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Gene Review

Stat3  -  signal transducer and activator of...

Mus musculus

Synonyms: 1110034C02Rik, AW109958, Acute-phase response factor, Aprf, Signal transducer and activator of transcription 3
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Disease relevance of Stat3


High impact information on Stat3

  • In this issue of Cell, and add a new transcriptional operating system to the known Oct4 and Stat3 systems required for early embryonal stem cell potency and self-renewal [6].
  • Despite intact expression and phosphorylation of Stat3alpha, overall Stat3 activity was impaired in Stat3beta(-/-) cells [7].
  • Alternative splicing of the gene for Stat3, a transcription factor activated by the IL-6 family of cytokines, produces two isoforms: Stat3alpha and a dominant-negative variant, Stat3beta [7].
  • Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock [7].
  • In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis [8].

Psychiatry related information on Stat3

  • These data demonstrate that Stat3-dependent signaling in AgRP neurons in the ARC controls locomotor activity independently of AgRP regulation [9].

Chemical compound and disease context of Stat3

  • Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth [3].
  • Our findings, taken together, suggest that tyrosine kinases transduce signals through Stat3 protein that contribute to the growth and survival of human breast cancer cells in culture and potentially in vivo [10].
  • Furthermore, blockade of activated Stat3 in highly metastatic C4 cells significantly suppressed the invasiveness of the tumor cells, inhibited tumor growth, and prevented metastasis in nude mice [11].
  • RESULTS: We show that the levels of activated Stat3 are associated with the progression of androgen-independent prostate cancer [12].
  • However, these mice did not develop glucose intolerance or obesity over a period of 6 months, demonstrating that Stat3 is dispensable for the generation and physiology of beta-cells [13].

Biological context of Stat3

  • Specific inhibition of Stat3 signal transduction by PIAS3 [14].
  • PIAS3 blocked the DNA-binding activity of Stat3 and inhibited Stat3-mediated gene activation [14].
  • To address the function of this signaling molecule in mammary epithelial apoptosis, we have generated a conditional knockout of Stat3 using the Cre-lox recombination system [15].
  • Our findings suggest that IGFBP-5 is a direct or indirect target for Stat3 and its upregulation is essential to normal involution [15].
  • Stat3 may be a key molecule which determines the cellular decision from cell growth to differentiation in M1 cells [16].

Anatomical context of Stat3

  • Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3 [15].
  • Furthermore, enterocolitis was significantly improved and IFN-gamma production by T cells was reduced in TLR4/Stat3 double-mutant mice, indicating that TLR4-mediated recognition of microbial components triggers aberrant IL-12p40 production by myeloid cells, leading to the development of enterocolitis [2].
  • We show here that disruption of Stat3 signaling by using dominant-negative Stat3beta protein in NIH 3T3 fibroblasts suppresses c-Myc expression concomitant with inhibition of v-Src-induced transformation [17].
  • In normal NIH 3T3 cells, disruption of Stat3 signaling with dominant-negative Stat3beta protein inhibits PDGF-induced mitogenesis in a manner that is reversed by ectopic c-Myc expression [17].
  • We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression [3].

Associations of Stat3 with chemical compounds

  • Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals [1].
  • The studies reported here were undertaken to determine which, if any, of these tyrosine residues participated in Stat3/beta recruitment and activation [4].
  • Treatment of C4HD cells with MPA induced Stat3 binding to DNA [3].
  • Y744 is followed at the +3 position by Cys (C); YXXC, represents a novel motif implicated in the recruitment and activation of Stat3 [4].
  • To identify small molecule inhibitors of Stat3, we investigated the ability of the Stat3 SH2 domain-binding peptide, PY*LKTK (where Y* represents phosphotyrosine), to disrupt Stat3 activity in vitro [18].

Physical interactions of Stat3


Enzymatic interactions of Stat3


Regulatory relationships of Stat3


Other interactions of Stat3

  • Even in the absence of Stat1, which is essential for IFN-gamma signaling pathways, Stat3 mutant mice developed chronic enterocolitis [2].
  • Ectopic expression of c-Myc is able to partially reverse this inhibition, suggesting that c-Myc is a downstream effector of Stat3 signaling in v-Src transformation [17].
  • Here we report a novel signaling pathway of EphA4, which involves activation of the tyrosine kinase Jak2 and the transcriptional activator Stat3 [31].
  • Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells [32].
  • However, Stat3 activation during involution was independent of the IL-6 status [27].

