Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Constitutive activation of Stat3α in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2)

Oncogene volume 21, pages 2058–2065 (2002)Cite this article

Abstract

Members of the normally latent family of transcription factors signal/inducers and activators of transcription (Stat) are activated in a number of human tumors and tumor-derived cell lines. In the case of Stat3, it is believed that this activation leads to the induction of survival signals as well as increased proliferation. In this study, we demonstrate that Stat3 is constitutively activated in glioma and medulloblastoma tumors and that the activated protein localizes predominantly to the tumor endothelial cells in the highly vascularized glioma tumors. Our efforts to elucidate potential mechanism(s) for this activated protein have shown that coexpression of Stat3α and the vascular endothelial growth factor receptor-2 (VEGFR-2) result in ligand-independent activation of Stat3α tyrosine phosphorylation and subsequent transcriptional activation in non-endothelial cells. We also show that activated Stat3α can increase transcription from the vascular endothelial growth factor (VEGF) gene. Taken together, these results suggest that the activated Stat3α found in brain tumors may be due to the endothelial tyrosine kinase VEGFR-2 and that Stat3α may play a central role in autocrine VEGF activation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, Bigner DD . 1995 Cell Growth Differ. 6: 1251–1259

  • Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell Jr JE . 1998 Mol. Cell Biol. 18: 2553–2558

  • Cao X, Tay A, Guy GR, Tan YH . 1996 Mol. Cell Biol. 16: 1595–1603

  • Carroll RS, Zhang J, Bello L, Melnick MB, Maruyama T, Black P McL . 1999 Cancer 86: 1335–1341

  • 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 Immunity 10: 105–115

  • David M, Wong L, Flavell R, Thompson SA, Wells A, Larner AC, Johnson GR . 1996 J. Biol. Chem. 271: 9185–9188

  • Filmus J, Pollak MN, Cairncross JG, Buick RN . 1985 Biochem. Biophys. Res. Commun. 131: 207–215

  • Fleming RY, Ellis LM, Parikh NU, Liu W, Staley CA, Gallick GE . 1997 Surgery 122: 501–507

  • Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, Ethier SP, Jove R . 1997 Cell Growth Differ. 8: 1267–1276

  • Gorman CM, Merlino GT, Willingham MC, Pastan I, Howard BH . 1982 Proc. Natl. Acad. Sci. USA 79: 6777–6781

  • Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhelm MF, Endo S, Johnson DE, Huang L, He Y, Kin JD . 2000 PNAS 97: 4227–4232

  • Hatva E, Kaipainen A, Mentula P, Jaaskelainen J, Paetau A, Haltia M, Alitalo K . 1995 Am. J. Pathol. 146: 368–378

  • He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB . 1999 J. Biol. Chem. 274: 25130–25135

  • Ijichi A, Sakuma S, Tofilon PJ . 1995 Glia. 14: 87–93

  • Kiuchi N, Nakajima K, Ichiba M, Fukada T, Narimatsu M, Mizuno K, Hibi M, Hirano T . 1999 J. Exp. Med. 189: 63–73

  • Korpelainen EI, Karkkainen M, Gunji Y, Vikkula M, Alitalo K . 1999 Oncogene 18: 1–8

  • Levey AP, Levy NS, Wegner S, Goldberg MA . 1995 J. Biol. Chem. 270: 13333–13340

  • Libermann TA, Razon N, Bartal AD, Yarden Y, Schlessinger J, Soreq H . 1984 Cancer Res. 44: 753–760

  • Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ulrich A, Schlessinger J . 1985 Nature 313: 144–147

  • Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP . 1995a Nature 375: 577–581

  • Mukhopadhyay D, Tsiokas L, Sukhatme VP . 1995b Cancer Res. 55: 6161–6165

  • Ni Z, Lou W, Leman ES, Gao AC . 2000 Cancer Res. 60: 1225–1228

  • Nielsen M, Kaestel CG, Eriksen KW, Woetmann A, Stokkedal T, Kaltoft K, Geisler C, Ropke C, Odum N . 1999 Leukemia 13: 735–738

  • Pietsch T, Valter MM, Wolf HK, von Deimling A, Huang HJ, Cavenee WK, Weistler OD . 1997 Acta. Neuropathol. (Berl) 93: 109–117

  • Schaefer LK, Menter DG, Schaefer TS . 2000a Cell. Signal. 12: 143–151

  • Schaefer LK, Wang S, Schaefer TS . 1999 Biochem. Biophys. Commun. 266: 481–487

  • Schaefer TS, Sanders LK, Nathans D . 1995 Proc. Natl. Acad. Sci. USA 92: 9097–9101

  • Schaefer TS, Sanders LK, Park OK, Nathans D . 1997 Mol. Cell Biol. 17: 5307–5316

  • Schaefer TS, Wang S, Schaefer TS . 2000b Cytokine 12: 1647–1655

  • Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N, Kiessling M . 1994 Int. J. Cancer 56: 72–77

  • Schwechheimer K, Huang S, Cavenee WK . 1995 Int. J. Cancer 62: 145–148

  • Shweiki D, Itin A, Soffer D, Keshet E . 1992 Nature 359: 843–845

  • Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell Jr JE, Yancopoulos GD . 1995 Science 267: 1349–1353

  • Theurillat JP, Hainfellner J, Maddalena A, Weissenberger J, Aguzzi A . 1999 Am. J. Pathol. 154: 581–590

  • Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R . 1998 Mol. Cell Biol. 18: 2545–2552

  • Weber-Nordt RM, Egen C, Wehinger J, Ludwig W, Gouilleux-Gruart V, Mertelsmann R, Finke J . 1996 Blood 88: 809–816

  • Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B . 1992 Proc. Natl. Acad. Sci. USA 89: 2965–2969

  • Xia Z, Baer MR, Block AW, Baumann H, Wetzler M . 1998 Cancer Res. 58: 3173–3180

  • Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R . 1995 Science 269: 81–83

Download references

Acknowledgements

We thank B Terman for providing the VEGFR-2 expression plasmid, V Sukhatme for the VEGF reporter plasmid, D Yu for the wild-type erbB-2 expression plasmid and J Richards for the α-2 macroglobulin luciferase reporter. We also thank D Fults (University of Utah) for providing medulloblastoma tumor specimen. We thank U Steinkoenig for preparation of the manuscript. We also gratefully acknowledge support from The Anthony D Bullock III Foundation.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Laura K Schaefer, Zhiyong Ren & Timothy S Schaefer

  2. Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Gregory N Fuller

  3. Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Timothy S Schaefer

Authors
  1. Laura K Schaefer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiyong Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gregory N Fuller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Timothy S Schaefer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy S Schaefer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schaefer, L., Ren, Z., Fuller, G. et al. Constitutive activation of Stat3α in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene 21, 2058–2065 (2002). https://doi.org/10.1038/sj.onc.1205263

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205263

Keywords

This article is cited by

Search

Advanced search

Quick links