Skip to main content

Advertisement

SpringerLink
Log in

The Biological Functions of the Versatile Transcription Factors STAT3 and STAT5 and New Strategies for their Targeted Inhibition

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Signal transducers and activators of transcription (STATs) comprise a unique family of transcription factors, which transmit the interactions of cytokines, hormones and growth factors with their cell surface receptors into transcriptional programs. The mechanism of STAT activation has been well-established and comprises tyrosine phosphorylation, dimerization, nuclear translocation, binding to specific DNA response elements, recruitment of co-activators or co-repressors and transcriptional induction or repression of target genes. Gene deletion, microarrays, proteomics and chromatin immunoprecipitation experiments have revealed target genes with a broad range of functions regulated by STAT3 and STAT5. In the mammary gland, STAT5-induced genes contribute mainly to the prolactin dependent lobulo-alveolar development, whereas STAT3 induced genes control apoptosis during involution. Crucial effects have also been observed in other tissues. The germ line deletion of STAT3 or STAT5 causes early embryonal or perinatal lethality in mice. STAT5 is also required for proliferation of T- and B-cells and hematopoietic stem cell self-renewal. Deregulated STAT activity is often found associated with tumorigenesis and activated STATs seem to be limiting components in tumor cells. This review summarizes the functions of STAT3 and STAT5 in different cell types and the strategies that are used to counteract their action in tumor cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

Abbreviations

STAT:

signal transducer and activator of transcription

JAK:

janus kinase

EGFR:

epidermal growth factor receptor

SH2:

SRC homology domain 2

TAD:

transactivation domain

SOCS:

suppressors of cytokine signaling

PIAS:

protein inhibitors of activated STATs

PI3K:

phosphatidylinositol 3-kinase

IL-2:

interleukin-2

ERK:

extracellular signal-regulated kinase

JNK:

Jun N-terminal kinase

HNSCC:

head and neck squamous cell carcinoma

VEGF:

vascular endothelial growth factor

TGF:

transforming growth factor

BLG:

β-lactoglobulin

PTD:

protein transduction domain

MAPK:

mitogen-activated protein kinase

References

  1. Calo V, Migliavacca M, Bazan V, Macaluso M, Buscemi M, Gebbia N, et al. STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol 2003;197(2):157–68.

    PubMed  CAS  Google Scholar 

  2. Wittig I, Groner B. Signal transducer and activator of transcription 5 (STAT5), a crucial regulator of immune and cancer cells. Curr Drug Targets Immune Endocr Metabol Disord 2005;5(4):449–63.

    PubMed  CAS  Google Scholar 

  3. Valentino L, Pierre J. JAK/STAT signal transduction: regulators and implication in hematological malignancies. Biochem Pharmacol 2006;71(6):713–21.

    PubMed  CAS  Google Scholar 

  4. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 2005;5(8):593–605.

    PubMed  CAS  Google Scholar 

  5. O'Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov 2004;3(7):555–64.

    PubMed  Google Scholar 

  6. Chen W, Daines MO, Khurana Hershey GK. Turning off signal transducer and activator of transcription (STAT): the negative regulation of STAT signaling. J Allergy Clin Immunol 2004;114(3):476–89; quiz 490.

    PubMed  CAS  Google Scholar 

  7. Alexander WS, Hilton DJ. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol 2004;22:503–29.

    PubMed  CAS  Google Scholar 

  8. Ehret GB, Reichenbach P, Schindler U, Horvath CM, Fritz S, Nabholz M, et al. DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites. J Biol Chem 2001;276(9):6675–88.

    PubMed  CAS  Google Scholar 

  9. Clarkson RW, Boland MP, Kritikou EA, Lee JM, Freeman TC, Tiffen PG, et al. The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development. Mol Endocrinol 2006;20(3):675–85.

    PubMed  CAS  Google Scholar 

  10. LeBaron MJ, Xie J, Rui H. Evaluation of genome-wide chromatin library of Stat5 binding sites in human breast cancer. Mol Cancer 2005;4(1):6.

    PubMed  Google Scholar 

  11. Gass S, Harris J, Ormandy C, Brisken C. Using gene expression arrays to elucidate transcriptional profiles underlying prolactin function. J Mammary Gland Biol Neoplasia 2003;8(3):269–85.

