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Signalling

STATs: transcriptional control and biological impact

Nature Reviews Molecular Cell Biology volume 3, pages 651–662 (2002)Cite this article

Key Points

  • Signal transducer and activator of transcription (STAT) proteins are latent in the cytoplasm until activated through receptor-mediated tyrosine phosphorylation — often, but not exclusively by kinases of the JAK family — leading to SH2-domain-dependent dimerization and nuclear translocation.

  • STAT nuclear translocation depends on sequence motifs formed during dimerization, and they remain nuclear until dephosphorylated by a nuclear tyrosine phosphatase, allowing subsequent active nuclear export. So, the most common cycle of STAT activation involves cytoplasmic recruitment to activated cell-surface receptors, tyrosine phosphorylation, receptor release and dimerization, nuclear translocation and DNA binding, coactivator recruitment and gene transcription, nuclear dephosphorylation, and return to the cytoplasm by active nuclear export, followed by possible reactivation due to continued kinase activity.

  • Negative regulators of STATs include cytoplasmic tyrosine phosphatases that counteract Janus kinase (JAK) action, induced suppressor of cytokine signalling (SOCS) proteins that inhibit receptor and JAK function, proteins that inhibit activated STAT (PIAS) proteins that prevent STAT DNA binding, nuclear phosphatases that deactivate STATs, and truncated STAT proteins that can function in a dominant-inhibitory mode.

  • Transcriptional activation of target gene expression relies on coactivator recruitment by STAT transactivation domains, relying on a variety of acetyltransferases, minichromosome maintenance (MCM) proteins, and additional factors yet to be identified.

  • STAT proteins participate in many signalling systems, providing an almost universal paradigm for signalling from cytokine receptors and a commonly used system for growth factor receptors. Target genes dependent on STATs influence growth, survival, apoptosis, host defence, stress and differentiation functions, depending on the signalling pathway and the target tissue. Characterization of JAK and STAT mutations in a variety of organisms, from slime moulds to flies to mice to humans, is beginning to clarify the variety of STAT-dependent biological processes in vivo.

Abstract

Extracellular proteins bound to cell-surface receptors can change nuclear gene expression patterns in minutes, with far-reaching consequences for development, cell growth and homeostasis. The signal transducer and activator of transcription (STAT) proteins are among the most well studied of the latent cytoplasmic signal-dependent transcription-factor pathways. In addition to several roles in normal cell decisions, dysregulation of STAT function contributes to human disease, making the study of these proteins an important topic of current research.

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Figure 1: Canonical JAK–STAT pathway.
Figure 2: Janus kinase domain structure.
Figure 3: STAT domain structure and protein binding sites.
Figure 4: The negative regulators of STAT proteins.

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References

  1. Fu, X.-Y., Schindler, C., Improta, T., Aebersold, R. & Darnell, J. E. Jr. The proteins of ISGF-3: the interferon α-induced transcriptional activator, define a gene family involved in signal transduction. Proc. Natl Acad. Sci. USA 89, 7840–7843 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schindler, C., Fu, X.-Y., Improta, T., Aebersold, R. & Darnell, J. E. Jr. Proteins of transcription factor ISGF-3: one gene encodes the 91 and 84 kDa ISGF-3 proteins that are activated by inteferon-α. Proc. Natl Acad. Sci. USA 89, 7836–7839 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schindler, C., Shuai, K., Prezioso, V. R. & Darnell, J. E. Jr. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 257, 809–815 (1992).This paper showed that STAT proteins are tyrosine phosphorylated in response to IFN.

    Article  CAS  PubMed  Google Scholar 

  4. Darnell, J. E. Jr, Kerr, I. M. & Stark, G. M. Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Stark, G. R., Kerrr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. O'Shea, J. J. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 7, 1–11 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Horvath, C. M. STAT proteins and transcriptional responses to extracellular signals. Trends Biochem. Sci. 25, 496–502 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Vinkemeier, U. et al., DNA binding of in vitro 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 (1996).This provided the basis for STAT crystallization of proteolytic fragments and also the indication that cooperative interaction between dimeric STAT molecules contributes to DNA binding.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Heinrich, P. C., Behrmann, I., Muller-Newen, G., Schaper, F. & Braeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J. 334, 297–314 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Greenlund, A. C. et al. Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process. Immunity 2, 677–687 (1995).Evidence is provided for the mechanism of STAT recruitment and release by cytokine receptors.

