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Gene Review

STAT1  -  signal transducer and activator of...

Homo sapiens

Synonyms: CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, ...

STAT1 is a founding member of the Signal Transducers and Activators of Transcription family of transcription factors. Interferons are secreted cytokines produced in response to viral infections. STAT1 is involved in regulating genes due to a signal by either type I, type II, or type III interferons.


Disease relevance of STAT1


Psychiatry related information on STAT1

  • Alteration of transcription factors NF-kappaB and STAT1 in Alzheimer's disease brains [6] .
  • In this review we focus on a number of transcription factor families (homeobox, STAT, and Ets), and on inhibitors of transcription factors (Id), which have been implicated in controlling the cell cycle not only in normal mammary gland development but also in breast tumorigenesis [7].
  • From analysis of the reaction time course using the pH stat assay, it was shown that during accumulation of the reaction products (ADP and creatine phosphate), among several anions added, nitrate proved the most effective in inhibiting catalytic activity [8].

High impact information on STAT1

  • Here we discuss one of the early signaling pathways activated by chemokines, the JAK/STAT pathway [9].
  • The Janus family of protein tyrosine kinases (JAKs) and STAT transcription factors regulate cellular processes involved in cell growth, differentiation, and transformation through their association with cytokine receptors [10].
  • The pathway uses a novel mechanism in which cytosolic latent transcription factors, known as signal transducers and activators of transcription (STATs), are tyrosine phosphorylated by Janus family tyrosine kinases (Jaks), allowing STAT protein dimerization and nuclear translocation [11].
  • JAK/STAT signaling effects have been attributed largely to direct transcriptional regulation by STAT of specific target genes that promote antiviral response, modulation of immune system and regulation of tumor cell proliferation or survival [12] [13].
  • Phosphorylation and acetylation switch regulates Stat1 activity [12] [14]
  • Arginine methylation of STAT1 is controversial [15].

Chemical compound and disease context of STAT1


Biological context of STAT1

  • Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription [20]. However, this observation was challenged [21],
  • STAT1 protein is essential for cell growth suppression in response to IFN-gamma [22].
  • Analysis of the genomic loci proximal to these binding sites introduced new candidate STAT1 and STAT2 target genes, several of which are affiliated with proliferation and apoptosis [23].
  • Using chromatin immunoprecipitation and DNA microarray analysis (ChIP-chip), we have identified the regions of human chromosome 22 bound by STAT1 and STAT2 in interferon-treated cells [23].
  • Additionally, BZLF1 inhibits IFN-gamma-induced STAT1 tyrosine phosphorylation and nuclear translocation [24].
  • Addition of septic sera to 2fTGH cells induced apoptosis by activating caspase 8, caspase 3 and DNA fragmentation factor 40 (DFF 40). Interestingly, the addition of septic sera to cells which lack STAT1 (U3A cells) did not activate DFF 40. U3A cells were also shown to be resistant to septic serum induced apoptosis. These data suggest that DFF 40 mediated apoptosis plays a significant role in mediating sepsis induced cellular dysfunction [25].

Anatomical context of STAT1

  • STAT proteins activated by thrombopoietin in a megakaryocytic cell line were purified and shown to be STAT1 and STAT3 [26].
  • Human T-cell leukemia virus type 2 induces survival and proliferation of CD34(+) TF-1 cells through activation of STAT1 and STAT5 by secretion of interferon-gamma and granulocyte macrophage-colony-stimulating factor [27].
  • To study the role of STAT1 in DNA damage-induced apoptosis in B lymphocytes, its active form, STAT1alpha, was specifically inhibited by the overexpression of STAT1beta, the STAT1alpha truncated inhibitory isoform [28].
  • IFN-gamma was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A) [29].
  • The membrane-distal cytoplasmic region of human granulocyte colony-stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation [30].

Associations of STAT1 with chemical compounds


Physical interactions of STAT1

  • DNA-STAT complexes were detected in all Bcr/Abl-transformed cell lines and they were supershifted by antibodies against STAT1 and STAT5 [34].
  • Significantly, STAT1 proteins mutated at Ser-727 bind poorly to BRCA1, reinforcing the importance of Ser-727 in the recruitment of transcriptional coactivators by STAT proteins [35].
  • STAT1 also binds but only when STAT2 is present [36].
  • The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors [37].
  • Tandem arrays of stat1 binding sites combined with proteomics were used to identify Stat1 binding and interaction partners [38].Several previously known partners of STAT1, as well as new partners, were identified. These include the upstream stimulatory factors 1 and 2 (USF1, USF2), NFAT, TBP, NFE2, NFκB, and NF1. Both USF1 and NFκB are well known to interact with STAT1, but the other five TFs are previously unreported STAT1 interaction partners.
  • Treatment of HepG2 cells with culture medium containing recombinant KSHV-encoded vIL-6 led to rapid induction of JAK1 phosphorylation and a nuclear DNA-binding activity found to contain STAT1 and STAT3 [39].
  • Stat1 interacts with a wide variety of cytokine and growth factor receptors and associated kinases. STAT1 has been shown to interact with Protein kinase R, Src, IRF1, STAT3, MCM5, STAT2, CD117, Fanconi anemia, complementation group C, CREB-binding protein, Interleukin 27 receptor, alpha subunit, PIAS1, BRCA1, Epidermal growth factor receptor,PTK2, Mammalian target of rapamycin (mTOR), IFNAR2,PRKCD,TRADD, C-jun, Calcitriol receptor, IRF-9 and GNB2L1.
  • Enzymatic interactions of STAT1
  • Jak1 may therefore be the enzyme that phosphorylates Tyr 701 in Stat91 [40].
  • Both STAT1 (including Y701- and S727-phosphorylated forms) and STAT2 could readily be detected in RSV-infected cells [41].
  • Notably a polypeptide representing the kinase domain of Jak3 (Jak3-JH1) gained the ability to tyrosine phosphorylate STAT1, suggesting that the changes in substrate recognition may be influenced by domains outside the kinase domain [42].
  • Upon activation of signaling by IL-6 or orthovanadate the respective Tyr-phosphorylated STAT species were now also observed in the membrane raft fraction but in a form deficient in DNA binding [43].
  • IFN-gamma stimulation generates phosphorylated-STAT1 even in the presence of the C or the D1 [44].

Co-localisations of STAT1

  • Double-fluorescence staining confirmed that STAT1 protein co-localized exclusively with CD68, indicating the presence of a subset of STAT1-expressing TAM localized principally in the vicinity of tumor cells [45].

Regulatory relationships of STAT1

  • The STAT signaling pathway appears to negatively regulate the cell cycle by inducing CDK inhibitors in response to cytokines [22].
  • The protein inhibitor of activated STAT (PIAS) family has been suggested to negatively regulate STAT signaling [46].
  • We therefore sought to define the specific role of FANCC protein in signal transduction through receptors that activate STAT1 [37].
  • It is, therefore, possible that IFN-induced growth inhibition of mammary epithelial cells is counteracted by other cytokines that also use Stat1 [47].
  • We found that two of the four tyrosine modules that are important for APRF activation also activate STAT1 [48].

Other interactions of STAT1


Analytical, diagnostic and therapeutic context of STAT1


  1. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Lin, W., Choe, W.H., Hiasa, Y., Kamegaya, Y., Blackard, J.T., Schmidt, E.V., Chung, R.T. Gastroenterology (2005) [Pubmed]
  2. A human cytomegalovirus antagonist of type I IFN-dependent signal transducer and activator of transcription signaling. Paulus, C., Krauss, S., Nevels, M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Prolonged STAT1 activation related to the growth arrest of malignant lymphoma cells by interferon-alpha. Grimley, P.M., Fang, H., Rui, H., Petricoin, E.F., Ray, S., Dong, F., Fields, K.H., Hu, R., Zoon, K.C., Audet, S., Beeler, J. Blood (1998) [Pubmed]
  4. STAT1 mediates differentiation of chronic lymphocytic leukemia cells in response to Bryostatin 1. Battle, T.E., Frank, D.A. Blood (2003) [Pubmed]
  5. Interferon-alpha resistance in a cutaneous T-cell lymphoma cell line is associated with lack of STAT1 expression. Sun, W.H., Pabon, C., Alsayed, Y., Huang, P.P., Jandeska, S., Uddin, S., Platanias, L.C., Rosen, S.T. Blood (1998) [Pubmed]
  6. Alteration of transcription factors NF-kappaB and STAT1 in Alzheimer's disease brains. Kitamura, Y., Shimohama, S., Ota, T., Matsuoka, Y., Nomura, Y., Taniguchi, T. Neurosci. Lett. (1997) [Pubmed]
  7. Transcriptional control of the cell cycle in mammary gland development and tumorigenesis. Coletta, R.D., Jedlicka, P., Gutierrez-Hartmann, A., Ford, H.L. Journal of mammary gland biology and neoplasia. (2004) [Pubmed]
  8. Interaction of brain-type creatine kinase with its transition state analog: kinetics of inhibition and conformational changes. Grossman, S.H., Garcia-Rubio, L.H. J. Enzym. Inhib. (1987) [Pubmed]
  9. Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation. Mellado, M., Rodríguez-Frade, J.M., Mañes, S., Martínez-A, C. Annu. Rev. Immunol. (2001) [Pubmed]
  10. Negative regulation of cytokine signaling pathways. Yasukawa, H., Sasaki, A., Yoshimura, A. Annu. Rev. Immunol. (2000) [Pubmed]
  11. Jaks and STATs: biological implications. Leonard, W.J., O'Shea, J.J. Annu. Rev. Immunol. (1998) [Pubmed]
  12. The JAK-STAT pathway at twenty. Stark, G.R., Darnell JE, J.r. Immunity. (2012) [Pubmed]
  13. JAK signaling globally counteracts heterochromatic gene silencing. Shi, S., Calhoun, H.C., Xia, F., Li, J., Le, L., Li, W.X. Nat. Genet. (2006) [Pubmed]
  14. Regulation of STAT signaling by acetylation. Zhuang, S. Cell. Signal. (2013) [Pubmed]
  15. Arginine methylation of STAT1: a reassessment. Meissner, T., Krause, E., Lödige, I., Vinkemeier, U. Cell (2004) [Pubmed]
  16. STAT1: a modulator of chemotherapy-induced apoptosis. Thomas, M., Finnegan, C.E., Rogers, K.M., Purcell, J.W., Trimble, A., Johnston, P.G., Boland, M.P. Cancer Res. (2004) [Pubmed]
  17. Inhibition of IFN-gamma-mediated inducible nitric oxide synthase induction by the peroxisome proliferator-activated receptor gamma agonist, 15-deoxy-delta 12,14-prostaglandin J2, involves inhibition of the upstream Janus kinase/STAT1 signaling pathway. Chen, C.W., Chang, Y.H., Tsi, C.J., Lin, W.W. J. Immunol. (2003) [Pubmed]
  18. The induction and activation of STAT1 by all-trans-retinoic acid are mediated by RAR beta signaling pathways in breast cancer cells. Shang, Y., Baumrucker, C.R., Green, M.H. Oncogene (1999) [Pubmed]
  19. A soluble factor(s) secreted from CD8(+) T lymphocytes inhibits human immunodeficiency virus type 1 replication through STAT1 activation. Chang, T.L., Mosoian, A., Pine, R., Klotman, M.E., Moore, J.P. J. Virol. (2002) [Pubmed]
  20. Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription. Mowen, K.A., Tang, J., Zhu, W., Schurter, B.T., Shuai, K., Herschman, H.R., David, M. Cell (2001) [Pubmed]
  21. Are STATS arginine-methylated?. Komyod, W., Bauer, U.M., Heinrich, P.C., Haan, S., Behrmann, I. J. Biol. Chem. (2005) [Pubmed]
  22. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Chin, Y.E., Kitagawa, M., Su, W.C., You, Z.H., Iwamoto, Y., Fu, X.Y. Science (1996) [Pubmed]
  23. Global changes in STAT target selection and transcription regulation upon interferon treatments. Hartman, S.E., Bertone, P., Nath, A.K., Royce, T.E., Gerstein, M., Weissman, S., Snyder, M. Genes Dev. (2005) [Pubmed]
  24. Inhibition of IFN-gamma signaling by an Epstein-Barr virus immediate-early protein. Morrison, T.E., Mauser, A., Wong, A., Ting, J.P., Kenney, S.C. Immunity (2001) [Pubmed]
  25. Septic sera induces apoptosis and DNA fragmentation factor 40 activation in fibroblasts. Brabant, D., Michael, P., Bleiblo, F., Saleh, M., Narain, R., Tai, T.C., Ramana, C.V., Parrillo, J.E., Kumar, A., Kumar, A. Biochem. Biophys. Res. Commun. (2011) [Pubmed]
  26. Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation. Gurney, A.L., Wong, S.C., Henzel, W.J., de Sauvage, F.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  27. Human T-cell leukemia virus type 2 induces survival and proliferation of CD34(+) TF-1 cells through activation of STAT1 and STAT5 by secretion of interferon-gamma and granulocyte macrophage-colony-stimulating factor. Bovolenta, C., Pilotti, E., Mauri, M., Turci, M., Ciancianaini, P., Fisicaro, P., Bertazzoni, U., Poli, G., Casoli, C. Blood (2002) [Pubmed]
  28. Differential roles of STAT1alpha and STAT1beta in fludarabine-induced cell cycle arrest and apoptosis in human B cells. Baran-Marszak, F., Feuillard, J., Najjar, I., Le Clorennec, C., Béchet, J.M., Dusanter-Fourt, I., Bornkamm, G.W., Raphaël, M., Fagard, R. Blood (2004) [Pubmed]
  29. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Chin, Y.E., Kitagawa, M., Kuida, K., Flavell, R.A., Fu, X.Y. Mol. Cell. Biol. (1997) [Pubmed]
  30. The membrane-distal cytoplasmic region of human granulocyte colony-stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation. de Koning, J.P., Dong, F., Smith, L., Schelen, A.M., Barge, R.M., van der Plas, D.C., Hoefsloot, L.H., Löwenberg, B., Touw, I.P. Blood (1996) [Pubmed]
  31. PKCepsilon is a permissive link in integrin-dependent IFN-gamma signalling that facilitates JAK phosphorylation of STAT1. Ivaska, J., Bosca, L., Parker, P.J. Nat. Cell Biol. (2003) [Pubmed]
  32. p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. Goh, K.C., Haque, S.J., Williams, B.R. EMBO J. (1999) [Pubmed]
  33. Arginine/lysine-rich structural element is involved in interferon-induced nuclear import of STATs. Melen, K., Kinnunen, L., Julkunen, I. J. Biol. Chem. (2001) [Pubmed]
  34. Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. Carlesso, N., Frank, D.A., Griffin, J.D. J. Exp. Med. (1996) [Pubmed]
  35. Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. Ouchi, T., Lee, S.W., Ouchi, M., Aaronson, S.A., Horvath, C.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  36. Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling. Li, X., Leung, S., Kerr, I.M., Stark, G.R. Mol. Cell. Biol. (1997) [Pubmed]
  37. The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. Pang, Q., Fagerlie, S., Christianson, T.A., Keeble, W., Faulkner, G., Diaz, J., Rathbun, R.K., Bagby, G.C. Mol. Cell. Biol. (2000) [Pubmed]
  38. Construction of a novel oligonucleotide array-based transcription factor interaction assay platform and its uses for profiling STAT1 cofactors in mouse fibroblast cells. Zeng, L., Sun, Y., Xie, L., Wei, L., Ren, Y., Zhao, J., Qin, W., Mitchelson, K., Cheng, J. Proteomics. (2013) [Pubmed]
  39. A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. Molden, J., Chang, Y., You, Y., Moore, P.S., Goldsmith, M.A. J. Biol. Chem. (1997) [Pubmed]
  40. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Shuai, K., Ziemiecki, A., Wilks, A.F., Harpur, A.G., Sadowski, H.B., Gilman, M.Z., Darnell, J.E. Nature (1993) [Pubmed]
  41. Paramyxoviridae use distinct virus-specific mechanisms to circumvent the interferon response. Young, D.F., Didcock, L., Goodbourn, S., Randall, R.E. Virology (2000) [Pubmed]
  42. Differential substrate recognition capabilities of Janus family protein tyrosine kinases within the interleukin 2 receptor (IL2R) system: Jak3 as a potential molecular target for treatment of leukemias with a hyperactive Jak-Stat signaling machinery. Witthuhn, B.A., Williams, M.D., Kerawalla, H., Uckun, F.M. Leuk. Lymphoma (1999) [Pubmed]
  43. Cytokine signaling: STATS in plasma membrane rafts. Sehgal, P.B., Guo, G.G., Shah, M., Kumar, V., Patel, K. J. Biol. Chem. (2002) [Pubmed]
  44. The C-terminal half-fragment of the Sendai virus C protein prevents the gamma-activated factor from binding to a gamma-activated sequence site. Gotoh, B., Komatsu, T., Takeuchi, K., Yokoo, J. Virology (2003) [Pubmed]
  45. The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma. Alvaro, T., Lejeune, M., Camacho, F.I., Salvad??, M.T., S??nchez, L., Garc??a, J.F., Lopez, C., Ja??n, J., Bosch, R., Pons, L.E., Bellas, C., Piris, M.A. Haematologica (2006) [Pubmed]
  46. PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Liu, B., Mink, S., Wong, K.A., Stein, N., Getman, C., Dempsey, P.W., Wu, H., Shuai, K. Nat. Immunol. (2004) [Pubmed]
  47. Prolactin activates Stat1 but does not antagonize Stat1 activation and growth inhibition by type I interferons in human breast cancer cells. Schaber, J.D., Fang, H., Xu, J., Grimley, P.M., Rui, H. Cancer Res. (1998) [Pubmed]
  48. Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of a novel phosphotyrosine motif mediating STAT1 activation. Gerhartz, C., Heesel, B., Sasse, J., Hemmann, U., Landgraf, C., Schneider-Mergener, J., Horn, F., Heinrich, P.C., Graeve, L. J. Biol. Chem. (1996) [Pubmed]
  49. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Dupuis, S., Jouanguy, E., Al-Hajjar, S., Fieschi, C., Al-Mohsen, I.Z., Al-Jumaah, S., Yang, K., Chapgier, A., Eidenschenk, C., Eid, P., Al Ghonaium, A., Tufenkeji, H., Frayha, H., Al-Gazlan, S., Al-Rayes, H., Schreiber, R.D., Gresser, I., Casanova, J.L. Nat. Genet. (2003) [Pubmed]
  50. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. Hong, F., Jaruga, B., Kim, W.H., Radaeva, S., El-Assal, O.N., Tian, Z., Nguyen, V.A., Gao, B. J. Clin. Invest. (2002) [Pubmed]
  51. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. Beadling, C., Guschin, D., Witthuhn, B.A., Ziemiecki, A., Ihle, J.N., Kerr, I.M., Cantrell, D.A. EMBO J. (1994) [Pubmed]
  52. Inhibition of Stat1-mediated gene activation by PIAS1. Liu, B., Liao, J., Rao, X., Kushner, S.A., Chung, C.D., Chang, D.D., Shuai, K. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  53. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Savage, K.J., Monti, S., Kutok, J.L., Cattoretti, G., Neuberg, D., De Leval, L., Kurtin, P., Dal Cin, P., Ladd, C., Feuerhake, F., Aguiar, R.C., Li, S., Salles, G., Berger, F., Jing, W., Pinkus, G.S., Habermann, T., Dalla-Favera, R., Harris, N.L., Aster, J.C., Golub, T.R., Shipp, M.A. Blood (2003) [Pubmed]
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