    PubMed  Google Scholar 

  12. Naylor MJ, Oakes SR, Gardiner-Garden M, Harris J, Blazek K, Ho TW, et al. Transcriptional changes underlying the secretory activation phase of mammary gland development. Mol Endocrinol 2005;19(7):1868–83.

    PubMed  CAS  Google Scholar 

  13. Walton KD, Wagner KU, Rucker EB, 3rd, Shillingford JM, Miyoshi K, Hennighausen L. Conditional deletion of the bcl-x gene from mouse mammary epithelium results in accelerated apoptosis during involution but does not compromise cell function during lactation. Mech Dev 2001;109(2):281–93.

    PubMed  CAS  Google Scholar 

  14. Dolznig H, Grebien F, Deiner EM, Stangl K, Kolbus A, Habermann B, et al. Erythroid progenitor renewal versus differentiation: genetic evidence for cell autonomous, essential functions of EpoR, Stat5 and the GR. Oncogene 2006;25(20):2890–900.

    PubMed  CAS  Google Scholar 

  15. Wakao H, Gouilleux F, Groner B. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. Embo J 1994;13(9):2182–91.

    PubMed  CAS  Google Scholar 

  16. Stocklin E, Wissler M, Gouilleux F, Groner B. Functional interactions between Stat5 and the glucocorticoid receptor. Nature 1996;383(6602):726–8.

    PubMed  CAS  Google Scholar 

  17. Proietti C, Salatino M, Rosemblit C, Carnevale R, Pecci A, Kornblihtt AR, et al. Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells. Mol Cell Biol 2005;25(12):4826–40.

    PubMed  CAS  Google Scholar 

  18. Joung YH, Lim EJ, Lee MY, Park JH, Ye SK, Park EU, et al. Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells. Exp Mol Med 2005;37(4):353–64.

    PubMed  CAS  Google Scholar 

  19. Magne S, Caron S, Charon M, Rouyez MC, Dusanter-Fourt I. STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression. Mol Cell Biol 2003;23(24):8934–45.

    PubMed  CAS  Google Scholar 

  20. Brockman JL, Schuler LA. Prolactin signals via Stat5 and Oct-1 to the proximal cyclin D1 promoter. Mol Cell Endocrinol 2005;239(1–2):45–53.

    PubMed  CAS  Google Scholar 

  21. Brisken C, Ayyannan A, Nguyen C, Heineman A, Reinhardt F, Tan J, et al. IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Dev Cell 2002;3(6):877–87.

    PubMed  CAS  Google Scholar 

  22. Moon JJ, Rubio ED, Martino A, Krumm A, Nelson BH. A permissive role for phosphatidylinositol 3-kinase in the Stat5-mediated expression of cyclin D2 by the interleukin-2 receptor. J Biol Chem 2004;279(7):5520–7.

    PubMed  CAS  Google Scholar 

  23. Xu M, Nie L, Kim SH, Sun XH. STAT5-induced Id-1 transcription involves recruitment of HDAC1 and deacetylation of C/EBPbeta. Embo J 2003;22(4):893–904.

    PubMed  CAS  Google Scholar 

  24. Paukku K, Yang J, Silvennoinen O. Tudor and nuclease-like domains containing protein p100 function as coactivators for signal transducer and activator of transcription 5. Mol Endocrinol 2003;17(9):1805–14.

    PubMed  CAS  Google Scholar 

  25. Litterst CM, Kliem S, Lodrini M, Pfitzner E. Coactivators in gene regulation by STAT5. Vitam Horm 2005;70:359–86.

    PubMed  CAS  Google Scholar 

  26. Moriggl R, Gouilleux-Gruart V, Jahne R, Berchtold S, Gartmann C, Liu X, et al. Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Mol Cell Biol 1996;16(10):5691–700.

    PubMed  CAS  Google Scholar 

  27. Yamashita H, Iwase H, Toyama T, Fujii Y. Naturally occurring dominant-negative Stat5 suppresses transcriptional activity of estrogen receptors and induces apoptosis in T47D breast cancer cells. Oncogene 2003;22(11):1638–52.

    PubMed  CAS  Google Scholar 

  28. Pircher TJ, Petersen H, Gustafsson JA, Haldosen LA. Extracellular signal-regulated kinase (ERK) interacts with signal transducer and activator of transcription (STAT) 5a. Mol Endocrinol 1999;13(4):555–65.

