Interferons as a paradigm for cytokine signal transduction

Cellular and Molecular Life Sciences

Volumn 55, Issue 12, 1999, Pages 1509-1522

  Schindler, C ^a   Brutsaert, S ^a  

^a Columbia University ^*  (United States)

Author keywords

Cytokines; Interferons; JAKs; Signal transduction; STATs

Indexed keywords

CYTOKINE; INTERFERON; RECEPTOR;

IMMEDIATE EARLY GENE; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; CYTOKINES; DNA-BINDING PROTEINS; HUMANS; INTERFERONS; SIGNAL TRANSDUCTION; TRANS-ACTIVATORS;

EID: 0032832056     PISSN: 1420682X     EISSN: None     Source Type: Journal    
DOI: 10.1007/s000180050391     Document Type: Review

References (177)

1. Larner A. C., Jonak G., Cheng Y. S., Korant B. D., Knight E. and Darnell J. E. Jr (1984) Transcriptional induction of two genes in human cells by beta interferon. Proc. Natl. Acad. Sci. USA 81: 6733-6737
2. Friedman R. L., Manly S. P., McMahon M., Kerr J. M. and Stark G. R. (1984) Transcriptional and post-transcriptional regulation of interferon-induced gene expression in human cells. Cell 38: 745-755
3. Schindler C., Fu X.-Y., Improta T., Aebersold R. and Darnell J. E. (1992) Proteins of transcription factor ISGF-3: one gene encodes the 91- and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc. Natl. Acad. USA 89: 7836-7839
4. Fu X.-Y., Schindler C., Improta T., Aebersold R. and Darnell J. E. (1992) The proteins of ISGF-3, the IFN-α induced transcription activator, define a new family of signal transducers. Proc. Natl. Acad. Sci. USA 89: 7840-7843
5. Schindler C., Shuai K., Prezioso V. and Darnell J. E. (1992) Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 257: 809-813
6. Velazquez L., Fellous M., Stark G. R. and Pellegrini S. (1992) A protein tyrosine kinase in the interferon α/β signaling pathway. Cell 70: 313-322
7. Darnell J. E. (1997) STATs and gene regulation. Science 277: 1630-1635
8. Ihle J. (1995) Cytokine receptor signaling. Nature 377: 591-594
9. Schindler C. and Strehlow I. (1999) Cytokines and signaling. In: Hormones and Signaling, vol. 2, O'Malley B. W. (ed.), Academic Press, San Diego
10. Pestka S., Langer J. A., Zoon K. C. and Samuel C. E. (1987) Interferons and their actions. Annu. Rev. Biochem. 56: 727-777
11. DeMaeyer E. and DeMaeyer-Giugnard J. (1988) Interferons and Other Regulatory Cytokines, Wiley, New York
12. Pestka S. (1997) The human interferon alpha species and hybrid proteins. Semin. Oncol. 24: S9-4-S9-17
13. Tanaka H. and Samuel C. E. (1994) Mechanism of interferon action: structure of the mouse PKR gene encoding the interferon-inducible RNA-dependent protein kinase. Proc. Natl. Acad. Sci. USA 91: 7995-7999
14. Cohen B., Peretz D., Vaiman D., Benech P. and Chebath J. (1988) Enhancer-like interferon responsive sequences of the human and murine (2′-5′) oligoadenylate synthetase gene promoters. EMBO J. 7: 1411-1419
15. Hug H., Costas M., Staeheli P., Aebi M. and Weissmann C. (1988) Organization of the murine Mx gene and characterization of its interferon and virus inducible promoter. Mol. Cell. Biol. 8: 3065-3079
16. Levy D. E., Kessler D. S., Pine R., Reich N. and Darnell J. E. (1988) Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 2: 383-393
17. Reich N. C., Evans B., Levy D. E., Fahey D. E., Knight E. and Darnell J. E. (1987) Interferon-induced transcription of a gene encoding a 15 kDa protein depends on an upstream enhancer element. Proc. Natl. Acad. Sci. USA 84: 6394-6398
18. Porter A., Chernajovsky Y., Dale T. C., Gilbert C. S., Stark G. R. and Kerr I. M. (1988) Interferon response element of the human gene 6-16. EMBO J. 7: 85-92
19. Levy D. E., Kessler D. S., Pine R. I. and Darnell J. E. (1989) Cytoplasmic activation of ISGF3, the positive regulator of interferon-α stimulated transcription, reconstituted in vitro. Genes Dev. 3: 1362-1372
20. Escalante C. R., Yie J., Thanos D. and Aggarwal A. K. (1998) Structure of IRF-1 with bound DNA reveals determinants of interferon regulation. Nature 391: 103-106
