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. 1996 Apr;16(4):1419–1424. doi: 10.1128/mcb.16.4.1419

Inhibition of alpha interferon but not gamma interferon signal transduction by phorbol esters is mediated by a tyrosine phosphatase.

E Petricoin 3rd 1, M David 1, K Igarashi 1, C Benjamin 1, L Ling 1, S Goelz 1, D S Finbloom 1, A C Larner 1
PMCID: PMC231126  PMID: 8657115

Abstract

Previous studies have indicated that the expression of viral oncoproteins, cell transformation, or phorbol ester treatment of cells can inhibit alpha/beta interferon (IFN-alpha/beta)-induced gene expression. The mechanisms by which these promoters of cell growth exert their inhibitory effects vary, but in most instances they involve a disruption of the IFN-alpha/beta-induced transcription complex ISGF3 such that the DNA-binding component of this complex (the 48-kDa ISGF3gamma protein) does not bind to the interferon-stimulated response element (ISRE). In this report, we demonstrated that phorbol ester treatment of human peripheral blood monocytes dramatically inhibits activation of IFN-alpha/B-stimulated early response genes but by a mechanism which does not involve abrogation of the ISRE binding of ISGF3gamma. Phorbol ester treatment of monocytes inhibited IFN alpha-stimulated tyrosine phosphorylation of the transcription factors Stat1alpha, Stat2, and Stat3 and of the tyrosine kinase Tyk2 but had no effect on IFN-gamma activation of Stat1alpha. IFNalpha-stimulated tyrosine phosphorylation of Jak1 and the alpha subunit of the IFN-alpha receptor were unaffected by phorbol 12-myristate 13-acetate (PMA). Moreover, PMA caused the dephosphorylation of Tyk2 but not of Jak1, which was activated by IFN. Pretreatment of cells with vanadate prevented the effects of PMA with regard to PMA-induced Tyk2 dephosphorylation. These observations suggest that PMA exerts its inhibitory effects by activation of a tyrosine phosphatase which selectively regulates Tyk2 but not Jak1 activity.