    PubMed  CAS  Google Scholar 

  29. Haq R, Halupa A, Beattie BK, Mason JM, Zanke BW, Barber DL, et al. Regulation of erythropoietin-induced STAT serine phosphorylation by distinct mitogen-activated protein kinases. J Biol Chem 2002;277(19):17359–66.

    PubMed  CAS  Google Scholar 

  30. Goh KC, Haque SJ, Williams BR, Pircher TJ, Petersen H, Gustafsson JA, et al. p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J 1999;18(20):5601–8.

    PubMed  CAS  Google Scholar 

  31. Jain N, Zhang T, Fong SL, Lim CP, Cao X, Chung J, et al. Repression of Stat3 activity by activation of mitogen-activated protein kinase (MAPK). Oncogene 1998;17(24):3157–67.

    PubMed  CAS  Google Scholar 

  32. Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol 1997;17(11):6508–16.

    PubMed  CAS  Google Scholar 

  33. Sengupta TK, Talbot ES, Scherle PA, Ivashkiv LB. Rapid inhibition of interleukin-6 signaling and Stat3 activation mediated by mitogen-activated protein kinases. Proc Natl Acad Sci USA 1998;95(19):11107–12.

    PubMed  CAS  Google Scholar 

  34. Muller P, Kuttenkeuler D, Gesellchen V, Zeidler MP, Boutros M. Identification of JAK/STAT signalling components by genome-wide RNA interference. Nature 2005;436(7052):871–5.

    PubMed  Google Scholar 

  35. Cui Y, Riedlinger G, Miyoshi K, Tang W, Li C, Deng CX, et al. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol 2004;24(18):8037–47.

    PubMed  CAS  Google Scholar 

  36. Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 1997;11(2):179–86.

    PubMed  CAS  Google Scholar 

  37. Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, et al. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci USA 1997;94(14):7239–44.

    PubMed  CAS  Google Scholar 

  38. Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, et al. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 1999;10(2):249–59.

    PubMed  CAS  Google Scholar 

  39. Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci USA 1997;94(8):3801–04.

    PubMed  CAS  Google Scholar 

  40. Akira S. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 2000;19(21):2607–11.

    PubMed  CAS  Google Scholar 

  41. Chapman RS, Lourenco PC, Tonner E, Flint DJ, Selbert S, Takeda K, et al. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev 1999;13(19):2604–16.

    PubMed  CAS  Google Scholar 

  42. Miyoshi K, Shillingford JM, Smith GH, Grimm SL, Wagner KU, Oka T, et al. Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium. J Cell Biol 2001;155(4):531–42.

    PubMed  CAS  Google Scholar 

  43. Hennighausen L, Robinson GW. Information networks in the mammary gland. Nat Rev Mol Cell Biol 2005;6(9):715–25.

    PubMed  CAS  Google Scholar 

  44. Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell 2001;1(4):467–75.

    PubMed  CAS  Google Scholar 

  45. Rane SG, Reddy EP. JAKs, STATs and Src kinases in hematopoiesis. Oncogene 2002;21(21):3334–58.

    PubMed  CAS  Google Scholar 

  46. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 2003;3(11):900–11.

    PubMed  CAS  Google Scholar 

  47. Pfitzner E, Kliem S, Baus D, Litterst CM. The role of STATs in inflammation and inflammatory diseases. Curr Pharm Des 2004;10(23):2839–50.

    PubMed  CAS  Google Scholar 

  48. Yao Z, Cui Y, Watford WT, Bream JH, Yamaoka K, Hissong BD, et al. Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci USA 2006;103(4):1000–5.

    PubMed  CAS  Google Scholar 

  49. Goetz CA, Harmon IR, O'Neil JJ, Burchill MA, Johanns TM, Farrar MA. Restricted STAT5 activation dictates appropriate thymic B versus T cell lineage commitment. J Immunol 2005;174(12):7753–63.

    PubMed  CAS  Google Scholar 

  50. Scheeren FA, Naspetti M, Diehl S, Schotte R, Nagasawa M, Wijnands E, et al. STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression. Nat Immunol 2005;6(3):303–13.

    PubMed  CAS  Google Scholar 

  51. Buitenhuis M, Baltus B, Lammers JW, Coffer PJ, Koenderman L. Signal transducer and activator of transcription 5a (STAT5a) is required for eosinophil differentiation of human cord blood-derived CD34+ cells. Blood 2003;101(1):134–42.