21. Kessler D. S., Levy D. E. and Darnell J. E. (1988) Two interferon-induced nuclear factor bind a single promoter clement in interferon-stimulated genes. Proc. Natl. Acad. Sci. USA 85: 8521-8525
22. Kessler D. S., Veals S. A., Fu X.-Y. and Levy D. E. (1990) Interferon-α regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator. Genes Dev. 4: 1753-1765
23. Veals S. A., Schindler C., Leonard D., Fu X.-Y., Aebersold R., Darnell J. E. et al. (1992) Subunit of an IFN-α responsive transcription factor is related to interferon regulatory factor and Myb families of DNA binding proteins. Mol. Cell. Biol. 12: 3315-3324
24. Quershi S. A., Salditt-Georgieff M. and Darnell J. E. (1995) Tyrosine phosphorylated Stat1 and Stat2 plus a 48 kDa protein all contact DNA in forming interferon-stimulated-gene factor 3. Proc. Natl. Acad. Sci. USA 92: 3829-3833
25. Improta T., Schindler C., Horvath C. M., Kerr I. M., Stark G. R. and Darnell J. E. (1994) Transcription factor ISGF-3 formation requires phosphorylated Stat91 protein, but Stat113 protein is phosphorylated independent of Stat91 protein. Proc. Natl. Acad. Sci. USA 91: 4776-4780
26. Shuai K., Stark G. R., Kerr I. M. and Darnell J. E. (1993) A single phosphotyrosine residue of Stat91 required for gene activation by interferon-γ. Science 261: 1743-1744
27. Shuai K., Hovarth C. M., Tsai-Huang L. H., Quereshi S. A., Cowburn D. and Darnell J. E. (1994) Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 76: 821-828
28. Gupta S., Yan H., Wong L. H., Ralph S., Krolewski J. and Schindler C. (1996) The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction of IFN-α signals. EMBO J. 15: 1075-1084
29. Pellegrini S., John J., Shearer M., Kerr I. M. and Stark G. R. (1989) Use of a selectable marker regulated by alpha interferon to obtain mutations in the signaling pathway. Mol. Cell. Biol. 9: 4605-4612
30. McKendry R., John J., Flavell D., Müller M., Kerr I. M. and Stark G. R. (1991) High frequency mutagenesis of human cells and characterization of a mutant unresponsive to both α and β interferons. Proc. Natl. Acad. Sci. USA 88: 11455-11459
31. Leung S., Qureshi S. A., Kerr I. M., Darnell J. E. and Stark G. R. (1995) Role of STAT2 in the alpha interferon signaling pathway. Mol. Cell. Biol. 15: 1312-1317
32. Darnell J. E., Kerr I. M. and Stark G. M. (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415-1421
33. Müller M., Laxton C., Briscoe J., Schindler C., Improta T., Darnell J. E. et al. (1993) Complementation of a mutant cell line: central role of the 91-kDa polypeptide of ISGF-3 in the interferon-α and γ signal transduction pathways. EMBO J. 12: 4221-4228
34. John J., McKendry R., Pellegrini S., Flavell D., Kerr I. M. and Stark G. (1991) Isolation and characterization of a new mutant human cell line unresponsive to alpha and beta interferons. Mol. Cell. Biol. 11: 4189-4195
35. Qureshi S. A., Leung S., Kerr I. M., Stark G. R. and Darnell J. E. (1996) Function of Stat2 protein in transcriptional activation by alpha interferon. Mol. Cell. Biol. 16: 288-293
36. Müller M., Briscoe J., Laxton C., Guschin D., Ziemiecki A., Silvennoinen O. et al. (1993) The protein tyrosine kinase Jak-1 complements defects in the interferon-α/β and -γ signal transduction pathways. Nature 366: 129-135
37. Lutfalla G., Holland S. J., Cinato E., Monneron D., Reboul J., Rogers N. et al. (1995) Mutant USA cells are complemented by an interferon-alpha beta receptor subunit generated by alternative processing of a new member of a cytokine receptor gene cluster. EMBO J. 14: 5100-5108
38. Novick D., Cohen B. and Rubinstein M. (1994) The human interferon α/β receptor: characterization and molecular cloning. Cell 77: 391-400
39. Colamonici O. R., Yan H., Domanski P., Handa R., Smalley D., Mullersman J. et al. (1994) Direct binding and tyrosine phosphorylation of the α-subunit of the type 1 IFN receptor by the p135-tyk2 tyrosine kinase. Mol. Cell. Biol. 14: 8133-8142
40. Farrar M. A. and Schreiber R. D. (1993) The molecular cell biology of interferon-γ and its receptor. Annu. Rev. Immunol. 11: 571-611