    Article  CAS  PubMed  Google Scholar 

  11. Rane, S. G. & Reddy, E. P. JAKs, STATs and Src kinases in hematopoiesis. Oncogene 21, 3334–3358 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Luo, H., Hanratty, W. P. & Dearolf, C. R. An amino acid substitution in the Drosophila hopTum-l Jak kinase causes leukemia-like defects. EMBO J. 14, 1412–1420 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zeidler, M. P., Bach, E. A. & Perrimon, N. The roles of the Drosophila JAK/STAT pathway. Oncogene 19, 2598–2606 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Constantinescu, S. N. et al. Ligand-independent oligomerizaiton of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc. Natl Acad. Sci. USA 98, 4379–4384 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Collum, R. G., Brutsaert, S., Lee, G. & Schindler, C. A Stat3-interacting protein (StIP1) regulates cytokine signal transduction. Proc. Natl Acad. Sci. USA 97, 10120–10125 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Usacheva, A. et al. The WD motif-containing protein receptor for activated protein kinase C (RACK1) is required for recruitment and activation of signal transducer and activator of transcription 1 through the type I interferon receptor. J. Biol. Chem. 276, 22948–22953 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Kim, J.-H., Lane, W. S. & Reinberg, D. Human Elongator facilitates RNA polymerase II transcription through chromatin. Proc. Natl Acad. Sci. USA 99, 1241–1246 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lackmann, M. et al. Biomolecular interaction analysis of IFN γ-induced signaling events in whole-cell lysates: prevalence of latent STAT1 in high-molecular weight complexes. Growth Factors 16, 39–51 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Chatterjee-Kishore, M., Wright, K. L., Ting, J. P. & Stark, G. R. How Stat1 mediates constitutive gene expression: a complex of unphosphorylated Stat1 and IRF1 supports transcription of the LMP2 gene. EMBO J. 19, 4111–4122 (2000).This paper indicates an alternative, non-canonical mechanism for transcriptional activation by STATs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen, X. et al. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 93, 827–839 (1998).This paper reports the three-dimensional structure of STAT1.

    Article  CAS  PubMed  Google Scholar 

  21. Ndubuisi, M. I., Guo, G. G., Fried, V. A., Etlinger, J. D. & Sehgal, P. B. Cellular physiology of STAT3: where's the cytoplasmic monomer? J. Biol. Chem. 274, 25499–25509 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Bluyssen, H. A. R., Durbin, J. E. & Levy, D. E. ISGF3γp48, a specificity switch for IFN activated transcription factors. Cytokine Growth Factor Rev. 7, 11–17 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Wong, L. H. et al. Isolation and characterization of a human STAT1 gene regulatory element. Inducibility by interferon (IFN) types I and II and role of IRF regulatory factor-1. J. Biol. Chem. 277, 19408–19417 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Decker, T. & Kovarik, P. Serine phosphorylation of STATs. Oncogene 19, 2628–2637 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Okamoto, T., Schlegel, A., Scherer, P. E. & Lisanti, M. P. Caveolins, a family of scaffolding proteins for organizing 'preassembled signaling complexes' at the plasma membrane. J. Biol. Chem. 273, 5419–5422 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Sehgal, P. B., Guo, G. G., Shah, M., Kumar, V. & Patel, K. Cytokine signaling. STATs in plasma membrane rafts. J. Biol. Chem. 177, 12067–12074 (2002).

    Article  CAS  Google Scholar 

  27. Taniguchi, T. & Takaoka, A. A weak signal for strong responses: interferon-α/β revisited. Nature Rev. Mol. Cell. Biol. 2, 378–386 (2001).

    Article  CAS  Google Scholar 

  28. Schlegel, A. & Lisanti, M. P. The caveolin triad: caveolae biogenesis, cholesterol trafficking, and signal transduction. Cytokine Growth Factor Rev. 12, 41–51 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Krebs, D. L. & Hilton, D. J. SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19, 378–387 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Bianchi, M., Meng, C. & Ivashkiv, L. B. Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids. Proc. Natl Acad. Sci. USA 97, 9573–9578 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, I. H., Li, W. P., Hisert, K. B. & Ivashkiv, L. B. Inhibition of interleukin 2 signaling and signal transducer and activator of transcription (STAT)5 activation during T cell receptor-mediated feedback inhibition of T cell expansion. J. Exp. Med. 190, 1263–1274 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. David, M., Petricoin, E. III & Larner, A. C. Activation of protein kinase A inhibits interferon induction of the Jak/Stat pathway in U266 cells. J. Biol. Chem. 271, 4585–4588 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Darnell, J. E. Jr. STATs and gene regulation. Science 277, 1630–1635 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Becker, S., Groner, B. & Muller, C. W. Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature 394, 145–151 (1998).This paper reports on the three-dimensional structure of STAT3.

