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. 2004 Jan 15;377(Pt 2):367–378. doi: 10.1042/BJ20031166

Interferon regulatory factor-2 drives megakaryocytic differentiation.

Emilia Stellacci 1, Ugo Testa 1, Eleonora Petrucci 1, Eleonora Benedetti 1, Roberto Orsatti 1, Tiziana Feccia 1, Marit Stafsnes 1, Eliana M Coccia 1, Giovanna Marziali 1, Angela Battistini 1
PMCID: PMC1223861  PMID: 14505489

Abstract

IRFs [IFN (interferon) regulatory factors] constitute a family of transcription factors involved in IFN signalling and in the development and differentiation of the immune system. IRF-2 has generally been described as an antagonist of IRF-1-mediated transcription of IFN and IFN-inducible genes; however, it has been recently identified as a transcriptional activator of some genes, such as those encoding histone H4, VCAM-1 (vascular cell adhesion molecule-1) and Fas ligand. Biologically, IRF-2 plays an important role in cell growth regulation and has been shown to be a potential oncogene. Studies in knock-out mice have also implicated IRF-2 in the differentiation and functionality of haematopoietic cells. Here we show that IRF-2 expression in a myeloid progenitor cell line leads to reprogramming of these cells towards the megakaryocytic lineage and enables them to respond to thrombopoietin, as assessed by cell morphology and expression of specific differentiation markers. Up-regulation of transcription factors involved in the development of the megakaryocytic lineage, such as GATA-1, GATA-2, FOG-1 (friend of GATA-1) and NF-E2 (nuclear factor-erythroid-2), and transcriptional stimulation of the thrombopoietin receptor were also demonstrated. Our results provide evidence for a key role for IRF-2 in the induction of a programme of megakaryocytic differentiation, and reveal a remarkable functional diversity of this transcription factor in the regulation of cellular responses.