41. Decker T., Lew D. J., Mirkovitch J. and Darnell J. E. (1991) Cytoplasmic activation of GAF, an IFN-γ regulated DNA binding factor. EMBO J. 10: 927-932
42. Lew D. J., Decker T., Strehlow I. and Darnell J. E. (1991) Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons. Mol. Cell. Biol. 11: 182-191
43. Pearse R. N., Feinman R., Shuai K., Darnell J. E. and Ravetch J. V. (1993) Interferon gamma-induced transcription of the high affinity Fc receptor for IgG requires assembly of a complex that includes the 91 kDa subunit of transcription factor ISGF-3. Proc. Natl. Acad. Sci. USA 90: 4314-4318
44. Khan K. D., Shuai K., Lindwall G., Maher S. E., Darnell J. E. and Bothwell A. L. (1993) Induction of the Ly-6A/E gene by interferon α/β and γ requires a DNA element to which a tyrosine-phosphorylated 91-kDa protein binds. Proc. Natl. Acad. Sci. USA 90: 6806-6810
45. Wagner B. J., Hayes T. E., Hoban C. J. and Cochran B. H. (1990) The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter. EMBO J. 9: 4477-4484
46. Wakao H., Gouilleux F. and Groner B. (1994) Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the proloactin response. EMBO J. 13: 2182-2191
47. Wegenka U. A., Buschmann J., Lütticken C., Heinrich P. and Horn F. (1993) Acute-phase response factor, a nuclear factor binding to acute phase response elements, is rapidly activated by interleukin-6 at the post translation level. Mol. Cell. Biol. 13: 276-288
48. Shuai K., Schindler C, Prezioso V. and Darnell J. E. (1992) Activation of transcription by IFN-γ: tyrosine phosphorylation of a 91-kDa DNA binding protein. Science 258: 1808-1812
49. Silvennoinen O., Ihle J., Schlessinger J. and Levy D. E. (1993) Interferon-induced nuclear signaling by JAK protein tyrosine kinases. Nature 366: 583-585
50. Igarashi K., Garotta G., Ozmen L., Ziemiecki A., Wilks A. F., Harpur A. G. et al. (1994) Interferon-γ induces tyrosine phosphorylation of interferon-γ receptor and regulated association of protein tyrosine kinases, Jak1 and Jak2, with its receptor. J. Biol. Chem. 269: 14333-14336
51. Bach E. A., Szabo S. J., Dighe A. S., Ashkenazi A., Aguet M., Murphy K. M. et al. (1995) Ligand induced autoregulation of the IFN-γ receptor β chain expression in T helper cell subsets. Science 270: 1215-1218
52. Kotenko S., Izotova L., Pollack B., Mariano T., Donnelly R., Muthukumaran G. et al. (1995) Interaction between the components of the interferon-γ receptor complex. J. Biol. Chem. 270: 20915-20921
53. Kaplan D. H., Greenlund A. C., Tanner J. W., Shaw A. S. and Schreiber R. D. (1996) Identification of an interferon-γ receptor α-chain sequence required for Jak1 binding. J. Biol. Chem. 271: 9-12
54. Farrar M. A., Campbell J. D. and Schreiber R. D. (1992) Identification of a functionally important sequence in the C terminus of the interferon-γ receptor. Proc. Natl. Acad. Sci. USA 89: 11706-11710
55. Cook J. R., Jung V., Schwartz B., Wang P. and Pestka S. (1992) Structural analysis of the human interferon-γ receptor: a small segment of the intracellular domain is specifically required for class I major histocompatibility complex antigen induction and antiviral activity. Proc. Natl. Acad. Sci. USA 89: 11317-11321
56. Greenlund A. L., Farrar M. A., Viviano B. L. and Schreiber R. D. (1994) Ligand-induced IFN-γ receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 13: 1591-1600
57. Greenlund A. L., Morales M. O., Viviano B. L., Yan H., Krolewski J. and Schreiber R. D. (1995) STAT recruitment by tyrosine phosphorylated receptors: an ordered, reversible affinity driven process. Immunity 2: 677-687
58. Heim M. H., Kerr I. M., Stark G. R. and Darnell J. E. (1995) Contribution of STAT SH2 groups to specific interferon signaling by the JAK-STAT pathway. Science 267: 1347-1349
59. Zhong Z., Wen Z. and Darnell J. E. (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95-98
60. Silvennoinen O., Schindler C., Schlessinger J. and Levy D. E. (1993) Ras-independent signal transduction in response to growth factors and cytokines by tyrosine phosphorylation of a common transcription factor. Science 261: 1737-1739