Analytical, diagnostic and therapeutic context of Stat3


  1. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Gao, Q., Mezei, G., Nie, Y., Rao, Y., Choi, C.S., Bechmann, I., Leranth, C., Toran-Allerand, D., Priest, C.A., Roberts, J.L., Gao, X.B., Mobbs, C., Shulman, G.I., Diano, S., Horvath, T.L. Nat. Med. (2007) [Pubmed]
  2. Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. Kobayashi, M., Kweon, M.N., Kuwata, H., Schreiber, R.D., Kiyono, H., Takeda, K., Akira, S. J. Clin. Invest. (2003) [Pubmed]
  3. Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells. Proietti, C., Salatino, M., Rosemblit, C., Carnevale, R., Pecci, A., Kornblihtt, A.R., Molinolo, A.A., Frahm, I., Charreau, E.H., Schillaci, R., Elizalde, P.V. Mol. Cell. Biol. (2005) [Pubmed]
  4. Identification of a novel Stat3 recruitment and activation motif within the granulocyte colony-stimulating factor receptor. Chakraborty, A., Dyer, K.F., Cascio, M., Mietzner, T.A., Tweardy, D.J. Blood (1999) [Pubmed]
  5. Effects of plasmid-based Stat3-specific short hairpin RNA and GRIM-19 on PC-3M tumor cell growth. Zhang, L., Gao, L., Li, Y., Lin, G., Shao, Y., Ji, K., Yu, H., Hu, J., Kalvakolanu, D.V., Kopecko, D.J., Zhao, X., Xu, D.Q. Clin. Cancer Res. (2008) [Pubmed]
  6. Nanog: a new recruit to the embryonic stem cell orchestra. Cavaleri, F., Schöler, H.R. Cell (2003) [Pubmed]
  7. Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Yoo, J.Y., Huso, D.L., Nathans, D., Desiderio, S. Cell (2002) [Pubmed]
  8. Stat3 as an oncogene. Bromberg, J.F., Wrzeszczynska, M.H., Devgan, G., Zhao, Y., Pestell, R.G., Albanese, C., Darnell, J.E. Cell (1999) [Pubmed]
  9. Activation of Stat3 signaling in AgRP neurons promotes locomotor activity. Mesaros, A., Koralov, S.B., Rother, E., Wunderlich, F.T., Ernst, M.B., Barsh, G.S., Rajewsky, K., Brüning, J.C. Cell Metab. (2008) [Pubmed]
  10. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Garcia, R., Bowman, T.L., Niu, G., Yu, H., Minton, S., Muro-Cacho, C.A., Cox, C.E., Falcone, R., Fairclough, R., Parsons, S., Laudano, A., Gazit, A., Levitzki, A., Kraker, A., Jove, R. Oncogene (2001) [Pubmed]
  11. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Xie, T.X., Wei, D., Liu, M., Gao, A.C., Ali-Osman, F., Sawaya, R., Huang, S. Oncogene (2004) [Pubmed]
  12. Stat3 enhances the growth of LNCaP human prostate cancer cells in intact and castrated male nude mice. DeMiguel, F., Lee, S.O., Lou, W., Xiao, X., Pflug, B.R., Nelson, J.B., Gao, A.C. Prostate (2002) [Pubmed]
  13. The transcription factor Stat3 is dispensable for pancreatic beta-cell development and function. Lee, J.Y., Hennighausen, L. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  14. Specific inhibition of Stat3 signal transduction by PIAS3. Chung, C.D., Liao, J., Liu, B., Rao, X., Jay, P., Berta, P., Shuai, K. Science (1997) [Pubmed]
  15. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Chapman, R.S., Lourenco, P.C., Tonner, E., Flint, D.J., Selbert, S., Takeda, K., Akira, S., Clarke, A.R., Watson, C.J. Genes Dev. (1999) [Pubmed]
  16. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. Nakajima, K., Yamanaka, Y., Nakae, K., Kojima, H., Ichiba, M., Kiuchi, N., Kitaoka, T., Fukada, T., Hibi, M., Hirano, T. EMBO J. (1996) [Pubmed]
  17. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Bowman, T., Broome, M.A., Sinibaldi, D., Wharton, W., Pledger, W.J., Sedivy, J.M., Irby, R., Yeatman, T., Courtneidge, S.A., Jove, R. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  18. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. Turkson, J., Ryan, D., Kim, J.S., Zhang, Y., Chen, Z., Haura, E., Laudano, A., Sebti, S., Hamilton, A.D., Jove, R. J. Biol. Chem. (2001) [Pubmed]