    PubMed  CAS  Google Scholar 

  52. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 2004;10(1):48–54.

    PubMed  Google Scholar 

  53. Schuringa JJ, Wu K, Morrone G, Moore MA. Enforced activation of STAT5A facilitates the generation of embryonic stem-derived hematopoietic stem cells that contribute to hematopoiesis in vivo. Stem Cells 2004;22(7):1191–204.

    PubMed  CAS  Google Scholar 

  54. Wierenga AT, Schepers H, Moore MA, Vellenga E, Schuringa JJ. STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves downmodulation of C/EBP{alpha}. Blood 2006;107(11):4326–33.

    PubMed  CAS  Google Scholar 

  55. Kato Y, Iwama A, Tadokoro Y, Shimoda K, Minoguchi M, Akira S, et al. Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis. J Exp Med 2005;202(1):169–79.

    PubMed  CAS  Google Scholar 

  56. Tulina N, Matunis E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science 2001;294(5551):2546–9.

    PubMed  CAS  Google Scholar 

  57. Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 2001;294(5551):2542–5.

    PubMed  CAS  Google Scholar 

  58. Singh SR, Chen X, Hou SX. JAK/STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila. Cell Res 2005;15(1):1–5.

    PubMed  CAS  Google Scholar 

  59. Manhes C, Goffin V, Kelly PA, Touraine P. Autocrine prolactin as a promotor of mammary tumour growth. J Dairy Res 2005;72 Spec No:58–65.

    Google Scholar 

  60. Xi S, Zhang Q, Gooding WE, Smithgall TE, Grandis JR. Constitutive activation of Stat5b contributes to carcinogenesis in vivo. Cancer Res 2003;63(20):6763–71.

    PubMed  CAS  Google Scholar 

  61. Sternberg DW, Gilliland DG. The role of signal transducer and activator of transcription factors in leukemogenesis. J Clin Oncol 2004;22(2):361–71.

    PubMed  CAS  Google Scholar 

  62. Mitchell TJ, John S. Signal transducer and activator of transcription (STAT) signalling and T-cell lymphomas. Immunology 2005;114(3):301–12.

    PubMed  CAS  Google Scholar 

  63. Kelly JA, Spolski R, Kovanen PE, Suzuki T, Bollenbacher J, Pise-Masison CA, et al. Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma. J Exp Med 2003;198(1):79–89.

    PubMed  CAS  Google Scholar 

  64. Clevenger CV. Roles and regulation of stat family transcription factors in human breast cancer. Am J Pathol 2004;165(5):1449–60.

    PubMed  CAS  Google Scholar 

  65. Chan KS, Carbajal S, Kiguchi K, Clifford J, Sano S, DiGiovanni J. Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis. Cancer Res 2004;64(7): 2382–9.

    PubMed  CAS  Google Scholar 

  66. Song L, Turkson J, Karras JG, Jove R, Haura EB. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 2003;22(27):4150–65.

    PubMed  CAS  Google Scholar 

  67. Barton BE, Karras JG, Murphy TF, Barton A, Huang HF. Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther 2004;3(1):11–20.

    PubMed  CAS  Google Scholar 

  68. Xi S, Zhang Q, Dyer KF, Lerner EC, Smithgall TE, Gooding WE, et al. Src kinases mediate STAT growth pathways in squamous cell carcinoma of the head and neck. J Biol Chem 2003;278(34):31574–83.

    PubMed  CAS  Google Scholar 

  69. Moriggl R, Sexl V, Kenner L, Duntsch C, Stangl K, Gingras S, et al. Stat5 tetramer formation is associated with leukemogenesis. Cancer Cell 2005;7(1):87–99.

    PubMed  CAS  Google Scholar 

  70. Zhang Q, Thomas SM, Xi S, Smithgall TE, Siegfried JM, Kamens J, et al. SRC family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells. Cancer Res 2004;64(17):6166–73.

    PubMed  CAS  Google Scholar 

  71. Chim CS, Wong KY, Loong F, Srivastava G. SOCS1 and SHP1 hypermethylation in mantle cell lymphoma and follicular lymphoma: implications for epigenetic activation of the Jak/STAT pathway. Leukemia 2004;18(2):356–8.

    PubMed  CAS  Google Scholar 

  72. Kanda N, Seno H, Konda Y, Marusawa H, Kanai M, Nakajima T, et al. STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene 2004;23(28):4921–9.