61. Sadowski H. B., Shuai K., Darnell J. E. and Gilman M. Z. (1993) A common nuclear signal transduction pathway activated by growth factors and cytokine receptors. Science 261: 1739-1744
62. Heinrich P. C., Bernmann I., Müller-Newen G., Scharper F. and Graeve L. (1998) Interleukin-6-type cytokine signaling through the gp130/JAK/STAT pathway. Biochem. J. 334: 297-313
63. Bonni A., Frank D. A., Schindler C. and Greenberg M. E. (1993) Characterization of a pathway for ciliary neurotropic factor signaling to the nucleus. Science 262: 1575-1579
64. Durbin J. E., Hackenmiller R., Simon M. C. and Levy D. E. (1996) Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84: 443-450
65. Meraz M. A., White J. M., Sheehan K. C., Bach E. A., Rodig S. J., Dighe A. S. et al. (1996) Targeted disruption of the Stat1 gene in mice reveals unexpected physiological specificity in the JAK-STAT pathway. Cell 84: 431-442
66. Park C., Lecomte M.-J. and Schindler C. (1999) Murine Stat2 is uncharacteristically divergent. Nucl. Acids Res., in press
67. Zhong Z., Wen Z. and Darnell J. E. (1994) Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proc. Natl. Acad. Sci. USA 91: 4806-4810
68. Wegenka U. M., Lütticken C., Buschmann J., Yuan J., Lottspeich F., Mueller-Esterl W. et al. (1994) The interleukin-6-regulated acute phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. Mol. Cell. Biol. 14: 3186-3196
69. Raz R., Durbin J. E. and Levy D. E. (1994) Acute phase response factor and additional members of the Interferon stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. J. Biol. Chem. 269: 24391-24395
70. Akira S., Nishio Y., Inoue M., Wang X.-J., Wei S., Matsusaka T. et al. (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gpl 30-mediated signaling pathway. Cell 77: 63-71
71. Minami M., Inoue M., Wei S., Takeda K., Matsumoto M., Kishimoto T. et al. (1996) Stat3 activation is a critical step in gp-130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc. Natl. Acad. Sci. USA 93: 3963-3966
72. Nakajima K., Yamanaka Y., Nakae K., Kojima H., Ichiba M., Kiuchi N. et al. (1996) A central role for Stat3 in IL-6 induced regulation of growth and differentiation in MI leukemia cells hybridoma. EMBO J. 15: 3651-3658
73. Faris M., Kokot N. und Nel A. E. (1997) Involvement of Stat3 in interleukin-6 induced IgM production in a human B-cell line. Immunology 90: 350-357
74. Bonni A., Sun Y., Nadal-Vicens M., Bhatt A., Frank D. A., Rozovosky I. et al. (1997) Regulation of gliogensis in the central nervous system by the JAK-STAT signaling pathway. Science 278: 477-483
75. Niwa H., Burdon T., Chambers I. and Smith A. (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of Stat3. Genes Dev. 12: 2048-2060
76. Raz R., Lee C, K., Cannizzaro L. A., D'Eustachio P. and Levy D. E. (1999) Essential role of State3 for embryonic stem cell pluripotency. Proc. Natl. Acad. Sci. USA 96: 2846-2851
77. Turkson J., Bowman T., Garcia R., Caldenhoven E., Groot R. P. D. and Jove R. (1998) Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol. Cell. Biol. 18: 2545-2552
78. Danial N. N., Pernis A. and Rothman P. B. (1995) JAK-STAT signaling induced by the v-abl oncogene. Science 269: 1875-1877
79. Bromberg J. F., Horvath C. M., Besser D., Lathem W. W. and Darnell J. E. (1998) Stat3 activation is required for cellular transformation by v-src. Mol. Cell. Biol. 18: 2553-2558
80. Migone T.-S., Lin J.-X., Cereseto A., Mulloy J. C., O'Shea J. J., Franchini G. et al. (1995) Constitutively activated JAK-STAT pathway in T cells transformed with HTLV-1. Science 269: 1035-1042
81. Karras J. G., Wang Z., Huo L., Howard R. G., Frank D. A. and Rothstein T. L. (1997) Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in normal, self-renewing B-1 cells but only inducibly expressed in conventional B lymphocytes. J. Exp. Med. 185: 1035-1042
82. Yu C.-L., Meyer D. J., Campbell G. S., Larner A. C., Cater-Su C., Schwartz J. et al. (1995) Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269: 81-83