    Article  CAS  PubMed  Google Scholar 

  35. Yang, E., Henriksen, M. A., Schaefer, O., Zakharova, N. & Darnell, J. E. Jr. Dissociation time from DNA determines transcriptional function in a STAT1 linker mutant. J. Biol. Chem. 277, 13455–13462 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Vinkemeier, U., Moarefi, I., Darnell, J. E. Jr & Kuriyan, J. Structure of the amino-terminal protein interaction domain of STAT-4. Science 279, 1048–1052 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Murphy, T. L., Geissal, E. D., Farrar, D. & Murphy, K. M. Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation. Mol. Cell. Biol. 20, 7121–7131 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu, X., Ya-Lin, S. & Hoey, T. Cooperative DNA binding and sequence selective recognition conferred by the Stat amino terminal domain. Science 273, 794–797 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, X. & Darnell, J. E. Jr. Functional importance of Stat3 tetramerization in activation of the α2-macroglobulin gene. J. Biol. Chem. 276, 33576–33581 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. John, S., Vinkemeier, U., Soldaini, E., Darnell, J. E. Jr & Leonard, W. J. The significance of tetramerization in promoter recruitment by Stat5. Mol. Cell. Biol. 19, 1910–1918 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Strehlow, I. & Schindler, C. Amino-terminal signal transducer and activator of transcription (STAT) domains regulate nuclear translocation and STAT deactivation. J. Biol. Chem. 273, 28049–28056 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Shuai, K., Liao, J. Y. & Song, M. M. Enhancement of antiproliferative activity of γ interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. Mol. Cell. Biol. 16, 4932–4941 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mattaj, I. W. & Englmeier, L. Nucleocytoplasmic transport: the soluble phase. Annu. Rev. Biochem. 67, 265–306 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Sekimoto, T., Imamoto, N., Nakajima, K., Hirano, T. & Yoneda, Y. Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1. EMBO J. 16, 7067–7077 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. McBride, K. M., Banninger, G., McDonald, C. & Reich, N. C. Regulated nuclear import of the STAT1 transcription factor by direct binding of importin-α. EMBO J. 21, 1754–1763 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fagerlund, R., Melén, K., Kinnunen, L. & Julkunen, I. Argine/lysine-rich NLSs mediate interactions between dimeric STATs and importin α5. J. Biol. Chem. 277, 30072–30078 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Melen, K., Kinnunen, L. & Julkunen, I. Arginine/lysine-rich structural element is involved in interferon-induced nuclear import of STATs. J. Biol. Chem. 276, 16447–16455 (2001).

    CAS  PubMed  Google Scholar 

  48. Meyer, T., Begitt, A., Lodige, I., van Rossum, M. & Vinkemeier, U. Constitutive and IFN-γ-induced nuclear import of STAT1 proceed through independent pathways. EMBO J. 21, 344–354 (2002).References 44–48 outline distinct mechanisms for constitutive and induced STAT nuclear translocation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kumar, A., Commane, M., Flickinger, T. W., Horvath, C. M. & Stark, G. R. Defective TNF-α-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 278, 1630–1632 (1997).This provides evidence that unphosphorylated STAT1 has a function distinct from the activated form.

    Article  CAS  PubMed  Google Scholar 

  50. McBride, K. M., McDonald, C. & Reich, N. C. Nuclear export signal located within the DNA-binding domain of the STAT1transcription factor. EMBO J. 19, 6196–6206 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Begitt, A., Meyer, T., van Rossum, M. & Vinkemeier, U. Nucleocytoplasmic translocation of STAT1 is regulated by leucine-rich export signal in the coiled-coil domain. Proc. Natl Acad. Sci. USA 97, 10418–10423 (2000).References 50 and 51 describe sequences involved in nuclear export.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Haspel, R. L. & Darnell, J. E. Jr. A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1. Proc. Natl Acad. Sci. USA 96, 10188–10193 (1999).Provides evidence that downregulation of STAT activation occurs by dephosphorylation in the nucleus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ibarra-Sanchez, M. J. et al. The T-cell protein tyrosine phosphatase. Semin. Immunol. 12, 379–386 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. ten Hoeve, J. et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol. 22 (in the press).This reports on the identification of a potential STAT nuclear phosphatase.

  55. Aoki, N. & Matsuda, T. A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus. Mol. Endocrinol. 16, 58–69 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Simonocic, P. D., Lee-Loy, A., Barber, D. L., Tremblay, M. L. & McGlade, C. J. The T cell protein tyrosine phosphatase is a negative regulator of Janus family kinases 1 and 3. Curr. Biol. 12, 446–453 (2002).