    PubMed  CAS  Google Scholar 

  73. Diaz N, Minton S, Cox C, Bowman T, Gritsko T, Garcia R, et al. Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res 2006;12(1):20–8.

    PubMed  CAS  Google Scholar 

  74. Nikitakis NG, Siavash H, Sauk JJ. Targeting the STAT pathway in head and neck cancer: recent advances and future prospects. Curr Cancer Drug Targets 2004;4(8):637–51.

    PubMed  CAS  Google Scholar 

  75. Silva CM. Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 2004;23(48):8017–23.

    PubMed  CAS  Google Scholar 

  76. Sultan AS, Xie J, LeBaron MJ, Ealley EL, Nevalainen MT, Rui H. Stat5 promotes homotypic adhesion and inhibits invasive characteristics of human breast cancer cells. Oncogene 2005;24(5):746–60.

    PubMed  CAS  Google Scholar 

  77. Nevalainen MT, Xie J, Torhorst J, Bubendorf L, Haas P, Kononen J, et al. Signal transducer and activator of transcription-5 activation and breast cancer prognosis. J Clin Oncol 2004;22(11):2053–60.

    PubMed  CAS  Google Scholar 

  78. Li H, Zhang Y, Glass A, Zellweger T, Gehan E, Bubendorf L, et al. Activation of signal transducer and activator of transcription-5 in prostate cancer predicts early recurrence. Clin Cancer Res 2005;11(16):5863–8.

    PubMed  CAS  Google Scholar 

  79. Iavnilovitch E, Cardiff RD, Groner B, Barash I. Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice. Int J Cancer 2004;112(4):607–19.

    PubMed  CAS  Google Scholar 

  80. Iavnilovitch E, Groner B, Barash I. Overexpression and forced activation of stat5 in mammary gland of transgenic mice promotes cellular proliferation, enhances differentiation, and delays postlactational apoptosis. Mol Cancer Res 2002;1(1):32–47.

    PubMed  CAS  Google Scholar 

  81. Turkson J. STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets 2004;8(5):409–22.

    PubMed  CAS  Google Scholar 

  82. Turkson J, Zhang S, Palmer J, Kay H, Stanko J, Mora LB, et al. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity. Mol Cancer Ther 2004;3(12):1533–42.

    PubMed  CAS  Google Scholar 

  83. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 2002;8(4):945–54.

    PubMed  CAS  Google Scholar 

  84. Ling X, Arlinghaus RB. Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice. Cancer Res 2005;65(7):2532–6.

    PubMed  CAS  Google Scholar 

  85. Redell MS, Tweardy DJ. Targeting transcription factors for cancer therapy. Curr Pharm Des 2005;11(22):2873–87.

    PubMed  CAS  Google Scholar 

  86. Turkson J, Ryan D, Kim JS, Zhang Y, Chen Z, Haura E, et al. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J Biol Chem 2001;276(48):45443–55.

    PubMed  CAS  Google Scholar 

  87. Turkson J, Kim JS, Zhang S, Yuan J, Huang M, Glenn M, et al. Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther 2004;3(3):261–9.

    PubMed  CAS  Google Scholar 

  88. Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi S, Mai JC, et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci USA 2003;100(7):4138–43.

    PubMed  CAS  Google Scholar 

  89. Xi S, Gooding WE, Grandis JR. In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy. Oncogene 2005;24(6):970–9.

    PubMed  CAS  Google Scholar 

  90. Ahonen TJ, Xie J, LeBaron MJ, Zhu J, Nurmi M, Alanen K, et al. Inhibition of transcription factor Stat5 induces cell death of human prostate cancer cells. J Biol Chem 2003;278(29): 27287–92.

    PubMed  CAS  Google Scholar 

  91. Muthian G, Raikwar HP, Johnson C, Rajasingh J, Kalgutkar A, Marnett LJ, et al. COX-2 Inhibitors Modulate IL-12 Signaling Through JAK-STAT Pathway Leading to Th1 Response in Experimental Allergic Encephalomyelitis. J Clin Immunol 2006; 26(1):73–85.

    PubMed  CAS  Google Scholar 

  92. Nikitakis NG, Siavash H, Hebert C, Reynolds MA, Hamburger AW, Sauk JJ. 15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells. Br J Cancer 2002;87(12):1396–1403.