83. Kiuchi N., Nakajima K., Ichiba M., Fukada T., Narimatsu M., Mizuno K. et al. (1999) STAT3 is required for the gp130-mediated full activation of the c-myc gene. J. Exp. Med. 189: 63-73
84. Schwarze M. M. and Hawley R. G. (1995) Prevention of myeloma cell apoptosis by ectopic bel-2 expression or interleukin 6-mediated up-regulation of bcl-xL. Cancer Res. 55: 2262-2265
85. Fukada T., Hibi M., Yamanaka Y., Takahashi-Tezuka M., Fujitani Y., Yamaguchi T. et al. (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5: 449-460
86. Takeda K., Kaisho T., Yoshida N., Takeda J., Kishimoto T. and Akira S. (1998) Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 161: 4652-4660
87. Takeda K., Clausen B. E., Kaisho T., Tsujimura T., Terada N., Förster I. et al. (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10: 39-49
88. Riley J. K., Takeda K., Akira S. and Schreiber R. D. (1999) IL-10 receptor signaling through the JAK-STAT pathway: requirement for two distinct receptor derived signals for anti-inflammatory action. J. Biol Chem. 274: 16513-16521
89. Jacobson N. G., Szabo S. J., Weber-Nordt R. M., Zhong Z., Schreiber R. D., Darnell J. E. et al. (1995) Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J. Exp. Med. 181: 1755-1762
90. Herrada G. and Wolgemuth D. J. (1997) The mouse transcription factor Stat4 is expressed in haploid male germ cells and is present in the perinuclear theca of spermatozoa. J. Cell Sci. 110: 1543-1553
91. Azam M., Erdjument-Bromage H., Kreider B. L., Xia M., Quelle F., Basu R. et al. (1995) Interleukin-3 signals through multiple isoforms of Stat5. EMBO J. 14: 1402-1411
92. Mui A., Wakao H., O'Farrell A. M., Harada N. and Miyajima A. (1995) Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two Stat5 homologues. EMBO J. 14: 1166-1175
93. Liu X., Robinson G. W., Gouilleux F., Groner B. and Hennighausen L. (1995) Cloning and expression of Stat5 and an additional homolog (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc. Natl. Acad. Sci. USA 92: 8831-8835
94. Verdier F., Rabionet R., Gouilleux F., Beisenherz-Huss C., Varlet P., Muller O. et al. (1998) A sequence of the CIS gene promoter interacts preferentially with two associated STAT5A dimers: a distinct biochemical difference between STAT5A and STAT5B. Mol. Cell. Biol. 18: 5852-5860
95. Boucheron C., Dumon S., Santos S. C., Moriggl R., Hennighausen L., Gisselbrecht S. et al. (1998) A single amino acid in the DNA binding regions of STAT5A and STAT5B confers distinct DNA binding specificities. J. Biol. Chem. 273: 33936-33941
96. Gouilleux F., Pallard C., Dusanter-Fourt I., Wakao H., Haldosen L.-A., Norstedt G. et al. (1995) Prolactin, growth hormone, erythropoeitin and granulocyte-macrophage colony stimulating factor induce MGF-Stat5 DNA binding activity. EMBO J. 14: 2005-2013
97. Pallard C., Gouilleux F., Benit L., Cocault L., Souyri M., Levy D. et al. (1995) Thrombopoietin activates a Stat5-like factor in hematopoietic cells. EMBO J. 14: 2847-2856
98. Quelle F. W., Wang D., Nosaka T., Thierfelder W. E., Stravopodis D., Weinstein Y. et al. (1996) Erythropoietin induces activation of Stat5 through association with specific tyrosines on the receptor that are not required for a mitogenic response. Mol. Cell. Biol. 16: 1622-1631
99. Hou J., Schindler U., Henzel W. J., Wong S. C. and McKnight S. L. (1995) Identification and purification of human Stat proteins activated in response to interleukin-2. Immunity 2: 321-329
100. Lin J.-X., Migone T. S., Tsang M., Friedmann M., Weartherbee J. A., Zhou L. et al. (1995) The role of shared receptor motifs and common STAT proteins in the generation of cytokine pleitropy and redundancy by IL-2, Il-4, Il-7, IL-13, and IL-15. Immunity 2: 231-339
101. Yoshimura A., Ohkubo T., Kiguchi T., Jenkins N. A., Gilbert D. J., Copeland N. G. et al. (1995) A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine phosphorylated interluekin 3 and erythropoietin receptors. EMBO J. 14: 2816-2826
102. Yoshimura A., Ichihara M., Kinjyo I., Moriyama M., Copeland N. G., Gilbert D. J. et al. (1996) Mouse oncostatin M: an immediate early gene induced by multiple cytokines through the JAK-STAT5 pathway. EMBO J. 15: 1055-1063
