Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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PKA-Mediated Stabilization of FoxH1 Negatively Regulates ERα Activity

  • Yum, Jinah (Department of Life Science and Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Jeong, Hyung Min (College of Pharmacy and Research Institute of Drug Development, Chonnam National University) ;
  • Kim, Seulki (Department of Life Science and Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Seo, Jin Won (College of Pharmacy and Research Institute of Drug Development, Chonnam National University) ;
  • Han, Younho (College of Pharmacy and Research Institute of Drug Development, Chonnam National University) ;
  • Lee, Kwang-Youl (College of Pharmacy and Research Institute of Drug Development, Chonnam National University) ;
  • Yeo, Chang-Yeol (Department of Life Science and Division of Life and Pharmaceutical Sciences, Ewha Womans University)
  • Received : 2009.05.15
  • Accepted : 2009.05.28
  • Published : 2009.07.31
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Abstract

Estrogen receptor ${\alpha}$ ($ER{\alpha}$) mediates the mitogenic effects of estrogen. $ER{\alpha}$ signaling regulates the normal growth and differentiation of mammary tissue, but uncontrolled $ER{\alpha}$ activation increases the risk to breast cancer. Estrogen binding induces ligand-dependent $ER{\alpha}$ activation, thereby facilitating $ER{\alpha}$ dimerization, promoter binding and coactivator recruitment. $ER{\alpha}$ can also be activated in a ligand-independent manner by many signaling pathways, including protein kinase A (PKA) signaling. However, in several $ER{\alpha}$-positive breast cancer cells, PKA inhibits estrogen-dependent cell growth. FoxH1 represses the transcriptional activities of estrogen receptors and androgen receptors (AR). Interestingly, FoxH1 has been found to inhibit the PKA-induced and ligand-induced activation of AR. In the present study, we examined the effects of PKA activation on the ability of FoxH1 to represses $ER{\alpha}$ transcriptional activity. We found that PKA increases the protein stability of FoxH1, and that FoxH1 inhibits PKA-induced and estradiol-induced activation of an estrogen response element (ERE). Furthermore, in MCF7 cells, FoxH1 knockdown increased the PKA-induced and estradiol-induced activation of the ERE. These results suggest that PKA can negatively regulate $ER{\alpha}$, at least in part, through FoxH1.

Keywords

Acknowledgement

Supported by : Korea Research Foundation

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