    Article  Google Scholar 

  57. Aoki, N. & Matsuda, T. A cytosolic protein-tyrosine phosphatase PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b. J. Biol. Chem. 275, 39718–39726 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. You, M., Yu, D. H. & Feng, G. S. Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol. Cell. Biol. 19, 2416–2424 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. David, M., Chen, H. E., Goelz, S., Larner, A. C. & Neel, B. G. Differential regulation of the α/β interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol. Cell. Biol. 15, 7050–7058 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lee, C.-K., Bluyssen, H. A. R. & Levy, D. E. Regulation of interferon-α responsiveness by the duration of Janus kinase activity. J. Biol. Chem. 272, 21872–21877 (1997).Evidence that the duration of STAT activity is tightly coupled to the kinetics of JAK catalytic activity.

    Article  CAS  PubMed  Google Scholar 

  61. Klingmuller, U., Lorenz, U., Cantley, L. C., Neel, B. G. & Lodish, H. Specific recruitment of SH-PTP-1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80, 729–738 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Dong, F., Qiu, Y., Yi, T., Touw, I. P. & Larner, A. C. The carboxyl terminus of the granulocyte colony-stimulating factor receptor, truncated in patients with severe congenital neutropenia/acute myeloid leukemia, is required for SH2-containing phosphatase-1 suppression of Stat activation. J. Immunol. 167, 6447–6452 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Zabolotny, J. M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489–495 (2002).Together with reference 61 , this shows that receptor-associated phosphatases participate in controlling JAK–STAT signalling.

    Article  CAS  PubMed  Google Scholar 

  64. Starr, R. & Hilton, D. J. Negative regulation of the JAK/STAT pathway. Bioassays 21, 47–52 (1999).

    Article  CAS  Google Scholar 

  65. Endo, T. A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921–924 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Naka, T. et al. Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924–929 (1997).References 64–66 identify the family of SOCS negative regulators.

    Article  CAS  PubMed  Google Scholar 

  67. Yoshimura, A. et al. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J. 14, 2816–2826 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Egwuagu, C. E. et al. Suppressors of cytokine signaling proteins are differentially expressed in TH1 and TH2 cells: implications for TH cell lineage commitment and maintenance. J. Immunol. 168, 3181–3187 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Metcalf, D. et al. Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppresor of cytokine signaling-1 (SOCS-1). Proc. Natl Acad. Sci. USA 99, 943–948 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhang, J. G. et al. The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo. Proc. Natl Acad. Sci. USA 98, 13261–13265 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Marine, J. C. et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98, 617–627 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Roberts, A. W. et al. Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc. Natl Acad. Sci. USA 98, 9324–9329 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Krebs, D. L. et al. Socs-6 binds to insulin receptor substrate 4, and mice lacking the Socs-6 gene exhibit mild growth retardation. Mol. Cell. Biol. 22, 4567–4578 (2002).References 68–73 give accounts of defects in Socs knockouts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chung, C. D. et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science 278, 1803–1805 (1997).

    Article  CAS  PubMed  Google Scholar 

  75. Shuai, K. Modulation of STAT signaling by STAT-interacting proteins. Oncogene 19, 2638–2644 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Zeidler, M. P., Perrimon, N. & Strutt, D. I. Polarity determination in the Drosophila eye: a novel role for unpaired and JAK/STAT signaling. Genes Dev. 13, 1342–1353 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Betz, A., Lampen, N., Martinek, S., Young, M. W. & Darnell, J. E. Jr. A Drosophila PIAS homologue negatively regulates Stat92E. Proc. Natl Acad. Sci. USA 98, 9563–9568 (2001).References 74 and 77 report the discovery of negative activity of PIAS on STATs in cell culture and in flies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jackson, P. K. A new RING for SUMO: wrestling transcriptional responses into nuclear bodies with PIAS family E3 SUMO ligases. Genes Dev. 15, 3053–3058 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Yoo, J. Y., Huso, D. L., Nathans, D. & Desiderio, S. Specific ablation of Stat3β distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Cell 108, 331–344 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Henriksen, M., Betz, A., Fuccillo, M. V. & Darnell, J. E. Jr. Negative regulation of STAT92E by an N-terminally truncated STAT protein derived from an alternative promoter site. Genes Dev. (in the press).

  81. Yan, R., Small, S., Desplan, C., Dearolf, C. R. & Darnell, J.E. Jr. Identification of a Stat gene that functions in Drosophila development. Cell 84, 421–430 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Hou, X. S., Melnick, M. B. & Perrimon, N. Marelle acts downstream of the Drosophila HOP/JAK kinase and encodes a protein similar to the mammalian STATs. Cell 84, 411–419 (1996).Identification of the JAK–STAT pathway in Drosophila.