    PubMed  CAS  Google Scholar 

  93. Angell JE, Lindner DJ, Shapiro PS, Hofmann ER, Kalvakolanu DV. Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J Biol Chem 2000;275(43): 33416–26.

    PubMed  CAS  Google Scholar 

  94. Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT, et al. GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. EMBO J 2003;22(6):1325–35.

    PubMed  CAS  Google Scholar 

  95. Le Gouill S, Pellat-Deceunynck C, Harousseau JL, Rapp MJ, Robillard N, Bataille R, et al. Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells. Leukemia 2002;16(9):1664–7.

    PubMed  CAS  Google Scholar 

  96. Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res 2003;63(6):1270–9.

    PubMed  CAS  Google Scholar 

  97. Nagel-Wolfrum K, Buerger C, Wittig I, Butz K, Hoppe-Seyler F, Groner B. 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 2004;2(3):170–82.

    PubMed  CAS  Google Scholar 

  98. Mi Z, Mai J, Lu X, Robbins PD. Characterization of a class of cationic peptides able to facilitate efficient protein transduction in vitro and in vivo. Mol Ther 2000;2(4):339–47.

    PubMed  CAS  Google Scholar 

  99. Konnikova L, Simeone MC, Kruger MM, Kotecki M, Cochran BH. Signal transducer and activator of transcription 3 (STAT3) regulates human telomerase reverse transcriptase (hTERT) expression in human cancer and primary cells. Cancer Res 2005;65(15):6516–20.

    PubMed  CAS  Google Scholar 

  100. Nefedova Y, Nagaraj S, Rosenbauer A, Muro-Cacho C, Sebti SM, Gabrilovich DI. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res 2005;65(20):9525–35.

    PubMed  CAS  Google Scholar 

  101. Aoki Y, Feldman GM, Tosato G. Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 2003;101(4):1535–42.

    PubMed  CAS  Google Scholar 

  102. Buerger C, Nagel-Wolfrum K, Kunz C, Wittig I, Butz K, Hoppe-Seyler F, et al. Sequence-specific peptide aptamers, interacting with the intracellular domain of the epidermal growth factor receptor, interfere with Stat3 activation and inhibit the growth of tumor cells. J Biol Chem 2003;278(39):37610–21.

    PubMed  CAS  Google Scholar 

  103. Jang HD, Yoon K, Shin YJ, Kim J, Lee SY. PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit. J Biol Chem 2004;279(23):24873–80.

    PubMed  CAS  Google Scholar 

  104. Wang LH, Yang XY, Mihalic K, Xiao W, Li D, Farrar WL. Activation of estrogen receptor blocks interleukin-6-inducible cell growth of human multiple myeloma involving molecular cross-talk between estrogen receptor and STAT3 mediated by co-regulator PIAS3. J Biol Chem 2001;276(34):31839–44.

    PubMed  CAS  Google Scholar 

  105. He B, You L, Uematsu K, Zang K, Xu Z, Lee AY, et al. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA 2003;100(24):14133–8.

    PubMed  CAS  Google Scholar 

  106. Nagai H, Naka T, Terada Y, Komazaki T, Yabe A, Jin E, et al. Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas. J Hum Genet 2003;48(2):65–9.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank M. Grez, S. Stein and H. Kunkel for providing the lentiviral expression vector and for their helpful support in the handling and production of viral particles. We acknowledge the Deutsche Forschungsgemeinschaft for financial support of this work (grant number GR 536/9-1).

Author information

Authors and Affiliations

  1. Georg-Speyer-Haus, Institute for Biomedical Research, Paul-Ehrlich-Strasse 42, D-60596, Frankfurt am Main, Germany

    Sylvane Desrivières, Christian Kunz, Vida Vafaizadeh, Corina Borghouts & Bernd Groner

  2. Institute of Animal Science, ARO, The Volcani Center, P.O. Box 6, 50250, Bet-Dagan, Israel

    Itamar Barash

Authors
  1. Sylvane Desrivières
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Kunz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Itamar Barash
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vida Vafaizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Corina Borghouts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bernd Groner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernd Groner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Desrivières, S., Kunz, C., Barash, I. et al. The Biological Functions of the Versatile Transcription Factors STAT3 and STAT5 and New Strategies for their Targeted Inhibition. J Mammary Gland Biol Neoplasia 11, 75–87 (2006). https://doi.org/10.1007/s10911-006-9014-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-006-9014-4

Keywords

Search

Navigation