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Selected References

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  1. Alexander W. S., Roberts A. W., Nicola N. A., Li R., Metcalf D. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood. 1996 Mar 15;87(6):2162–2170. [PubMed] [Google Scholar]
  2. Andrews N. C., Erdjument-Bromage H., Davidson M. B., Tempst P., Orkin S. H. Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature. 1993 Apr 22;362(6422):722–728. doi: 10.1038/362722a0. [DOI] [PubMed] [Google Scholar]
  3. Cantor Alan B., Katz Samuel G., Orkin Stuart H. Distinct domains of the GATA-1 cofactor FOG-1 differentially influence erythroid versus megakaryocytic maturation. Mol Cell Biol. 2002 Jun;22(12):4268–4279. doi: 10.1128/MCB.22.12.4268-4279.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Casella Ida, Feccia Tiziana, Chelucci Cristiana, Samoggia Paola, Castelli Germana, Guerriero Raffaella, Parolini Isabella, Petrucci Eleonora, Pelosi Elvira, Morsilli Ornella. Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. Blood. 2002 Oct 24;101(4):1316–1323. doi: 10.1182/blood-2002-07-2184. [DOI] [PubMed] [Google Scholar]
  5. Chow W. A., Fang J. J., Yee J. K. The IFN regulatory factor family participates in regulation of Fas ligand gene expression in T cells. J Immunol. 2000 Apr 1;164(7):3512–3518. doi: 10.4049/jimmunol.164.7.3512. [DOI] [PubMed] [Google Scholar]
  6. Coccia E. M., Del Russo N., Stellacci E., Orsatti R., Benedetti E., Marziali G., Hiscott J., Battistini A. Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2. Oncogene. 1999 Mar 25;18(12):2129–2137. doi: 10.1038/sj.onc.1202536. [DOI] [PubMed] [Google Scholar]
  7. Coccia E. M., Stellacci E., Valtieri M., Masella B., Feccia T., Marziali G., Hiscott J., Testa U., Peschle C., Battistini A. Ectopic expression of interferon regulatory factor-1 potentiates granulocytic differentiation. Biochem J. 2001 Dec 1;360(Pt 2):285–294. doi: 10.1042/0264-6021:3600285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Condorelli G. L., Tocci A., Botta R., Facchiano F., Testa U., Vitelli L., Valtieri M., Croce C. M., Peschle C. Ectopic TAL-1/SCL expression in phenotypically normal or leukemic myeloid precursors: proliferative and antiapoptotic effects coupled with a differentiation blockade. Mol Cell Biol. 1997 May;17(5):2954–2969. doi: 10.1128/mcb.17.5.2954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Duncan G. S., Mittrücker H. W., Kägi D., Matsuyama T., Mak T. W. The transcription factor interferon regulatory factor-1 is essential for natural killer cell function in vivo. J Exp Med. 1996 Nov 1;184(5):2043–2048. doi: 10.1084/jem.184.5.2043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fujiwara Y., Browne C. P., Cunniff K., Goff S. C., Orkin S. H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12355–12358. doi: 10.1073/pnas.93.22.12355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gabbianelli M., Sargiacomo M., Pelosi E., Testa U., Isacchi G., Peschle C. "Pure" human hematopoietic progenitors: permissive action of basic fibroblast growth factor. Science. 1990 Sep 28;249(4976):1561–1564. doi: 10.1126/science.2218497. [DOI] [PubMed] [Google Scholar]
  12. Guerriero R., Testa U., Gabbianelli M., Mattia G., Montesoro E., Macioce G., Pace A., Ziegler B., Hassan H. J., Peschle C. Unilineage megakaryocytic proliferation and differentiation of purified hematopoietic progenitors in serum-free liquid culture. Blood. 1995 Nov 15;86(10):3725–3736. [PubMed] [Google Scholar]
  13. Harada H., Kitagawa M., Tanaka N., Yamamoto H., Harada K., Ishihara M., Taniguchi T. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science. 1993 Feb 12;259(5097):971–974. doi: 10.1126/science.8438157. [DOI] [PubMed] [Google Scholar]
  14. Harada H., Willison K., Sakakibara J., Miyamoto M., Fujita T., Taniguchi T. Absence of the type I IFN system in EC cells: transcriptional activator (IRF-1) and repressor (IRF-2) genes are developmentally regulated. Cell. 1990 Oct 19;63(2):303–312. doi: 10.1016/0092-8674(90)90163-9. [DOI] [PubMed] [Google Scholar]
  15. Jesse T. L., LaChance R., Iademarco M. F., Dean D. C. Interferon regulatory factor-2 is a transcriptional activator in muscle where It regulates expression of vascular cell adhesion molecule-1. J Cell Biol. 1998 Mar 9;140(5):1265–1276. doi: 10.1083/jcb.140.5.1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lecine P., Blank V., Shivdasani R. Characterization of the hematopoietic transcription factor NF-E2 in primary murine megakaryocytes. J Biol Chem. 1998 Mar 27;273(13):7572–7578. doi: 10.1074/jbc.273.13.7572. [DOI] [PubMed] [Google Scholar]
  17. Lin R., Mustafa A., Nguyen H., Gewert D., Hiscott J. Mutational analysis of interferon (IFN) regulatory factors 1 and 2. Effects on the induction of IFN-beta gene expression. J Biol Chem. 1994 Jul 1;269(26):17542–17549. [PubMed] [Google Scholar]
  18. Lohoff M., Duncan G. S., Ferrick D., Mittrücker H. W., Bischof S., Prechtl S., Röllinghoff M., Schmitt E., Pahl A., Mak T. W. Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells. J Exp Med. 2000 Aug 7;192(3):325–336. doi: 10.1084/jem.192.3.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lohoff M., Ferrick D., Mittrucker H. W., Duncan G. S., Bischof S., Rollinghoff M., Mak T. W. Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. Immunity. 1997 Jun;6(6):681–689. doi: 10.1016/s1074-7613(00)80444-6. [DOI] [PubMed] [Google Scholar]
