• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of biochemjBJ Latest papers and much more!
Biochem J. Apr 15, 1998; 331(Pt 2): 381–385.
PMCID: PMC1219365

Expression of v-src in mammary epithelial cells induces transcription via STAT3.

Abstract

Transgenic mouse models of mammary tumorigenesis and analyses of human breast tumour samples have indicated a role for Src proteins in the tumorigenic process. The downstream effectors of Src function in mammary epithelial cells are less well understood. STAT proteins constitute a family of transcription factors whose activation by cytokine and non-cytokine receptors leads to tyrosine phosphorylation, dimerization and translocation from the cytoplasm to the nucleus. In the nucleus they activate the transcription of specific genes by binding to consensus DNA elements. STATs 1 and 3 can be activated by both cytokine and non-cytokine receptors, and bind as homodimers or heterodimers to viral simian sarcoma virus (sis)-inducible elements such as that found in the c-fos promoter. Here we report that one of the downstream effectors of Src function in mammary epithelial cells is STAT3. We demonstrate that v-src expression in mammary epithelial cells induces Tyr-705 phosphorylation, nuclear translocation and DNA binding of STAT3. Furthermore, we demonstrate that v-src can induce STAT3-dependent transcription. These observations are the first direct evidence that v-src can regulate transcription through the activation of STAT proteins, and add a further level of complexity to the understanding of the mode of action of v-src.

