TITLE

A novel activating function of c-Src and Stat3 on HGF transcription in mammary carcinoma cells

AUTHOR(S)
Wojcik, E. J.; Sharifpoor, S.; Miller, N. A.; Wright, T. G.; Watering, R.; Tremblay, E. A.; Swan, K.; Mueller, C. R.; Elliott, B. E.
PUB. DATE
May 2006
SOURCE
Oncogene;5/4/2006, Vol. 25 Issue 19, p2773
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
In the normal breast, hepatocyte growth factor (HGF) is primarily expressed by stromal cells, and stimulates in a paracrine manner epithelial cells expressing the HGF receptor (Met). In invasive human breast carcinomas, HGF and Met are frequently overexpressed, possibly establishing an autocrine HGF/Met loop that promotes tumour cell invasion. However, the mechanisms leading to autocrine HGF expression in carcinoma cells are not known. We previously demonstrated a cooperative effect between c-Src and Stat3 in the activation of HGF transcription in mammary carcinoma cells. The present report defines a novel Stat3 consensus site at nt −95 in the HGF promoter that is highly conserved in human and mouse, and is required for c-Src and Stat3 to activate HGF transcription in breast epithelial cells. DNA–protein binding studies demonstrated high affinity binding of a Stat3-containing complex to the nt −95 site. Endogenous Stat3 binding to this region of the HGF promoter in carcinoma cells expressing HGF was demonstrated using a chromatin immunoprecipitation assay. In addition, coexpression of Stat3 and activated c-Src caused increased expression of endogenous HGF mRNA and protein and marked cell scattering in breast epithelial cells. Our results delineate a novel c-Src/Stat3-dependent mechanism that regulates HGF promoter activity, and is linked to transformation of mammary epithelial cells.Oncogene (2006) 25, 2773–2784. doi:10.1038/sj.onc.1209306; published online 9 January 2006
ACCESSION #
20722636

 

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