  20. Luo W., Skalnik D. G. Interferon regulatory factor-2 directs transcription from the gp91phox promoter. J Biol Chem. 1996 Sep 20;271(38):23445–23451. doi: 10.1074/jbc.271.38.23445. [DOI] [PubMed] [Google Scholar]
  21. Marziali Giovanna, Perrotti Edvige, Ilari Ramona, Lulli Valentina, Coccia Eliana M., Moret Rémy, Kühn Lukas C., Testa Ugo, Battistini Angela. Role of Ets-1 in transcriptional regulation of transferrin receptor and erythroid differentiation. Oncogene. 2002 Nov 14;21(52):7933–7944. doi: 10.1038/sj.onc.1205925. [DOI] [PubMed] [Google Scholar]
  22. Matsumura I., Kawasaki A., Tanaka H., Sonoyama J., Ezoe S., Minegishi N., Nakajima K., Yamamoto M., Kanakura Y. Biologic significance of GATA-1 activities in Ras-mediated megakaryocytic differentiation of hematopoietic cell lines. Blood. 2000 Oct 1;96(7):2440–2450. [PubMed] [Google Scholar]
  23. Matsuyama T., Kimura T., Kitagawa M., Pfeffer K., Kawakami T., Watanabe N., Kündig T. M., Amakawa R., Kishihara K., Wakeham A. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell. 1993 Oct 8;75(1):83–97. [PubMed] [Google Scholar]
  24. Mikkola Hanna K. A., Klintman Jenny, Yang Haidi, Hock Hanno, Schlaeger Thorsten M., Fujiwara Yuko, Orkin Stuart H. Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature. 2003 Jan 19;421(6922):547–551. doi: 10.1038/nature01345. [DOI] [PubMed] [Google Scholar]
  25. Nguyen H., Hiscott J., Pitha P. M. The growing family of interferon regulatory factors. Cytokine Growth Factor Rev. 1997 Dec;8(4):293–312. doi: 10.1016/s1359-6101(97)00019-1. [DOI] [PubMed] [Google Scholar]
  26. Saura M., Zaragoza C., Bao C., McMillan A., Lowenstein C. J. Interaction of interferon regulatory factor-1 and nuclear factor kappaB during activation of inducible nitric oxide synthase transcription. J Mol Biol. 1999 Jun 11;289(3):459–471. doi: 10.1006/jmbi.1999.2752. [DOI] [PubMed] [Google Scholar]
  27. Sgarbanti Marco, Borsetti Alessandra, Moscufo Nicola, Bellocchi Maria C., Ridolfi Barbara, Nappi Filomena, Marsili Giulia, Marziali Giovanna, Coccia Eliana M., Ensoli Barbara. Modulation of human immunodeficiency virus 1 replication by interferon regulatory factors. J Exp Med. 2002 May 20;195(10):1359–1370. doi: 10.1084/jem.20010753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shivdasani R. A., Fujiwara Y., McDevitt M. A., Orkin S. H. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 1997 Jul 1;16(13):3965–3973. doi: 10.1093/emboj/16.13.3965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shivdasani R. A. Molecular and transcriptional regulation of megakaryocyte differentiation. Stem Cells. 2001;19(5):397–407. doi: 10.1634/stemcells.19-5-397. [DOI] [PubMed] [Google Scholar]
  30. Shivdasani R. A., Orkin S. H. The transcriptional control of hematopoiesis. Blood. 1996 May 15;87(10):4025–4039. [PubMed] [Google Scholar]
  31. Shivdasani R. A., Rosenblatt M. F., Zucker-Franklin D., Jackson C. W., Hunt P., Saris C. J., Orkin S. H. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell. 1995 Jun 2;81(5):695–704. doi: 10.1016/0092-8674(95)90531-6. [DOI] [PubMed] [Google Scholar]
  32. Sposi N. M., Zon L. I., Carè A., Valtieri M., Testa U., Gabbianelli M., Mariani G., Bottero L., Mather C., Orkin S. H. Cell cycle-dependent initiation and lineage-dependent abrogation of GATA-1 expression in pure differentiating hematopoietic progenitors. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6353–6357. doi: 10.1073/pnas.89.14.6353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Suggs S. V., Wallace R. B., Hirose T., Kawashima E. H., Itakura K. Use of synthetic oligonucleotides as hybridization probes: isolation of cloned cDNA sequences for human beta 2-microglobulin. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6613–6617. doi: 10.1073/pnas.78.11.6613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Taniguchi T., Ogasawara K., Takaoka A., Tanaka N. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol. 2001;19:623–655. doi: 10.1146/annurev.immunol.19.1.623. [DOI] [PubMed] [Google Scholar]
  35. Tenen D. G., Hromas R., Licht J. D., Zhang D. E. Transcription factors, normal myeloid development, and leukemia. Blood. 1997 Jul 15;90(2):489–519. [PubMed] [Google Scholar]
  36. Tsang A. P., Fujiwara Y., Hom D. B., Orkin S. H. Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. Genes Dev. 1998 Apr 15;12(8):1176–1188. doi: 10.1101/gad.12.8.1176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Valtieri M., Tweardy D. J., Caracciolo D., Johnson K., Mavilio F., Altmann S., Santoli D., Rovera G. Cytokine-dependent granulocytic differentiation. Regulation of proliferative and differentiative responses in a murine progenitor cell line. J Immunol. 1987 Jun 1;138(11):3829–3835. [PubMed] [Google Scholar]
  38. Vaughan P. S., van der Meijden C. M., Aziz F., Harada H., Taniguchi T., van Wijnen A. J., Stein J. L., Stein G. S. Cell cycle regulation of histone H4 gene transcription requires the oncogenic factor IRF-2. J Biol Chem. 1998 Jan 2;273(1):194–199. doi: 10.1074/jbc.273.1.194. [DOI] [PubMed] [Google Scholar]
  39. Vyas P., Ault K., Jackson C. W., Orkin S. H., Shivdasani R. A. Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood. 1999 May 1;93(9):2867–2875. [PubMed] [Google Scholar]

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