103. Yip-Schneider M. T., Horie M. and Broxmeyer H. E. (1995) Transcriptional induction of pim-1 protein kinase gene expression by IFN-γ and posttranscriptional effects on costimulation with steel factor. Blood 85: 3494-3502
104. Ram P. A., Park S.-H., Choi H. K. and Waxman D. J. (1996) Growth hormone activation of Stat1, Stat3, and Stat5 in rat liver. J. Biol. Chem. 271: 5929-5940
105. Eilers A., Baccarini M., Horn F., Hipskind R. A., Schindler C. and Decker T. (1994) A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site. Mol. Cell. Biol. 14: 1364-1373
106. Meinke A., Barahmand-Pour F., Woehrl S., Stoiber D. and Decker T. (1996) Activation of different Stat5 isoforms contributes to cell-type-restricted signaling in response to interferons. Mol. Cell. Biol. 16: 6937-6944
107. Lokuta M. A., McDowell M. A. and Paulnock D. M. (1998) Cutting edge: identification of an additional isoform of Stat5 expressed in immature macrophages. J. Immumol. 161: 1594-1597
108. Lucas D. M., Lokuta M. A., McDowell M. A., Doan J. E. and Paulnock D. M. (1998) Analysis of the IFN-gamma-signaling pathway in macrophages at different stages of maturation. J. Immunol. 160: 4337-4342
109. Woldman I., Mellitzer G., Kieslinger M., Buchhart D., Meinke A., Beug H. et al. (1997) STAT5 involvement in the differentiation response of primary chicken myeloid progenitor cells to chicken myelomonocytic growth factor. J. Immunol. 159: 877-886
110. Meyer J., Jücker M., Ostertag W. and Stocking C. (1998) Carboxy-truncated Stat5β is generated by a nucleus-associated serine protease in early hematopoietic progenitors. Blood 91: 1901-1908
111. Azam M., Lee C., Strehlow I. and Schindler C. (1997) Functionally distinct isoforms of Stat5 are generated by protein processing. Immunity 6: 691-701
112. Udy G. B., Towers R. P., Snell R. G., Wilkins R. J., Park S. H., Ram P. A. et al. (1997) Requirement of Stat5b for sexual dimorphism of body growth rates and liver gene expression. Proc. Natl. Acad. Sci. USA 94: 7239-7244
113. Liu X., Robinson G. W., Wagner K. U., Garrett L., Wynshaw-Boris A. and Hennighausen L. (1997) Stat5a is manadatory for adult mammary gland development and lactogenesis. Genes Dev. 11: 179-186
114. Teglund S., McKay C., Schuetz E., VanDeursen J. M., Stravopodis D., Wang D. et al. (1998) Stat5a and Stat5b proteins have essential roles and nonessential, or redundant, roles in cytokine responses. Cell 93: 841-850
115. Kontanides H. and Reich N. C. (1993) Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL-4. Science 262: 1265-1267
116. Schindler C., Kashleva H., Pernis A., Pine R. and Rothman P. (1994) STF-IL4: a novel IL-4 induced signal transducting factor. EMBO J. 13: 1265-1267
117. Hou J., Schindler U., Henzel W. J., Ho T. C., Brasseur M. and McKnight S. L. (1994) An interleukin-4 induced transcription factor: Il-4 Stat. Science 265: 1701-1705
118. Kaplan M. H., Schindler U., Smiley S. T. and Grusby M. J. (1996) Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells. Immunity 4: 313-319
119. Shimoda K., Deursen J. van, Sangster M. Y., Sarawar S. R., Carson R. T., Tripp R. A. et al. (1996) Lack of IL-4 induces Th2 response in IgE class switching mice with disrupted Stat6 gene. Nature 280: 630-633
120. Takeda K., Tanaka T., Shi W., Matsumoto M., Minami M., Kashiwamura S. et al. (1996) Essential role of Stat6 in IL-4 signalling. Nature 380: 627-630
121. Abbas A., Lichtman A. H. and Pober J. S. (1991) Cytokines In: Cellular and Molecular Immunology, 1st edn, pp. 239-260, Wonsiewicz M. J. (ed.). Saunders. Philadelphia
122. Copeland N. G., Gilbert D. J., Schindler C., Zhong Z., Wen Z., Darnell J. E. et al. (1995) Evolution of the mammalian STAT gene family. Genomics 29: 225-228
123. Vinkemeier U., Cohen S. L., Moarefi I., Chait B. T., Kuriyan J. and Darnell J. E. (1996) DNA binding of in vivo activated Stat1α, Stat1β and truncated Stat1: interaction between NH2-terminal domains stabilizes binding of two dimers to tandem DNA sites. EMBO J. 15: 5616-5626.