    Article  CAS  PubMed  Google Scholar 

  83. Seidel, H. M. et al. Spacing of palindromic half sites as a determinant of selective STAT DNA binding and transcriptional activity. Proc. Natl Acad. Sci. USA 92, 3041–3045 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ehret, G. B. et al. DNA binding specificity of different STAT proteins. Comparisons of in vitro specificity with natural target sites. J. Biol. Chem. 276, 6675–6688 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Der, S. D., Zhou, A., Williams, B. R. G. & Silverman, R. H. Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays. Proc. Natl Acad. Sci. USA 95, 15623–15628 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mowen, K. A. et al. Arginine methylation of STAT1 modulates IFNα/β-induced transcription. Cell 104, 731–741 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. McDonald, C. & Reich, N. C. Cooperation of the transcriptional co-activators CBP and p300 with Stat6. J. Interferon Cytokine Res. 19, 711–722 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Shankaranarayanan, P., Chaitidis, P., Kuhn, H. & Nigam, S. Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. J. Biol. Chem. 276, 42753–42760 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Zhang, Z., Jones, S., Hagood, J. S., Fuentes, N. L. & Fuller, G. M. STAT3 acts as a co-activator of glucocorticoid receptor signaling. J. Biol. Chem. 272, 30607–30610 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Shen, Y. & Darnell, J.E. Jr. Antiviral response in cells containing Stat1 with heterologous transactivation domains. J. Virol. 75, 2627–2633 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang, J. J. et al. Ser 727-dependent recruitment of MCM5 by Stat1α in IFN-γ-induced transcriptional activation. EMBO J. 17, 6963–6971 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Paulson, M. et al. Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J. Biol. Chem. 274, 25343–25349 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. Paulson, M., Press, C., Smith, E., Tanese, N. & Levy, D. E. IFN-stimulated transcription through a TBP-free acetyltransferase complex escapes viral shutoff. Nature Cell Biol. 4, 140–147 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Malik, S. & Roeder, R. G. Transcriptional regulation through Mediator-like co-activators in yeast and metazoan cells. Trends Biochem. Sci. 25, 277–283 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Look, D. C., Pelletier, M. R., Tidwell, R. M., Roswit, W. T. & Holtzman, M. J. Stat 1 depends on transcriptional synergy with Sp1. J. Biol. Chem. 270, 30264–30267 (1995).

    Article  CAS  PubMed  Google Scholar 

  96. Muhlethaler-Mottet, A., Di Berardino, W., Otten, L. A. & Mach, B. Activation of the MHC class II transactivator CIITA by interferon-γ requires cooperative interaction between Stat1 and USF-1. Immunity 8, 57–166 (1998).

    Article  Google Scholar 

  97. Stoecklin, E., Wissler, M., Gouilleux, F. & Groner, B. Functional interactions between Stat5 and the glucocorticoid receptor. Nature 383, 726–728 (1996).

    Article  CAS  Google Scholar 

  98. Delphin, S. & Stavenezer, J. Characterization of an interleukin 4 (IL-4) responsive region in the immunoglobulin heavy chain germline epsilon promoter: regulation by NF-IL-4, a C/EBP family member and NF-κB/p50. J. Exp. Med. 181, 181–192 (1995).

    Article  CAS  PubMed  Google Scholar 

  99. Zhu, M., John, S., Berg, M. & Leonard, W. J. Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNγ-mediated signaling. Cell 96, 121–130 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Schaefer, T. S., Sanders, L. K. & Nathans, D. Cooperative transcriptional activity of Jun and Stat3β, a short form of Stat3. Proc. Natl Acad. Sci. USA 92, 9097–9101 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nakashima, K. et al. Synergistic signaling in fetal brain by STAT3–Smad1 complex bridged by p300. Science 284, 479–482 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Ueda, T., Bruchovsky, N. & Sadar, M. D. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J. Biol. Chem. 277, 7076–7085 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Morris, A. C., Beresford, G. W., Mooney, M. R. & Boss, J. M. Kinetics of a γ interferon response: expression and assembly of CIITA promoter IV and inhibition by methylation. Mol. Cell. Biol. 22, 4781–4791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nusslein-Volhard, C. & Wieshaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 (1980).