Full Text

The Full Text of this article is available as a PDF (239K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hennipman A, van Oirschot BA, Smits J, Rijksen G, Staal GE. Tyrosine kinase activity in breast cancer, benign breast disease, and normal breast tissue. Cancer Res. 1989 Feb 1;49(3):516–521. [PubMed]
  • Ottenhoff-Kalff AE, Rijksen G, van Beurden EA, Hennipman A, Michels AA, Staal GE. Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product. Cancer Res. 1992 Sep 1;52(17):4773–4778. [PubMed]
  • Guy CT, Muthuswamy SK, Cardiff RD, Soriano P, Muller WJ. Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. Genes Dev. 1994 Jan;8(1):23–32. [PubMed]
  • Muthuswamy SK, Siegel PM, Dankort DL, Webster MA, Muller WJ. Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. Mol Cell Biol. 1994 Jan;14(1):735–743. [PMC free article] [PubMed]
  • Webster MA, Cardiff RD, Muller WJ. Induction of mammary epithelial hyperplasias and mammary tumors in transgenic mice expressing a murine mammary tumor virus/activated c-src fusion gene. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7849–7853. [PMC free article] [PubMed]
  • Smith MR, DeGudicibus SJ, Stacey DW. Requirement for c-ras proteins during viral oncogene transformation. Nature. 1986 Apr 10;320(6062):540–543. [PubMed]
  • Aftab DT, Kwan J, Martin GS. Ras-independent transformation by v-Src. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3028–3033. [PMC free article] [PubMed]
  • Gupta SK, Gallego C, Johnson GL, Heasley LE. MAP kinase is constitutively activated in gip2 and src transformed rat 1a fibroblasts. J Biol Chem. 1992 Apr 25;267(12):7987–7990. [PubMed]
  • Wyke AW, Lang A, Frame MC. Uncoupling of the pathways which link MAP kinase to c-fos transcription and AP-1 in response to growth stimuli. Cell Signal. 1996 Feb;8(2):131–139. [PubMed]
  • Xie W, Herschman HR. v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J Biol Chem. 1995 Nov 17;270(46):27622–27628. [PubMed]
  • Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994 Aug 18;370(6490):527–532. [PubMed]
  • Fukui Y, Hanafusa H. Requirement of phosphatidylinositol-3 kinase modification for its association with p60src. Mol Cell Biol. 1991 Apr;11(4):1972–1979. [PMC free article] [PubMed]
  • Ihle JN. STATs: signal transducers and activators of transcription. Cell. 1996 Feb 9;84(3):331–334. [PubMed]
  • Leaman DW, Pisharody S, Flickinger TW, Commane MA, Schlessinger J, Kerr IM, Levy DE, Stark GR. Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. Mol Cell Biol. 1996 Jan;16(1):369–375. [PMC free article] [PubMed]
  • David M, Wong L, Flavell R, Thompson SA, Wells A, Larner AC, Johnson GR. STAT activation by epidermal growth factor (EGF) and amphiregulin. Requirement for the EGF receptor kinase but not for tyrosine phosphorylation sites or JAK1. J Biol Chem. 1996 Apr 19;271(16):9185–9188. [PubMed]
  • Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 1995 Jul 7;269(5220):81–83. [PubMed]
  • Cao X, Tay A, Guy GR, Tan YH. Activation and association of Stat3 with Src in v-Src-transformed cell lines. Mol Cell Biol. 1996 Apr;16(4):1595–1603. [PMC free article] [PubMed]
  • Zong C, Yan R, August A, Darnell JE, Jr, Hanafusa H. Unique signal transduction of Eyk: constitutive stimulation of the JAK-STAT pathway by an oncogenic receptor-type tyrosine kinase. EMBO J. 1996 Sep 2;15(17):4515–4525. [PMC free article] [PubMed]
  • Chaturvedi P, Sharma S, Reddy EP. Abrogation of interleukin-3 dependence of myeloid cells by the v-src oncogene requires SH2 and SH3 domains which specify activation of STATs. Mol Cell Biol. 1997 Jun;17(6):3295–3304. [PMC free article] [PubMed]
  • Stamps AC, Davies SC, Burman J, O'Hare MJ. Analysis of proviral integration in human mammary epithelial cell lines immortalized by retroviral infection with a temperature-sensitive SV40 T-antigen construct. Int J Cancer. 1994 Jun 15;57(6):865–874. [PubMed]
  • Kaptein A, Paillard V, Saunders M. Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction. J Biol Chem. 1996 Mar 15;271(11):5961–5964. [PubMed]
  • Wagner BJ, Hayes TE, Hoban CJ, Cochran BH. The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter. EMBO J. 1990 Dec;9(13):4477–4484. [PMC free article] [PubMed]
  • Mitchell PJ, Barker KT, Martindale JE, Kamalati T, Lowe PN, Page MJ, Gusterson BA, Crompton MR. Cloning and characterisation of cDNAs encoding a novel non-receptor tyrosine kinase, brk, expressed in human breast tumours. Oncogene. 1994 Aug;9(8):2383–2390. [PubMed]
  • Kamalati T, Jolin HE, Mitchell PJ, Barker KT, Jackson LE, Dean CJ, Page MJ, Gusterson BA, Crompton MR. Brk, a breast tumor-derived non-receptor protein-tyrosine kinase, sensitizes mammary epithelial cells to epidermal growth factor. J Biol Chem. 1996 Nov 29;271(48):30956–30963. [PubMed]
  • Andrews NC, Faller DV. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 1991 May 11;19(9):2499–2499. [PMC free article] [PubMed]
  • Eilers A, Kanda K, Klose B, Krolewski J, Decker T. Constitutive STAT1 tyrosine phosphorylation in U937 monocytes overexpressing the TYK2 protein tyrosine kinase does not induce gene transcription. Cell Growth Differ. 1996 Jun;7(6):833–840. [PubMed]
  • Wen Z, Zhong Z, Darnell JE., Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995 Jul 28;82(2):241–250. [PubMed]
  • Wen Z, Darnell JE., Jr Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res. 1997 Jun 1;25(11):2062–2067. [PMC free article] [PubMed]
  • Campbell GS, Yu CL, Jove R, Carter-Su C. Constitutive activation of JAK1 in Src-transformed cells. J Biol Chem. 1997 Jan 31;272(5):2591–2594. [PubMed]
  • Zhang X, Blenis J, Li HC, Schindler C, Chen-Kiang S. Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science. 1995 Mar 31;267(5206):1990–1994. [PubMed]
  • David M, Petricoin E, 3rd, Benjamin C, Pine R, Weber MJ, Larner AC. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 1995 Sep 22;269(5231):1721–1723. [PubMed]
  • Winston LA, Hunter T. Intracellular signalling: putting JAKs on the kinase MAP. Curr Biol. 1996 Jun 1;6(6):668–671. [PubMed]
  • Beadling C, Ng J, Babbage JW, Cantrell DA. Interleukin-2 activation of STAT5 requires the convergent action of tyrosine kinases and a serine/threonine kinase pathway distinct from the Raf1/ERK2 MAP kinase pathway. EMBO J. 1996 Apr 15;15(8):1902–1913. [PMC free article] [PubMed]
  • Philp JA, Burdon TG, Watson CJ. Differential activation of STATs 3 and 5 during mammary gland development. FEBS Lett. 1996 Oct 28;396(1):77–80. [PubMed]
  • Watson CJ, Miller WR. Elevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts. Br J Cancer. 1995 Apr;71(4):840–844. [PMC free article] [PubMed]
  • Ishidoh K, Taniguchi S, Kominami E. Egr family member proteins are involved in the activation of the cathepsin L gene in v-src-transformed cells. Biochem Biophys Res Commun. 1997 Sep 18;238(2):665–669. [PubMed]
  • Jiang BH, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 1997 Dec 1;57(23):5328–5335. [PubMed]
  • Cabannes E, Vives MF, Bédard PA. Transcriptional and post-transcriptional regulation of kappaB-controlled genes by pp60v-src. Oncogene. 1997 Jul 3;15(1):29–43. [PubMed]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...