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Selected References

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  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. Akai H., Larner A. C. Phorbol ester-mediated down-regulation of an interferon-inducible gene. J Biol Chem. 1989 Feb 25;264(6):3252–3255. [PubMed] [Google Scholar]
  3. Colamonici O. R., Domanski P., Sweitzer S. M., Larner A., Buller R. M. Vaccinia virus B18R gene encodes a type I interferon-binding protein that blocks interferon alpha transmembrane signaling. J Biol Chem. 1995 Jul 7;270(27):15974–15978. doi: 10.1074/jbc.270.27.15974. [DOI] [PubMed] [Google Scholar]
  4. David M., Chen H. E., Goelz S., Larner A. C., Neel B. G. Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol Cell Biol. 1995 Dec;15(12):7050–7058. doi: 10.1128/mcb.15.12.7050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. David M., Petricoin E., 3rd, Benjamin C., Pine R., Weber M. J., Larner A. C. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 1995 Sep 22;269(5231):1721–1723. doi: 10.1126/science.7569900. [DOI] [PubMed] [Google Scholar]
  6. David M., Romero G., Zhang Z. Y., Dixon J. E., Larner A. C. In vitro activation of the transcription factor ISGF3 by interferon alpha involves a membrane-associated tyrosine phosphatase and tyrosine kinase. J Biol Chem. 1993 Mar 25;268(9):6593–6599. [PubMed] [Google Scholar]
  7. Evans R. M., Fraser N., Ziff E., Weber J., Wilson M., Darnell J. E. The initiation sites for RNA transcription in Ad2 DNA. Cell. 1977 Nov;12(3):733–739. doi: 10.1016/0092-8674(77)90273-2. [DOI] [PubMed] [Google Scholar]
  8. Finbloom D. S., Hoover D. L., Wahl L. M. The characteristics of binding of human recombinant interferon-gamma to its receptor on human monocytes and human monocyte-like cell lines. J Immunol. 1985 Jul;135(1):300–305. [PubMed] [Google Scholar]
  9. Garton A. J., Tonks N. K. PTP-PEST: a protein tyrosine phosphatase regulated by serine phosphorylation. EMBO J. 1994 Aug 15;13(16):3763–3771. doi: 10.1002/j.1460-2075.1994.tb06687.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Igarashi K., David M., Finbloom D. S., Larner A. C. In vitro activation of the transcription factor gamma interferon activation factor by gamma interferon: evidence for a tyrosine phosphatase/kinase signaling cascade. Mol Cell Biol. 1993 Mar;13(3):1634–1640. doi: 10.1128/mcb.13.3.1634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Igarashi K., David M., Larner A. C., Finbloom D. S. In vitro activation of a transcription factor by gamma interferon requires a membrane-associated tyrosine kinase and is mimicked by vanadate. Mol Cell Biol. 1993 Jul;13(7):3984–3989. doi: 10.1128/mcb.13.7.3984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Igarashi K., Garotta G., Ozmen L., Ziemiecki A., Wilks A. F., Harpur A. G., Larner A. C., Finbloom D. S. Interferon-gamma induces tyrosine phosphorylation of interferon-gamma receptor and regulated association of protein tyrosine kinases, Jak1 and Jak2, with its receptor. J Biol Chem. 1994 May 20;269(20):14333–14336. [PubMed] [Google Scholar]
  14. Ihle J. N., Witthuhn B. A., Quelle F. W., Yamamoto K., Thierfelder W. E., Kreider B., Silvennoinen O. Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem Sci. 1994 May;19(5):222–227. doi: 10.1016/0968-0004(94)90026-4. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Kanda K., Decker T., Aman P., Wahlström M., von Gabain A., Kallin B. The EBNA2-related resistance towards alpha interferon (IFN-alpha) in Burkitt's lymphoma cells effects induction of IFN-induced genes but not the activation of transcription factor ISGF-3. Mol Cell Biol. 1992 Nov;12(11):4930–4936. doi: 10.1128/mcb.12.11.4930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Klingmüller U., Lorenz U., Cantley L. C., Neel B. G., Lodish H. F. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995 Mar 10;80(5):729–738. doi: 10.1016/0092-8674(95)90351-8. [DOI] [PubMed] [Google Scholar]
  18. Larner A. C., David M., Feldman G. M., Igarashi K., Hackett R. H., Webb D. S., Sweitzer S. M., Petricoin E. F., 3rd, Finbloom D. S. Tyrosine phosphorylation of DNA binding proteins by multiple cytokines. Science. 1993 Sep 24;261(5129):1730–1733. doi: 10.1126/science.8378773. [DOI] [PubMed] [Google Scholar]
  19. Larner A. C., Finbloom D. S. Protein tyrosine phosphorylation as a mechanism which regulates cytokine activation of early response genes. Biochim Biophys Acta. 1995 May 12;1266(3):278–287. doi: 10.1016/0167-4889(95)00015-k. [DOI] [PubMed] [Google Scholar]
  20. Levy D. E., Kessler D. S., Pine R., Reich N., Darnell J. E., Jr Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 1988 Apr;2(4):383–393. doi: 10.1101/gad.2.4.383. [DOI] [PubMed] [Google Scholar]
  21. Müller M., Briscoe J., Laxton C., Guschin D., Ziemiecki A., Silvennoinen O., Harpur A. G., Barbieri G., Witthuhn B. A., Schindler C. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993 Nov 11;366(6451):129–135. doi: 10.1038/366129a0. [DOI] [PubMed] [Google Scholar]
  22. Peraldi P., Zhao Z., Filloux C., Fischer E. H., Van Obberghen E. Protein-tyrosine-phosphatase 2C is phosphorylated and inhibited by 44-kDa mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5002–5006. doi: 10.1073/pnas.91.11.5002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Petricoin E. F., 3rd, Hackett R. H., Akai H., Igarashi K., Finbloom D. S., Larner A. C. Modulation of interferon signaling in human fibroblasts by phorbol esters. Mol Cell Biol. 1992 Oct;12(10):4486–4495. doi: 10.1128/mcb.12.10.4486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Petricoin E., 3rd, David M., Fang H., Grimley P., Larner A. C., Vande Pol S. Human cancer cell lines express a negative transcriptional regulator of the interferon regulatory factor family of DNA binding proteins. Mol Cell Biol. 1994 Feb;14(2):1477–1486. doi: 10.1128/mcb.14.2.1477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Platanias L. C., Colamonici O. R. Interferon alpha induces rapid tyrosine phosphorylation of the alpha subunit of its receptor. J Biol Chem. 1992 Nov 25;267(33):24053–24057. [PubMed] [Google Scholar]
  26. Reich N., Evans B., Levy D., Fahey D., Knight E., Jr, Darnell J. E., Jr Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6394–6398. doi: 10.1073/pnas.84.18.6394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Symons J. A., Alcamí A., Smith G. L. Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity. Cell. 1995 May 19;81(4):551–560. doi: 10.1016/0092-8674(95)90076-4. [DOI] [PubMed] [Google Scholar]
  29. Tang T. L., Freeman R. M., Jr, O'Reilly A. M., Neel B. G., Sokol S. Y. The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell. 1995 Feb 10;80(3):473–483. doi: 10.1016/0092-8674(95)90498-0. [DOI] [PubMed] [Google Scholar]
  30. Uzé G., Lutfalla G., Gresser I. Genetic transfer of a functional human interferon alpha receptor into mouse cells: cloning and expression of its cDNA. Cell. 1990 Jan 26;60(2):225–234. doi: 10.1016/0092-8674(90)90738-z. [DOI] [PubMed] [Google Scholar]
  31. Veals S. A., Schindler C., Leonard D., Fu X. Y., Aebersold R., Darnell J. E., Jr, Levy D. E. Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Mol Cell Biol. 1992 Aug;12(8):3315–3324. doi: 10.1128/mcb.12.8.3315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Velazquez L., Fellous M., Stark G. R., Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. doi: 10.1016/0092-8674(92)90105-l. [DOI] [PubMed] [Google Scholar]
  33. Velazquez L., Mogensen K. E., Barbieri G., Fellous M., Uzé G., Pellegrini S. Distinct domains of the protein tyrosine kinase tyk2 required for binding of interferon-alpha/beta and for signal transduction. J Biol Chem. 1995 Feb 17;270(7):3327–3334. doi: 10.1074/jbc.270.7.3327. [DOI] [PubMed] [Google Scholar]
  34. Wilson K. C., Finbloom D. S. Interferon gamma rapidly induces in human monocytes a DNA-binding factor that recognizes the gamma response region within the promoter of the gene for the high-affinity Fc gamma receptor. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11964–11968. doi: 10.1073/pnas.89.24.11964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zhao Z., Shen S. H., Fischer E. H. Phorbol ester-induced expression, phosphorylation, and translocation of protein-tyrosine-phosphatase 1C in HL-60 cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5007–5011. doi: 10.1073/pnas.91.11.5007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. den Hertog J., Sap J., Pals C. E., Schlessinger J., Kruijer W. Stimulation of receptor protein-tyrosine phosphatase alpha activity and phosphorylation by phorbol ester. Cell Growth Differ. 1995 Mar;6(3):303–307. [PubMed] [Google Scholar]

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