    Article  CAS  PubMed  Google Scholar 

  105. Brown, S., Hu, N. & Hombria, J. C. Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr. Biol. 11, 1700–1705 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Yan, R., Lou, H., Darnell, J. E. Jr & Dearolf, C. R. A JAK–STAT pathway regulates wing vein formation in Drosophila. Proc. Natl Acad. Sci. USA 93, 5842–5847 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tulina, N. & Matunis, E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK–STAT signaling. Science 294, 2546–2549 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B. & Fuller, M. T. Stem cell self-renewal specified by JAK–STAT activation in response to a support cell cue. Science 294, 2542–2545 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Silver, D. L. & Montell, D. J. Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila. Cell 107, 831–841 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Teglund, S. et al. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93, 841–850 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Liu, X. et al. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 11, 179–186 (1997).

    Article  CAS  PubMed  Google Scholar 

  112. Socolovsky, M., Fallon, A. E., Wang, S., Brugnara, C. & Lodish, H. F. Fetal anemia and apoptosis of red cell progenitors in Stat5a−/−5b−/− mice: a direct role for Stat5 in Bcl-X(L)induction. Cell 98, 181–191 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Socolovsky, M., et al. Ineffective erythropoiesis in Stat5a(−/−) 5b(−/−) mice due to decreased survival of early erythroblasts. Blood 98, 3261–3273 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Moriggl, R. et al. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10, 249–259 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Bunting, K. D. et al. Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5. Blood 99, 479–487 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl Acad. Sci. USA 94, 3801–3804 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Akira, S. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 19, 2607–2611 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Levy, D. E. & Lee, C. K. What does Stat3 do? J. Clin. Invest. 109, 1143–1148 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Durbin, J. E., Hackenmiller, R., Simon, M. C. & Levy, D. E. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84, 443–450 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Meraz, M. A. et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK–STAT signaling pathway. Cell 84, 431–442 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Park, C., Li, S., Cha, E. & Schindler, C. Immune response in Stat2 knockout mice. Immunity 13, 795–804 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Dupuis, S. et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293, 300–303 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Alonzi, T. et al. Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation in the liver. Mol. Cell. Biol. 21, 1621–1632 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Takeda, K. et al. 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 (1998).

    CAS  PubMed  Google Scholar 

  125. Takeda, K. et al. Enhanced TH1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Lee, C.-K. et al. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity (in the press).

  127. Levy, D. E. & Garcia-Sastre, A. The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion. Cytokine Growth Factor Rev. 12, 143–156 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Miller, D. M. et al. Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. J. Exp. Med. 187, 675–683 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Parisien, J. P., Lau, J. F., Rodriguez, J. J., Ulane, C. M. & Horvath, C. M. Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of α/β interferon signal transduction. J. Virol. 76, 4190–4198 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Parisien, J. P. et al. The V protein of human parainfluenza virus 2 antagonizes type I interferon responses by destabilizing signal transducer and activator of transcription 2. Virology 283, 230–239 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Garcin, D., Curran, J., Itoh, M. & Kolakofsky, D. Longer and shorter forms of Sendai virus C proteins play different roles in modulating the cellular antiviral response. J. Virol. 75, 6800–6807 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Polyak, S. J. et al. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J. Virol. 75, 6095–6106 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. von Kobbe, C. et al. Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98. Mol. Cell 6, 1243–1252 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Her, L. S., Lund, E. & Dahlberg, J. E. Inhibition of Ran guanosine triphosphatase-dependent nuclear transport by the matrix protein of vesicular stomatitis virus. Science 276, 1845–1848 (1997).

    Article  CAS  PubMed  Google Scholar 

  135. Enninga, J., Levy, D. E., Blobel, G. & Fontoura, B.M. A. Role of nucleoporin induction in releasing an mRNA nuclear export block. Science 295, 1523–1525 (2002).References 127–135 show viral strategy for avoiding IFN response and cell strategy for survival.

    Article  CAS  PubMed  Google Scholar 

  136. Yalamanchili, P., Harris, K., Wimmer, E. & Dasgupta, A. Inhibition of basal transcription by poliovirus: a virus- encoded protease (3Cpro) inhibits formation of TBP–TATA box complex in vitro. J. Virol. 70, 2922–2929 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).

    Article  CAS  PubMed  Google Scholar 

  138. Kaplan, D. H. et al. Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice. Proc. Natl Acad. Sci. USA 95, 7556–7561 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lee, C. K., Smith, E., Gimeno, R., Gertner, R. & Levy, D. E. STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-γ. J. Immunol. 164, 1286–1292 (2000).

    Article  CAS  PubMed  Google Scholar 

  140. Lee, C. K. et al. Distinct requirements for IFNs and STAT1 in NK cell function. J. Immunol. 165, 3571–3577 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Bowman, T. & Jove, R. STAT Proteins and cancer. Cancer Control 6, 615–619 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Bromberg, J. F. et al. Stat3 as an oncogene. Cell 98, 295–303 (1999).

