol. 1993 Jan;13(1):690–702. doi: 10.1128/mcb.13.1.690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Veals S. A., Santa Maria T., Levy D. E. Two domains of ISGF3 gamma that mediate protein-DNA and protein-protein interactions during transcription factor assembly contribute to DNA-binding specificity. Mol Cell Biol. 1993 Jan;13(1):196–206. doi: 10.1128/mcb.13.1.196. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES