STAT Signaling in Glioma Cells

  • Karolina Swiatek-MachadoEmail author
  • Bozena Kaminska
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1202)


STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.


Cytokine and growth factor receptor signaling Protein tyrosine kinases STAT proteins Gliomas Transcription regulation 



B-cell lymphoma 2


B-cell lymphoma-extra large


Brahma-related gene 1


Epidermal growth factor receptor


IFNg-activated sequence


Glioblastoma multiforme


Glioma stem cells


Interferon g


IFN regulatory factor


IFN-a/b–stimulated response element


Janus kinase


Induced myeloid leukemia cell differentiation protein






Platelet-derived growth factor receptor


Protein inhibitors of activated STAT


Phosphatase and tensin homolog


Src homology domain 2


Suppressors of cytokine signaling


Signal transducers and activators of transcription




Vascular endothelial growth factor


Vascular endothelial growth factor receptor



We thank Kavita Ramji for a critical reading of the manuscript. Studies were supported by a grant N N405621938 from the Ministry of Science and Higher Education.


  1. Adach-Kilon A, Swiatek-Machado K, Kaminska B, Dabrowski M (2011) Signal transducer and activator of transcription 1 (Stat1) maintains basal mRNA expression of pro-survival Stat3-target genes in glioma C6 cells. J Cell Biochem 112:3685–3694PubMedCrossRefGoogle Scholar
  2. Akira S (2000) Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 19:2607–2611PubMedCrossRefGoogle Scholar
  3. Aziz MH, Hafeez BB, Sand JM, Pierce DB, Aziz SW, Dreckschmidt NE, Verma AK (2010) Protein kinase Cvarepsilon mediates Stat3Ser727 phosphorylation, Stat3-regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF-1, MEK1/2, and ERK1/2). Oncogene 29:3100–3109PubMedPubMedCentralCrossRefGoogle Scholar
  4. Baker BJ, Qin H, Benveniste EN (2008) Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes. Glia 56:1250–1262PubMedPubMedCentralCrossRefGoogle Scholar
  5. Battle TE, Frank DA (2002) The role of STATs in apoptosis. Curr Mol Med 2:381–392PubMedCrossRefGoogle Scholar
  6. Birner P, Toumangelova-Uzeir K, Natchev S, Guentchev M (2010) STAT3 tyrosine phosphorylation influences survival in glioblastoma. J Neurooncol 100:339–343PubMedCrossRefGoogle Scholar
  7. Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278:477–483PubMedCrossRefGoogle Scholar
  8. Borghouts C, Kunz C, Delis N, Groner B (2008) Monomeric recombinant peptide aptamers are required for efficient intracellular uptake and target inhibition. Mol Cancer Res 6:267–281PubMedCrossRefGoogle Scholar
  9. Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA, Jove R (2001) Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci U S A 98:7319–7324PubMedPubMedCentralCrossRefGoogle Scholar
  10. Brantley EC, Nabors LB, Gillespie GY, Choi YH, Palmer CA, Harrison K, Roarty K, Benveniste EN (2008) Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression. Clin Cancer Res 14:4694–4704PubMedCrossRefGoogle Scholar
  11. Bromberg JF (2001) Activation of STAT proteins and growth control. Bioessays 23:161–169PubMedCrossRefGoogle Scholar
  12. Bromberg J, Darnell JE Jr (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19:2468–2473PubMedCrossRefGoogle Scholar
  13. Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr (1998) Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 18:2553–2558PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr (1999) Stat3 as an oncogene. Cell 98:295–303PubMedCrossRefGoogle Scholar
  15. Broniscer A, Baker JN, Tagen M, Onar-Thomas A, Gilbertson RJ, Davidoff AM, Pai Panandiker AS, Leung W, Chin TK, Stewart CF, Kocak M, Rowland C, Merchant TE, Kaste SC, Gajjar A (2010) Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. J Clin Oncol 28:4762–4768PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cao S, Wang C, Zheng Q, Qiao Y, Xu K, Jiang T, Wu A (2010) STAT5 regulates glioma cell invasion by pathways dependent and independent of STAT5 DNA binding. Neurosci Lett 487:228–233PubMedCrossRefGoogle Scholar
  17. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10:105–115PubMedCrossRefGoogle Scholar
  18. Chen Z, Lund R, Aittokallio T, Kosonen M, Nevalainen O, Lahesmaa R (2003) Identification of novel IL-4/Stat6-regulated genes in T lymphocytes. J Immunol 171:3627–3635PubMedCrossRefGoogle Scholar
  19. Chen F, Xu Y, Luo Y, Zheng D, Song Y, Yu K, Li H, Zhang L, Zhong W, Ji Y (2010) Down-regulation of Stat3 decreases invasion activity and induces apoptosis of human glioma cells. J Mol Neurosci 40:353–359PubMedCrossRefGoogle Scholar
  20. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278:1803–1805PubMedCrossRefGoogle Scholar
  21. Croker BA, Kiu H, Nicholson SE (2008) SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19:414–422PubMedPubMedCentralCrossRefGoogle Scholar
  22. Danial NN, Rothman P (2000) JAK-STAT signaling activated by Abl oncogenes. Oncogene 19:2523–2531PubMedCrossRefGoogle Scholar
  23. Dasgupta A, Raychaudhuri B, Haqqi T, Prayson R, Van Meir EG, Vogelbaum M, Haque SJ (2009) Stat3 activation is required for the growth of U87 cell-derived tumours in mice. Eur J Cancer 45:677–684PubMedCrossRefGoogle Scholar
  24. de la Iglesia N, Konopka G, Lim KL, Nutt CL, Bromberg JF, Frank DA, Mischel PS, Louis DN, Bonni A (2008a) Deregulation of a STAT3-interleukin 8 signaling pathway promotes human glioblastoma cell proliferation and invasiveness. J Neurosci 28:5870–5878PubMedPubMedCentralCrossRefGoogle Scholar
  25. de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, Levy DE, Depinho RA, Bonni A (2008b) Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev 22:449–462PubMedPubMedCentralCrossRefGoogle Scholar
  26. de la Iglesia N, Puram SV, Bonni A (2009) STAT3 regulation of glioblastoma pathogenesis. Curr Mol Med 9:580–590PubMedPubMedCentralCrossRefGoogle Scholar
  27. Decker T, Kovarik P (2000) Serine phosphorylation of STATs. Oncogene 19:2628–2637PubMedCrossRefGoogle Scholar
  28. Ehret GB, Reichenbach P, Schindler U, Horvath CM, Fritz S, Nabholz M, Bucher P (2001) DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites. J Biol Chem 276:6675–6688PubMedCrossRefGoogle Scholar
  29. Friedman HS, Bigner DD (2005) Glioblastoma multiforme and the epidermal growth factor receptor. N Engl J Med 353:1997–1999PubMedCrossRefGoogle Scholar
  30. Fuh B, Sobo M, Cen L, Josiah D, Hutzen B, Cisek K, Bhasin D, Regan N, Lin L, Chan C, Caldas H, DeAngelis S, Li C, Li PK, Lin J (2009) LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model. Br J Cancer 100:106–112PubMedPubMedCentralCrossRefGoogle Scholar
  31. Fujio Y, Kunisada K, Hirota H, Yamauchi-Takihara K, Kishimoto T (1997) Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes. J Clin Invest 99:2898–2905PubMedPubMedCentralCrossRefGoogle Scholar
  32. Fujita M, Zhu X, Sasaki K, Ueda R, Low KL, Pollack IF, Okada H (2008) Inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma. J Immunol 180:2089–2098PubMedCrossRefGoogle Scholar
  33. Gabrusiewicz K, Ellert-Miklaszewska A, Lipko M, Sielska M, Frankowska M, Kaminska B (2011) Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas. PLoS One 6:e23902PubMedPubMedCentralCrossRefGoogle Scholar
  34. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021PubMedCrossRefGoogle Scholar
  35. Gao L, Li F, Dong B, Zhang J, Rao Y, Cong Y, Mao B, Chen X (2010) Inhibition of STAT3 and ErbB2 suppresses tumor growth, enhances radiosensitivity, and induces mitochondria-dependent apoptosis in glioma cells. Int J Radiat Oncol Biol Phys 77:1223–1231PubMedCrossRefGoogle Scholar
  36. Gesbert F, Griffin JD (2000) Bcr/Abl activates transcription of the Bcl-X gene through STAT5. Blood 96:2269–2276PubMedCrossRefGoogle Scholar
  37. Greenhalgh CJ, Hilton DJ (2001) Negative regulation of cytokine signaling. J Leukoc Biol 70:348–356PubMedGoogle Scholar
  38. Gu F, Hata R, Ma YJ, Tanaka J, Mitsuda N, Kumon Y, Hanakawa Y, Hashimoto K, Nakajima K, Sakanaka M (2005) Suppression of Stat3 promotes neurogenesis in cultured neural stem cells. J Neurosci Res 81:163–171PubMedCrossRefGoogle Scholar
  39. Gu J, Li G, Sun T, Su Y, Zhang X, Shen J, Tian Z, Zhang J (2008) Blockage of the STAT3 signaling pathway with a decoy oligonucleotide suppresses growth of human malignant glioma cells. J Neurooncol 89:9–17PubMedCrossRefGoogle Scholar
  40. Hartman SE, Bertone P, Nath AK, Royce TE, Gerstein M, Weissman S, Snyder M (2005) Global changes in STAT target selection and transcription regulation upon interferon treatments. Genes Dev 19:2953–2968PubMedPubMedCentralCrossRefGoogle Scholar
  41. Haspel RL, Darnell JE Jr (1999) A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1. Proc Natl Acad Sci U S A 96:10188–10193PubMedPubMedCentralCrossRefGoogle Scholar
  42. Hatiboglu MA, Wei J, Wu AS, Heimberger AB (2010) Immune therapeutic targeting of glioma cancer stem cells. Target Oncol 5:217–227PubMedPubMedCentralCrossRefGoogle Scholar
  43. Haybaeck J, Obrist P, Schindler CU, Spizzo G, Doppler W (2007) STAT-1 expression in human glioblastoma and peritumoral tissue. Anticancer Res 27:3829–3835PubMedGoogle Scholar
  44. He B, You L, Uematsu K, Zang K, Xu Z, Lee AY, Costello JF, McCormick F, Jablons DM (2003) SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci U S A 100:14133–14138PubMedPubMedCentralCrossRefGoogle Scholar
  45. Heim MH, Kerr IM, Stark GR, Darnell JE Jr (1995) Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 267:1347–1349PubMedCrossRefGoogle Scholar
  46. Heimberger AB, Priebe W (2008) Small molecular inhibitors of p-STAT3: novel agents for treatment of primary and metastatic CNS cancers. Recent Pat CNS Drug Discov 3:179–188PubMedCrossRefGoogle Scholar
  47. Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, Naeger LK, Sun YL, Kaplan MH (2003) Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses. EMBO J 22:4237–4248PubMedPubMedCentralCrossRefGoogle Scholar
  48. Horvath CM, Wen Z, Darnell JE Jr (1995) A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev 9:984–994PubMedCrossRefGoogle Scholar
  49. Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, Priebe W, Heimberger AB (2007) A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res 67:9630–9636PubMedCrossRefGoogle Scholar
  50. Ivashkiv LB, Hu X (2004) Signaling by STATs. Arthritis Res Ther 6:159–168PubMedPubMedCentralCrossRefGoogle Scholar
  51. Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, Kondo S, Priebe W, Kondo Y (2007) A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene 26:2435–2444PubMedCrossRefGoogle Scholar
  52. Jatiani SS, Cosenza SC, Reddy MV, Ha JH, Baker SJ, Samanta AK, Olnes MJ, Pfannes L, Sloand EM, Arlinghaus RB, Reddy EP (2010) A non-ATP-competitive dual inhibitor of JAK2 and BCR-ABL kinases: elucidation of a novel therapeutic spectrum based on substrate competitive inhibition. Genes Cancer 1:331–345PubMedPubMedCentralCrossRefGoogle Scholar
  53. John S, Vinkemeier U, Soldaini E, Darnell JE Jr, Leonard WJ (1999) The significance of tetramerization in promoter recruitment by Stat5. Mol Cell Biol 19:1910–1918PubMedPubMedCentralCrossRefGoogle Scholar
  54. Khan KD, Shuai K, Lindwall G, Maher SE, Darnell JE Jr, Bothwell AL (1993) Induction of the Ly-6A/E gene by interferon alpha/beta and gamma requires a DNA element to which a tyrosine-phosphorylated 91-kDa protein binds. Proc Natl Acad Sci U S A 90:6806–6810PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1–24PubMedCrossRefGoogle Scholar
  56. Konnikova L, Kotecki M, Kruger MM, Cochran BH (2003) Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 3:23PubMedPubMedCentralCrossRefGoogle Scholar
  57. Korpelainen EI, Karkkainen M, Gunji Y, Vikkula M, Alitalo K (1999) Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene 18:1–8PubMedCrossRefGoogle Scholar
  58. Kostianovsky AM, Maier LM, Anderson RC, Bruce JN, Anderson DE (2008) Astrocytic regulation of human monocytic/microglial activation. J Immunol 181:5425–5432PubMedCrossRefGoogle Scholar
  59. Kubo M, Ransom J, Webb D, Hashimoto Y, Tada T, Nakayama T (1997) T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6. EMBO J 16:4007–4020PubMedPubMedCentralCrossRefGoogle Scholar
  60. Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, Behrmann I, Tsiaris W, Sasaki A, Schneider-Mergener J, Yoshimura A, Neel BG, Heinrich PC, Schaper F (2003) SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem 278:661–671PubMedCrossRefGoogle Scholar
  61. Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi S, Mai JC, Robbins PD, Gadiparthi S, Burke NA, Watkins SF, Grandis JR (2003) Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci U S A 100:4138–4143PubMedPubMedCentralCrossRefGoogle Scholar
  62. Letimier FA, Passini N, Gasparian S, Bianchi E, Rogge L (2007) Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation. EMBO J 26:1292–1302PubMedPubMedCentralCrossRefGoogle Scholar
  63. Li GH, Wei H, Lv SQ, Ji H, Wang DL (2010) Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells. Int J Oncol 37:103–110PubMedGoogle Scholar
  64. Liang QC, Xiong H, Zhao ZW, Jia D, Li WX, Qin HZ, Deng JP, Gao L, Zhang H, Gao GD (2009) Inhibition of transcription factor STAT5b suppresses proliferation, induces G1 cell cycle arrest and reduces tumor cell invasion in human glioblastoma multiforme cells. Cancer Lett 273:164–171PubMedCrossRefGoogle Scholar
  65. Lin L, Hutzen B, Li PK, Ball S, Zuo M, DeAngelis S, Foust E, Sobo M, Friedman L, Bhasin D, Cen L, Li C, Lin J (2010) A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia 12:39–50PubMedPubMedCentralCrossRefGoogle Scholar
  66. Lindemann C, Hackmann O, Delic S, Schmidt N, Reifenberger G, Riemenschneider MJ (2011) SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. Acta Neuropathol 122:241–251PubMedCrossRefGoogle Scholar
  67. Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K (1998) Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A 95:10626–10631PubMedPubMedCentralCrossRefGoogle Scholar
  68. Lo RK, Cheung H, Wong YH (2003) Constitutively active Galpha16 stimulates STAT3 via a c-Src/JAK- and ERK-dependent mechanism. J Biol Chem 278:52154–52165PubMedCrossRefGoogle Scholar
  69. Lo HW, Cao X, Zhu H, Ali-Osman F (2008) Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Cancer Res 14:6042–6054PubMedPubMedCentralCrossRefGoogle Scholar
  70. Look DC, Pelletier MR, Tidwell RM, Roswit WT, Holtzman MJ (1995) Stat1 depends on transcriptional synergy with Sp1. J Biol Chem 270:30264–30267PubMedCrossRefGoogle Scholar
  71. Lord JD, McIntosh BC, Greenberg PD, Nelson BH (2000) The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. J Immunol 164:2533–2541PubMedCrossRefGoogle Scholar
  72. Lund RJ, Chen Z, Scheinin J, Lahesmaa R (2004) Early target genes of IL-12 and STAT4 signaling in th cells. J Immunol 172:6775–6782PubMedCrossRefGoogle Scholar
  73. Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE (1995) Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375:247–250PubMedCrossRefGoogle Scholar
  74. Martini M, Pallini R, Luongo G, Cenci T, Lucantoni C, Larocca LM (2008) Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme. Int J Cancer 123:2955–2960PubMedCrossRefGoogle Scholar
  75. Mizoguchi M, Betensky RA, Batchelor TT, Bernay DC, Louis DN, Nutt CL (2006) Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: correlation with EGFR status, tumor grade, and survival. J Neuropathol Exp Neurol 65:1181–1188PubMedCrossRefGoogle Scholar
  76. Nagel-Wolfrum K, Buerger C, Wittig I, Butz K, Hoppe-Seyler F, Groner B (2004) The interaction of specific peptide aptamers with the DNA binding domain and the dimerization domain of the transcription factor Stat3 inhibits transactivation and induces apoptosis in tumor cells. Mol Cancer Res 2:170–182PubMedGoogle Scholar
  77. Naik SM, Shibagaki N, Li LJ, Quinlan KL, Paxton LL, Caughman SW (1997) Interferon gamma-dependent induction of human intercellular adhesion molecule-1 gene expression involves activation of a distinct STAT protein complex. J Biol Chem 272:1283–1290PubMedCrossRefGoogle Scholar
  78. Ni Z, Bremner R (2007) Brahma-related gene 1-dependent STAT3 recruitment at IL-6-inducible genes. J Immunol 178:345–351PubMedCrossRefGoogle Scholar
  79. Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M (2000) Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A 97:6493–6498PubMedPubMedCentralCrossRefGoogle Scholar
  80. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ (1994) A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A 91:7727–7731PubMedPubMedCentralCrossRefGoogle Scholar
  81. Niwa H, Burdon T, Chambers I, Smith A (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12:2048–2060PubMedPubMedCentralCrossRefGoogle Scholar
  82. O’Shea JJ, Gadina M, Schreiber RD (2002) Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109(Suppl):S121–S131PubMedCrossRefGoogle Scholar
  83. O’Sullivan A, Chang HC, Yu Q, Kaplan MH (2004) STAT4 is required for interleukin-12-induced chromatin remodeling of the CD25 locus. J Biol Chem 279:7339–7345PubMedCrossRefGoogle Scholar
  84. Ouchi T, Lee SW, Ouchi M, Aaronson SA, Horvath CM (2000) Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. Proc Natl Acad Sci U S A 97:5208–5213PubMedPubMedCentralCrossRefGoogle Scholar
  85. Pesu M, Muul L, Kanno Y, O’Shea JJ (2006) Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma. Blood 108:983–985PubMedPubMedCentralCrossRefGoogle Scholar
  86. Premkumar DR, Jane EP, Agostino NR, Scialabba JL, Pollack IF (2010) Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells. J Carcinog 9:7PubMedPubMedCentralCrossRefGoogle Scholar
  87. Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA, Haque SJ (2002) Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21:8404–8413PubMedCrossRefGoogle Scholar
  88. Rajan P, McKay RD (1998) Multiple routes to astrocytic differentiation in the CNS. J Neurosci 18:3620–3629PubMedPubMedCentralCrossRefGoogle Scholar
  89. Ramana CV, Chatterjee-Kishore M, Nguyen H, Stark GR (2000) Complex roles of Stat1 in regulating gene expression. Oncogene 19:2619–2627PubMedCrossRefGoogle Scholar
  90. Raz R, Lee CK, Cannizzaro LA, D’Eustachio P, Levy DE (1999) Essential role of STAT3 for embryonic stem cell pluripotency. Proc Natl Acad Sci U S A 96:2846–2851PubMedPubMedCentralCrossRefGoogle Scholar
  91. Reddy EP, Korapati A, Chaturvedi P, Rane S (2000) IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled. Oncogene 19:2532–2547PubMedCrossRefGoogle Scholar
  92. Schaefer LK, Ren Z, Fuller GN, Schaefer TS (2002) Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene 21:2058–2065PubMedCrossRefGoogle Scholar
  93. Schiavone D, Avalle L, Dewilde S, Poli V (2011) The immediate early genes Fos and Egr1 become STAT1 transcriptional targets in the absence of STAT3. FEBS Lett 585:2455–2460PubMedCrossRefGoogle Scholar
  94. Schmidt D, Muller S (2003) PIAS/SUMO: new partners in transcriptional regulation. Cell Mol Life Sci 60:2561–2574PubMedCrossRefGoogle Scholar
  95. Senft C, Priester M, Polacin M, Schroder K, Seifert V, Kogel D, Weissenberger J (2010) Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells. J Neurooncol 101:393–403PubMedCrossRefGoogle Scholar
  96. Shen J, Li R, Li G (2009) Inhibitory effects of decoy-ODN targeting activated STAT3 on human glioma growth in vivo. In Vivo 23:237–243PubMedGoogle Scholar
  97. Sherry MM, Reeves A, Wu JK, Cochran BH (2009) STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 27:2383–2392PubMedPubMedCentralCrossRefGoogle Scholar
  98. Shuai K, Liu B (2005) Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5:593–605PubMedCrossRefGoogle Scholar
  99. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMedGoogle Scholar
  100. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  101. Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF (1999) Fetal anemia and apoptosis of red cell progenitors in Stat5a−/−5b−/− mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 98:181–191PubMedCrossRefGoogle Scholar
  102. Stea B, Falsey R, Kislin K, Patel J, Glanzberg H, Carey S, Ambrad AA, Meuillet EJ, Martinez JD (2003) Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD1839 (‘Iressa’). Cancer Lett 202:43–51PubMedCrossRefGoogle Scholar
  103. Stephanou A, Latchman DS (2005) Opposing actions of STAT-1 and STAT-3. Growth Factors 23:177–182PubMedCrossRefGoogle Scholar
  104. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefGoogle Scholar
  105. Su Y, Li G, Zhang X, Gu J, Zhang C, Tian Z, Zhang J (2008) JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment. Cancer Biol Ther 7:1243–1249PubMedCrossRefGoogle Scholar
  106. Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, 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 161:4652–4660PubMedGoogle Scholar
  107. Thieu VT, Yu Q, Chang HC, Yeh N, Nguyen ET, Sehra S, Kaplan MH (2008) Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. Immunity 29:679–690PubMedPubMedCentralCrossRefGoogle Scholar
  108. Turkson J (2004) STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets 8:409–422PubMedCrossRefGoogle Scholar
  109. Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R (1998) Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 18:2545–2552PubMedPubMedCentralCrossRefGoogle Scholar
  110. Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M, Frank DA, Holzman LB, Wu J, Sebti S, Jove R (1999) Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol Cell Biol 19:7519–7528PubMedPubMedCentralCrossRefGoogle Scholar
  111. Turkson J, Ryan D, Kim JS, Zhang Y, Chen Z, Haura E, Laudano A, Sebti S, Hamilton AD, Jove R (2001) Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J Biol Chem 276:45443–45455PubMedCrossRefGoogle Scholar
  112. Turkson J, Kim JS, Zhang S, Yuan J, Huang M, Glenn M, Haura E, Sebti S, Hamilton AD, Jove R (2004) Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther 3:261–269PubMedGoogle Scholar
  113. Valente AJ, Xie JF, Abramova MA, Wenzel UO, Abboud HE, Graves DT (1998) A complex element regulates IFN-gamma-stimulated monocyte chemoattractant protein-1 gene transcription. J Immunol 161:3719–3728PubMedGoogle Scholar
  114. Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6:425–436PubMedCrossRefGoogle Scholar
  115. Vila-Coro AJ, Rodriguez-Frade JM, Martin De Ana A, Moreno-Ortiz MC, Martinez AC, Mellado M (1999) The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J 13:1699–1710PubMedCrossRefGoogle Scholar
  116. Villalva C, Martin-Lanneree S, Cortes U, Dkhissi F, Wager M, Le Corf A, Tourani JM, Dusanter-Fourt I, Turhan AG, Karayan-Tapon L (2010) STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: a potential for targeted therapy? Int J Cancer 128:826–838CrossRefGoogle Scholar
  117. Wagner BJ, Hayes TE, Hoban CJ, Cochran BH (1990) The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter. EMBO J 9:4477–4484PubMedPubMedCentralCrossRefGoogle Scholar
  118. Wang H, Zhang W, Huang HJ, Liao WS, Fuller GN (2004) Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Invest 84:941–951PubMedCrossRefGoogle Scholar
  119. Wang H, Lathia JD, Wu Q, Wang J, Li Z, Heddleston JM, Eyler CE, Elderbroom J, Gallagher J, Schuschu J, MacSwords J, Cao Y, McLendon RE, Wang XF, Hjelmeland AB, Rich JN (2009) Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 27:2393–2404PubMedPubMedCentralCrossRefGoogle Scholar
  120. Wei J, Barr J, Kong LY, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Sawaya R, Lang FF, Heimberger AB (2010) Glioma-associated cancer-initiating cells induce immunosuppression. Clin Cancer Res 16:461–473PubMedPubMedCentralCrossRefGoogle Scholar
  121. Weissenberger J, Loeffler S, Kappeler A, Kopf M, Lukes A, Afanasieva TA, Aguzzi A, Weis J (2004) IL-6 is required for glioma development in a mouse model. Oncogene 23:3308–3316PubMedCrossRefGoogle Scholar
  122. Weissenberger J, Priester M, Bernreuther C, Rakel S, Glatzel M, Seifert V, Kogel D (2010) Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3 signaling pathway. Clin Cancer Res 16:5781–5795PubMedCrossRefGoogle Scholar
  123. Wen Z, Zhong Z, Darnell JE Jr (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241–250PubMedCrossRefGoogle Scholar
  124. Wirnsberger G, Hebenstreit D, Posselt G, Horejs-Hoeck J, Duschl A (2006) IL-4 induces expression of TARC/CCL17 via two STAT6 binding sites. Eur J Immunol 36:1882–1891PubMedPubMedCentralCrossRefGoogle Scholar
  125. Wong M, Fish EN (1998) RANTES and MIP-1alpha activate stats in T cells. J Biol Chem 273:309–314PubMedCrossRefGoogle Scholar
  126. Wormald S, Hilton DJ, Smyth GK, Speed TP (2006) Proximal genomic localization of STAT1 binding and regulated transcriptional activity. BMC Genomics 7:254PubMedPubMedCentralCrossRefGoogle Scholar
  127. Yang F, Brown C, Buettner R, Hedvat M, Starr R, Scuto A, Schroeder A, Jensen M, Jove R (2010) Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol Cancer Ther 9:953–962PubMedPubMedCentralCrossRefGoogle Scholar
  128. Yiin JJ, Hu B, Schornack PA, Sengar RS, Liu KW, Feng H, Lieberman FS, Chiou SH, Sarkaria JN, Wiener EC, Ma HI, Cheng SY (2010) ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain. Mol Cancer Ther 9:929–941PubMedPubMedCentralCrossRefGoogle Scholar
  129. Yoshimura A (2005) Negative regulation of cytokine signaling. Clin Rev Allergy Immunol 28:205–220PubMedCrossRefGoogle Scholar
  130. Yu H, Jove R (2004) The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 4:97–105PubMedCrossRefGoogle Scholar
  131. Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R (1995) Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269:81–83PubMedCrossRefGoogle Scholar
  132. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51PubMedCrossRefGoogle Scholar
  133. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809PubMedPubMedCentralCrossRefGoogle Scholar
  134. Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23:9392–9400PubMedCrossRefGoogle Scholar
  135. Yue P, Turkson J (2009) Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs 18:45–56PubMedPubMedCentralCrossRefGoogle Scholar
  136. Zhang F, Li C, Halfter H, Liu J (2003) Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells. Oncogene 22:894–905CrossRefGoogle Scholar
  137. Zhang Y, Cheng MB, Zhang YJ, Zhong X, Dai H, Yan L, Wu NH, Shen YF (2010) A switch from hBrm to Brg1 at IFNgamma-activated sequences mediates the activation of human genes. Cell Res 20:1345–1360PubMedCrossRefGoogle Scholar
  138. Zhou H, Miki R, Eeva M, Fike FM, Seligson D, Yang L, Yoshimura A, Teitell MA, Jamieson CA, Cacalano NA (2007) Reciprocal regulation of SOCS 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. Clin Cancer Res 13:2344–2353PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Laboratory of Transcription Regulation, Department of Cell BiologyNencki Institute of Experimental Biology, Polish Academy of SciencesWarsawPoland

Personalised recommendations