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HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1

Oncogene volume 20, pages 6215–6224 (2001)Cite this article

Abstract

In this study, we show that the ETS transcription factor ER81 directly binds to and activates the promoter of the matrix metalloproteinase gene, MMP-1. Further, the oncoprotein HER2/Neu synergizes with ER81 to stimulate MMP-1 transcription. The activation of ER81 by HER2/Neu is mediated by MAP kinases, which phosphorylate ER81 in its N-terminal activation domain. Four respective phosphorylation sites have been identified. Blocking phosphorylation at these sites decreases ER81 transcriptional activity, which can be further diminished by abolishment of phosphorylation at two non-MAP kinase sites. Altogether, our results reveal mechanisms of how phosphorylation of ER81 regulates the expression of target genes such as MMP-1, which may be important for many physiological processes from embryogenesis to adulthood as well as for tumor metastasis.

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Acknowledgements

We thank Dr J Travis, Dr Y Yarden and Dr J Cooper for generously providing the pGL2-MMP-1 reporter plasmid, the pLSV-HER2/Neu-V664E expression plasmid and the MKK7a expression plasmid, respectively. We further extend our thanks to Dr P Roche for providing the breast tumor samples and to K Rossow for providing the ER81 recombinant protein. DG Bosc is a research fellow of the National Cancer Institute of Canada supported with funds provided by the Terry Fox Run. This work was supported by the Mayo Foundation, the Mayo Clinic Cancer Center, a grant from the National Cancer Institute (CA85257), and a scholarship (to R Janknecht) from the Sidney Kimmel Foundation for Cancer Research.

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  1. Department of Biochemistry and Molecular Biology, Guggenheim Building 1501A, Mayo Clinic and Mayo Graduate School, 200 First Street SW, Rochester, MN 55905, USA

    Denis G Bosc, Basem S Goueli & Ralf Janknecht

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  1. Denis G Bosc
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  2. Basem S Goueli
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Correspondence to Ralf Janknecht.

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Bosc, D., Goueli, B. & Janknecht, R. HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1. Oncogene 20, 6215–6224 (2001). https://doi.org/10.1038/sj.onc.1204820

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