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Regulation of c-met expression by transcription repressor Daxx

Oncogene volume 27, pages 2177–2186 (2008)Cite this article

Abstract

The protooncogene c-met encodes the tyrosine kinase receptor for the hepatocyte growth factor/scatter factor (HGF/SF). While overexpression of c-met is documented in many types of tumors, the mechanism of c-met regulation remains elusive. Here, we demonstrate Daxx as a repressor of c-met transcription. The expression of c-met is elevated in Daxx knockout mouse cells and is reversed by Daxx reconstitution. C-met promoter analysis of Daxx−/− cells reveled changes in chromatin acetylation, but not in DNA methylation. Daxx binds to the mouse c-met promoter and Daxx-binding region is sufficient for transcription repression, while HDAC2 is associated with c-met promoter mostly in Daxx+/+ cells, pointing to Daxx-dependent HDAC2 recruitment as a potential mechanism of c-met repression. HGF-induced cell mobility and invasion confirmed augmented activity of c-Met/HGF pathway in Daxx−/− cells. Finally, inverse correlation between Daxx and c-Met in cancer cell lines and in metastatic breast cancer specimens suggests potential function of Daxx as a c-met repressor during cancer progression.

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Acknowledgements

We want to thank Dr Martha Campbell-Thompson and Tracy Clarke, Molecular Pathology Core, Department of Pathology, Immunology and Laboratory Medicine, UF for help in ICH. This work was supported by FAMRI Clinical Innovation Award 32088, Florida James & Esther King Biomedical Research Program 05NIR-07 and ACS-IRG-01-188-01 for VMM and AMI and by NIH AI 41136 for OVV and GGM.

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Authors and Affiliations

  1. Department of Anatomy & Cell Biology and Shands Cancer Center, University of Florida, Gainesville, FL, USA

    V M Morozov & A M Ishov

  2. Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL, USA

    N A Massoll

  3. The Wistar Institute, Philadelphia, PA, USA

    O V Vladimirova & G G Maul

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  1. V M Morozov
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  2. N A Massoll
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  3. O V Vladimirova
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  4. G G Maul
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  5. A M Ishov
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Correspondence to A M Ishov.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Morozov, V., Massoll, N., Vladimirova, O. et al. Regulation of c-met expression by transcription repressor Daxx. Oncogene 27, 2177–2186 (2008). https://doi.org/10.1038/sj.onc.1210865

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