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c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

Oncogene volume 29, pages 2238–2251 (2010)Cite this article

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Abstract

Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligand-activated transcription factors. Similar to other steroid hormone receptors, estrogen receptor α (ERα) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ERα associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ERα and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ERα can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ERα phosphorylation by c-Abl stabilizes ERα, resulting in enhanced ERα transcriptional activity and increased expression of endogenous ERα target genes. Furthermore, ERα phosphorylation at the Y-219 site affects DNA binding and dimerization by ERα. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Abl-induced accumulation of ERα and enhancement of ERα transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ERα function. Moreover, the ERα (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ERα expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer.

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Acknowledgements

This work was supported in part by the National Natural Science Foundation (30772605, 30700413, 30870500, 30871276 and 30530320) and by the Beijing Natural Science Foundation (7092081).

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  1. X He, Z Zheng and T Song: These authors contributed equally to this work.

Authors and Affiliations

  1. State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, PR China

    X He, Z Zheng, T Song, C Wei, H Ma, Q Ma, Q Ye & H Zhong

  2. Institute of Disease Control and Prevention, Beijing, PR China

    X He

  3. Key Laboratory for Molecular Enzymology and Engineering, JiLin University, Changchun, PR China

    Y Xu & W Shi

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He, X., Zheng, Z., Song, T. et al. c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation. Oncogene 29, 2238–2251 (2010). https://doi.org/10.1038/onc.2009.513

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