    Article  CAS  PubMed  Google Scholar 

  144. Bowman, T., Garcia, R., Turkson, J. & Jove, R. STATs in oncogenesis. Oncogene 19, 2474–2488 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Song, J. I. & Grandis, J. R. STAT signaling in head and neck cancer. Oncogene 19, 2489–2495 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. Yoshikawa, H. et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nature Genet. 28, 29–35 (2001).

    CAS  PubMed  Google Scholar 

  147. Zhang, Q. et al. Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma. J. Immunity 168, 466–474 (2002).

    Article  CAS  Google Scholar 

  148. Vignais, M. L., Sadowski, H. B., Watling, D., Rogers, N. C. & Gilman, M. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol. Cell. Biol. 16, 1759–1769 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Leaman, D. W. et al. Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. Mol. Cell. Biol. 16, 369–375 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Olayioye, M. A., Beuvink, I., Horsch, K., Daly, J. M. & Hynes, N. E. ErbB receptor-induced activation of Stat transcription factors is mediated by Src tyrosine kinases. J. Biol. Chem. 274, 17209–17218 (1999).

    Article  CAS  PubMed  Google Scholar 

  151. Wang, Y. Z. et al. Activation of Stat3 preassembled with platelet-derived growth factor β receptors requires Src kinase activity. Oncogene 19, 2075–2085 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Luchtefeld, M., Drexler, H. & Schieffer, B. Role of G β-subunit in angiotensin II-type 1 receptor signaling. Biochem. Biophys. Res. Commun. 280, 756–760 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Madamanchi, N. R., Li, S., Patterson, C. & Runge, M. S. Thrombin regulates vascular smooth muscle cell growth and heat shock proteins via the JAK–STAT pathway. J. Biol. Chem. 276, 18915–18924 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Park, E. S. et al. Involvement of JAK/STAT (Janus kinase/signal transducer and activator of transcription) in the thyrotropin signaling pathway. Mol. Endocrinol. 14, 662–670 (2000).

    Article  CAS  PubMed  Google Scholar 

  155. Yu, C. L. et al. Enhanced DNA-binding of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269, 81–83 (1995).

    Article  CAS  PubMed  Google Scholar 

  156. Cao, X., Tay, A., Guy, G. R. & Tan, Y. H. Activation and association of Stat3 with Src in v-Src-transformed cell lines. Mol. Cell. Biol. 16, 1595–1603 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Marrero, M. B. et al. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375, 247–250 (1995).

    Article  CAS  PubMed  Google Scholar 

  158. Nguyen, V. P. et al. Stat2 binding to the interferon-α receptor 2 subunit is not required for interferon-α signaling. J. Biol. Chem 277, 9713–9721 (2002).

    Article  CAS  PubMed  Google Scholar 

  159. Ramana, C.V., Chatterjee-Kishore, M., Nguyen, H. & Stark, G. R. Complex roles of Stat1 in regulating gene expression. Oncogene 19, 2619–2627 (2000).

    Article  CAS  PubMed  Google Scholar 

  160. Ramana, C. V., Gil, M. P., Schreiber, R. D. & Stark, G. R. Stat1-dependent and -independent pathways in IFN-γ-dependent signaling. Trends Immunol. 23, 96–101 (2002).

    Article  CAS  PubMed  Google Scholar 

  161. Chen, X. et al. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 93, 827–839 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Work in the authors' laboratories was supported by grants from the NIH.

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Authors and Affiliations

  1. Department of Pathology, New York University School of Medicine, New York, 10016, New York, USA

    David E. Levy & J. E. Darnell Jr

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DATABASES

LocusLink

androgen receptor

caveolin-1

CBP

C/EBP

CIS

c-Jun

EGF

EGF receptor

IFN-α receptor

Ifn-γ

IFN-γ

IFN-γ receptor

IGF-1

Il-4

IL-6

IL-12

importin-α5

IRF1

IRF9

JAK

Jak1

JAK1

leptin

LMP-2

MCM3

MCM5

Nmi

Nup98

p53

PIAS1

PIAS3

Ptp1b

PTP1B

Socs1

Stat1

STAT1

STAT3

STAT4

STAT5A

STAT5B

transforming growth factor-β

TYK2

Flybase

92E

dPIAS

eve

hopscotch

os

Cancer.gov

head and neck cancer

leukaemia

Glossary

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

CHAPERONE

Protein that mediates polypeptide folding or the assembly of another polypeptide-containing structure but does not form part of the completed structure or participate in its biological function.

HEPATOMA

Cancer of the liver.