124. Chen X., Winkemeier U., Zhao Y., Jeruzalmi D., Darnell J. E. and Kuriyan J. (1998) Crystal structure of a tyrosine phosphorylated Stat1 dimer bound to DNA. Cell 93: 827-839
125. Becker S., Groner B. and Müller C. W. (1998) Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature 394: 145-151
126. Xu X., Sun Y.-L. and Hoey T. (1996) Cooperative DNA binding and sequence-selective recognition conferred by the STAT amino-terminal domain. Science 273: 794-797
127. Vinkemeier U., Moarefi I., Darnell J. E. and Kuriyan J. (1998) Structure of the amino-terminal protein interaction domain of Stat-4. Science 279: 1048-1052
128. Zhang J. J., Vinkemeier U., Gu W., Chakravarti D., Horvath C. M. and Darnell J. E. (1996) Two contact regions between Stat1 and CBP/p300 in interferon-γ signaling. Proc. Natl. Acad. Sci. USA 93: 15092-15096
129. Strehlow I. and Schindler C. (1998) Amino terminal signal transducer and activator of transcription (STAT) domains regulate nuclear translocation and STAT deactivation. J. Biol. Chem. 273: 28049-28056
130. Shuai K., Liao J. and Song M. M. (1996) Enhancement of antiproliferative activity of gamma Interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. Mol. Cell. Biol. 16: 4932-4941
131. Horvath C. M., Stark G. R., Kerr I. M. and Darnell J. E. (1996) Interactions between STAT and non-STAT proteins in the interferon-stimulated gene factor 3 transcription complex. Mol. Cell. Biol. 16: 6957-6964
132. Martinez-Moczygemba M., Glutch M. J., French D. L. and Reich N. C. (1997) Distinct STAT structure promotes interaction of Stat2 with the p48 subunit of the interferon-α stimulated transcription factor ISGF3. J. Biol. Chem. 272: 20070-20076
133. Chung C. D., Liao J., Liu B., Rao X., Jay P., Berta P. et al. (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278: 1803-1805
134. Zhu M.-H., John S., Berg M. and Leonard W. J. (1999) Functional association of Nmi with Stat5 and Stat1 in IL-2 and IFNγ mediated signaling. Cell 96: 121-130
135. Liu B., Liao J., Rao X., Kushner S. A., Chung C. D., Chang D. D. et al. (1998) Inhibition of Stat1 mediated gene activation by PIAS1. Proc. Natl. Acad. Sci. USA 95: 10626-10631
136. Seidl H. M., Milocco L. H., Lamb P., Darnell J. E., Stein R. B. and Rosen J. B. (1995) Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. Proc. Natl. Acad. Sci. USA 92: 3041-3045
137. Horvath C. M., Wen Z. and Darnell J. E. (1995) A STAT protein domain that determines DNA sequence recognition suggests a novel DNA binding domain. Genes Dev. 9: 984-994
138. Schindler U., Wu P., Rothe M., Brasseur M. and McKnight S. L. (1995) Components of a STAT recognization code: evidence for two layers of molecular selectivity. Immunity 2: 689-697
139. Yamamoto K., Miura O., Hirosawa S. and Miyasaka N. (1997) Binding sequence of STAT4: STAT4 complex recognizes the IFN-gamma activation site (GAS)-like sequence (T/A)TTCC(C/G)GGAA(T/A). Biochem. Biophys. Res. Commun. 233: 126-132
140. Mikita T., Campbell D., Wu P., Williamson K. and Schindler U. (1996) Requirement for interleukin-4 induced gene expression and functional characterization of Stat6. Mol. Cell. Biol. 16: 5811-5820
141. Decker T., Kovarik P. and Meinke A. (1997) GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J. Interferon Cytokine Res. 17: 121-134
142. Hunter T. (1995) Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80: 225-236
143. Kawata T., Shevchenko A., Fukuzawa M., Jermyn K. A., Totty N. F., Zhukovskaya N. V. et al. (1997) SH2 signaling in a lower eukaryote: a STAT protein that regulates stalk cell differentiation in Dictyostelium. Cell 89: 909-916
144. Stahl N., Farruggella T. J., Boulton T. G., Zhong Z., Darnell J. E. and Yancopoulos G. D. (1995) Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 267: 1349-1352
145. Barahmand-Pour F., Meinke A., Groner B. and Decker T. (1998) Jak2-Stat5 interactions analyzed in yeast. J. Biol. Chem. 273: 12567-12575
146. Rothman P., Kreider B., Azam M., Levy D., Wegenka U., Eilers A. et al. (1994) Cytokines and growth factors signal through tyrosine phosphorylation of a family of related transcription factors. Immunity 1: 457-468
147. Ghislain J. and Fish E. N. (1996) Application of genomic DNA affinity chromatography identifies multiple interferon-alpha-regulated Stat2 complexes. J. Biol. Chem. 271: 12408-12413
148. Li X., Leung S., Qureshi S., Darnell J. E. and Stark G. R. (1996) Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-α. J. Biol. Chem. 271: 5790-5794
149. Caldenhoven E., Dijk T. B. van, Solari R., Armstrong J., Raaijmakers J. A., Lammers J.-W. et al. (1996) Stat3β, a splice variant of transcription Stat3, is a dominant negative regulator of transcription. J. Biol. Chem. 271: 13221-13227
150. Moriggl R., Gouilleux-Gruart V., Jaehne R., Berchtold S., Gatmann C., Liu X. et al. (1996) Deletion of the carboxy-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Mol. Cell. Biol. 16: 5691-5700