  19. Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. Campbell, G.S., Meyer, D.J., Raz, R., Levy, D.E., Schwartz, J., Carter-Su, C. J. Biol. Chem. (1995) [Pubmed]
  20. Stat3-dependent induction of BATF in M1 mouse myeloid leukemia cells. Senga, T., Iwamoto, T., Humphrey, S.E., Yokota, T., Taparowsky, E.J., Hamaguchi, M. Oncogene (2002) [Pubmed]
  21. Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition. Abell, K., Bilancio, A., Clarkson, R.W., Tiffen, P.G., Altaparmakov, A.I., Burdon, T.G., Asano, T., Vanhaesebroeck, B., Watson, C.J. Nat. Cell Biol. (2005) [Pubmed]
  22. Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction. Coffer, P.J., van Puijenbroek, A., Burgering, B.M., Klop-de Jonge, M., Koenderman, L., Bos, J.L., Kruijer, W. Oncogene (1997) [Pubmed]
  23. In vitro activation of Stat3 by epidermal growth factor receptor kinase. Park, O.K., Schaefer, T.S., Nathans, D. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  24. Inhibition of Stat3 activation in the endometrium prevents implantation: a nonsteroidal approach to contraception. Catalano, R.D., Johnson, M.H., Campbell, E.A., Charnock-Jones, D.S., Smith, S.K., Sharkey, A.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  25. Leptin activates Stat3, Stat1 and AP-1 in mouse adipose tissue. Bendinelli, P., Maroni, P., Pecori Giraldi, F., Piccoletti, R. Mol. Cell. Endocrinol. (2000) [Pubmed]
  26. Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver. Ruff-Jamison, S., Zhong, Z., Wen, Z., Chen, K., Darnell, J.E., Cohen, S. J. Biol. Chem. (1994) [Pubmed]
  27. Loss of interleukin 6 results in delayed mammary gland involution: a possible role for mitogen-activated protein kinase and not signal transducer and activator of transcription 3. Zhao, L., Melenhorst, J.J., Hennighausen, L. Mol. Endocrinol. (2002) [Pubmed]
  28. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Cheng, A., Uetani, N., Simoncic, P.D., Chaubey, V.P., Lee-Loy, A., McGlade, C.J., Kennedy, B.P., Tremblay, M.L. Dev. Cell (2002) [Pubmed]
  29. Leukemia inhibitory factor enhances mast cell growth in a mast cell/fibroblast co-culture system through stat3 signaling pathway of fibroblasts. Hiragun, T., Morita, E., Mihara, S., Tanaka, T., Gyotoku, E., Kameyoshi, Y., Yamamoto, S. FEBS Lett. (2000) [Pubmed]
  30. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Jenkins, B.J., Grail, D., Nheu, T., Najdovska, M., Wang, B., Waring, P., Inglese, M., McLoughlin, R.M., Jones, S.A., Topley, N., Baumann, H., Judd, L.M., Giraud, A.S., Boussioutas, A., Zhu, H.J., Ernst, M. Nat. Med. (2005) [Pubmed]
  31. Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle: implications in the regulation of acetylcholinesterase expression. Lai, K.O., Chen, Y., Po, H.M., Lok, K.C., Gong, K., Ip, N.Y. J. Biol. Chem. (2004) [Pubmed]
  32. Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells. Gamero, A.M., Potla, R., Wegrzyn, J., Szelag, M., Edling, A.E., Shimoda, K., Link, D.C., Dulak, J., Baker, D.P., Tanabe, Y., Grayson, J.M., Larner, A.C. J. Biol. Chem. (2006) [Pubmed]
  33. Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling. Ho, J.M., Beattie, B.K., Squire, J.A., Frank, D.A., Barber, D.L. Blood (1999) [Pubmed]
  34. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Akira, S., Nishio, Y., Inoue, M., Wang, X.J., Wei, S., Matsusaka, T., Yoshida, K., Sudo, T., Naruto, M., Kishimoto, T. Cell (1994) [Pubmed]
  35. Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis. Chan, K.S., Carbajal, S., Kiguchi, K., Clifford, J., Sano, S., DiGiovanni, J. Cancer Res. (2004) [Pubmed]
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