INNATE IMMUNE RESPONSE

This is crucial during the early phase of host defence against infection by pathogens (such as bacteria and viruses), before the antigen-specific, adaptive immune response is induced.

LIPID RAFTS

Dynamic assemblies of cholesterol and sphingolipids in the plasma membrane.

TRANSACTIVATION DOMAIN

A domain that is present within a transcription factor that enables the transcription factor to interact with proteins that are involved in binding RNA-polymerase to DNA in a sequence-specific manner.

NF-κB

(Nuclear factor of κB). A widely expressed transcription factor that is activated by cellular stress and can induce the expression of numerous anti-apoptotic genes.

COILED-COIL DOMAINS

A protein domain that forms a bundle of two or three α-helices. Short coiled-coil domains are involved in protein interactions, whereas long coiled-coil domains forming long rods occur in structural or motor proteins.

EUPLOID

A term that describes cells whose nuclei have an exact multiple of the haploid set of chromosomes.

UBIQUITIN

A 76-amino-acid protein that can be covalently attached to specific lysine residues in target proteins. This often forms multimeric polyubiquitin chains, which is thought to target the protein for destruction by the 26S proteasome.

PROTEASOME

Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

T HELPER 1/T HELPER 2

(TH1/TH2). Subsets of CD4+ T cells that are characterized by their cytokine-production profiles. TH1 cells primarily produce interferon-γ, and generally provide protection against intracellular pathogens, whereas TH2 cells mainly produce interleukin-4 (IL-4), IL-5 and IL-13, and are important for immunity to helminth parasites.

CASPASES

Cysteine proteases involved in apoptosis that cleave at specific aspartate residues.

HAEMATOPOIESIS

The commitment and differentiation processes that lead from a haematopoietic stem cell to the production of mature cells of all lineages — erythrocytes, myeloid cells (macrophages, mast cells, neutrophils and eosinophils), B and T cells, and natural killer cells.

RNA HELICASE

An ATP-dependent enzyme that catalyses the unwinding of RNA helices.

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

ENDOTOXIC SHOCK

Also known as septic shock. This is a serious, abnormal condition that occurs when an overwhelming infection leads to low blood pressure and low blood flow. Vital organs such as the brain, heart, kidneys and liver might not function properly or might fail.

DNA MICROARRAY

Array of polymerase chain reaction products (corresponding to either genomic or cDNA sequence) that is deposited onto solid glass slides.

MACROPHAGE

Any cell of the mononuclear phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.

HISTONE ACETYLTRANSFERASE

(HAT). An enzyme that adds acetyl groups to histones. Many HATs function as co-activators.

HISTONE

A family of small, highly conserved basic proteins, found in the chromatin of all eukaryotic cells, that associate with DNA to form a nucleosome.

CHROMATIN IMMUNOPRECIPITATION (ChIP) ASSAYS

ChIP assays can be used to monitor the association of DNA-binding proteins with specific promoters in vivo. Briefly, live cells are treated with crosslinking agents to tether the proteins to the DNA. The selected protein is then recovered by immunoprecipitation, the crosslinking is reversed and the co-precipitating DNA is screened for the enrichment of specific promoter fragments using the polymerase chain reaction (PCR).

HYPOMORPHIC ALLELE

A mutant gene that has a function similar to but weaker than the wild-type gene.

MONOCYTES

Large leukocytes of the mononuclear phagocyte system found in bone marrow and the bloodstream. Monocytes are derived from pluripotent stem cells and become macrophages when they enter the tissues.

ERYTHROPOIETIN

A hormone secreted by certain cells in the kidney, in response to a reduction in the amount of oxygen reaching the tissues, that stimulates red blood cell production.

CRE–LOXP

A site-specific recombination system derived from the Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, which leads to the excision of the intervening sequence.

NATURAL KILLER CELLS

(NK cells). Lymphocytes that confer innate immunity. They were originally defined on the basis of their cytolytic activity against tumour targets, but it is now recognized that they serve a broader role in host defence against invading pathogens.

HAEMATOPOIETIC PROGENITORS

Cells that have the ability to generate all types of haematopoietic cell (multipotentiality) and to replace themselves (self-renewal) during the whole lifespan of an individual. Multipotentiality can be assessed in vitro and in vivo, whereas self-renewal can only be determined by the in vivo detection of long-term reconstitution activity.

PICORNAVIRUS

Any of a group of RNA animal viruses that consist of naked, icosahedral 27-nm capsids with single-stranded infectious RNA (plus-strand) of 2.7 MDa.

MYELOMA

A malignant tumour of the bone marrow.

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Levy, D., Darnell, J. STATs: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3, 651–662 (2002). https://doi.org/10.1038/nrm909

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