151. Moriggl R., Berchtold S., Friedrich K., Standke G. J., Kammer W., Heim M. et al. (1997) Comparison of the transactivation domains of Stat5 and Stat6 in lymphoid cells and mammary epithelial cells. Mol. Cell. Biol. 17: 3663-3678
152. Mui A. L.-F., Wakao H., Kinoshita T., Kitamura T. and Miyajima A. (1996) Suppression of interluekin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation. EMBO J. 15: 2425-2433
153. Lu B., Reichel M., Fisher D. A., Smith J. F. and Rothman P. (1997) Identification of the Stat6 domain required for IL-4 induced activation of transcription. J. Immunol 159: 1255-1264
154. Sadowski I. and Ptashne M. (1989) A vector for expressing GAL (1 147) fusions in mammalian cells. Nucleic Acids Res. 18: 7539
155. Sasse J., Hemmann U., Schwartz C., Schiertshauer U., Heesel B., Landgraf C. et al. (1997) Mutational analysis of acute response factor/Stat3 activation and dimerization. Mol. Cell. Biol. 17: 4677-4686
156. Wang D., Stravopodis D., Teglund S., Kitazawa J. and Ihle J. N. (1996) Naturally occurring dominant negative variants of Stat5. Mol. Cell. Biol. 16: 6141-6148
157. Schaefer T. S., Sanders L. K. and Nathans D. (1995) Cooperative transcriptional activity of Jun and Stat2β, a short form of Stat3. Proc. Natl. Acad. Sci. USA 92: 9097-9101
158. Schaefer T. S., Sanders L. K., Park O. K. and Nathans D. (1997) Functional differences between Stat3α and Stat3β. Mol. Cell. Biol. 17: 5307-5316
159. Bovolenta C., Testolin L., Benussi L., Lievens P. M. and Liboi E. (1998) Positive selection of apoptosis-resistant cells correlates with activation of dominant-negative Stat5. J. Biol. Chem. 273: 20779-20784
160. Wozniak R. W., Rout M. P. and Aitchinson J. D. (1998) Karyopherins and kissing cousins. Trends Cell Biol. 8: 184-188
161. Sekimoto T., Nakajima K., Tachibana T., Hirano T. and Yoneda Y. (1996) Interferon-γ-dependent nuclear import of Stat1 is mediated by the GTPase activity of Ran/TC4. J. Biol. Chem. 271: 31017-31020
162. Sekimoto T., Imamoto N., Nakajima K., Tachibana T., Hirano T. and Yoneda Y. (1997) Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation of NPI-1, but not Rch1. EMBO J. 16: 7076-7077
163. Israel A. (1994) NF-AT come under control. Nature 369: 443-444
164. Finco T. S. and Baldwin A. S. (1995) Mechanistic aspects of NF-κB regulation: the emerging role of phosphorylation and protcolysis. Immunity 3: 263-272
165. Zhang Z., Blenis J., Li H.-C, Schindler C. and Chen-Kiang S. (1995) Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science 267: 1990-1994
166. Kumar A., Commane M., Flickinger T. W., Horvarth C. M. and Stark G. R. (1997) Defective TNF-α induced apoptosis in Stat1 null cells due to low constitutive levels of caspases. Science 278: 1630-1632
167. Schindler C. (1998) STATs as activators of apoptosis. Trends Cell Biol. 8: 97-98
168. Wong A. H.-T., Tam N. W. N., Yang Y.-L., Cuddihy A. R., Li S., Kirchhoff S. et al. (1997) Physical association between Stat1 and the interferon-inducible protein kinase PKR and implications for Interferon and double-stranded RNA signaling pathways. EMBO J. 16: 1291-1304
169. Pfeffer L. M., Mullersman J. E., Pfeffer S. R., Murti A., Shi W. and Yang C. H. (1997) Stat3 as an adapter to couple phosphatidylinostol 3-kinase to the INFAR1 chain of the type I interferon receptor. Science 276: 1418-1420
170. Proud C. G. (1995) PKR: a new name and new roles. Trends Biochem. Sci. 20: 241-246
171. Uzé G., Lutfalla G. and Gresser I. (1990) Genetic transfer of a functional human interferon-α receptor into most cells: cloning and expression of its cDNA. Cell 60: 225-234
172. Yang C. H., Shi W., Basu L., Murti A., Constantinescu S. N., Blatt L. et al. (1996) Direct association of STAT3 with the IFNAR-1 chain of the human type I interferon receptor. J. Biol. Chem. 271: 8057-8061
173. Kinoshita T., Yokota T., Arai K. and Miyajima A. (1995) Suppression of apoptotic death in hematopoictic cells by signaling through the IL-3/GM-CSF receptors. EMBO J. 14: 266-275
174. Fukada T., Ohtani T., Yoshida Y., Shirogane T., Nishida K., Nakajima K. et al. (1998) STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition. EMBO J. 17: 6670-6677
175. Chin Y. E., Kitagawa M., Su W.-C., You Z.-H., Iwamoto Y. and Fu X.-Y. (1996) Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21WAF1/CIP1 mediated by Stat1. Science 272: 719-722
176. Kaplan M. H., Daniel C., Schindler U. and Grusby M. J. (1998) Stat proteins control lymphocyte proliferation by regulating p27Kip1 expression. Mol. Cell. Biol. 18: 1996-2003
177. Matsumura I., Ishikawa J., Nakajima K., Oritani K., Tomiyama Y., Miyagawa J.-I. et al. (1997) Thrombopoietin induced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21WAF/Cip1 by STAT5. Mol. Cell. Biol. 17: 2933-2943