Browse > Article
http://dx.doi.org/10.1007/s10059-009-0099-7

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)
Publication Information
Molecules and Cells / v.28, no.1, 2009 , pp. 67-71 More about this Journal
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
estrogen receptor ${\alpha}$; FoxH1; protein kinase A; protein stability;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
Times Cited By Web Of Science : 0  (Related Records In Web of Science)
연도 인용수 순위
1 Cui, Y., Zhang, M., Pestell, R., Curran, E.M., Welshons, W.V., and Fuqua, S.A. (2004). Phosphorylation of estrogen receptor $\alpha$ blocks its acetylation and regulates estrogen sensitivity. Cancer Res. 64, 9199-9208   DOI   PUBMED   ScienceOn
2 Loven, M.A., Wood, J.R., and Nardulli, A.M. (2001). Interaction of estrogen receptors $\alpha$ and $\beta$ with estrogen response elements. Mol. Cell. Endocrinol. 181, 151-163   DOI   PUBMED   ScienceOn
3 Massague, J., and Gomis, R.R. (2006). The logic of TGF$\beta$ signaling. FEBS Lett. 580, 2811-2820   DOI   ScienceOn
4 Schier, A.F. (2003). Nodal signaling in vertebrate development. Annu. Rev. Cell Dev. Biol. 19, 589-621
5 Watanabe, M., and Whitman, M. (1999). FAST-1 is a key maternal effector of mesoderm inducers in the early Xenopus embryo. Development 126, 5621-5634   PUBMED
6 Chen, G., Nomura, M., Morinaga, H., Matsubara, E., Okabe, T., Goto, K., Yanase, T., Zheng, H., Lu, J., and Nawata, H. (2005). Modulation of androgen receptor transactivation by FoxH1: A newly identified androgen receptor corepressor. J. Biol. Chem. 280, 36355-36363   DOI   ScienceOn
7 Rogatsky, I., Trowbridge, J.M., and Garabedian, M.J. (1999). Potentiation of human estrogen receptor $\alpha$ transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin ACDK2 complex. J. Biol. Chem. 274, 22296-22302   DOI   PUBMED
8 Arnold, S.F., Obourn, J.D., Jaffe, H., and Notides, A.C. (1995). Phosphorylation of the human estrogen receptor on tyrosine 537 in vivo and by src family tyrosine kinases in vitro. Mol. Endocrinol. 9, 24-33   DOI   ScienceOn
9 Kofron, M., Puck, H., Standley, H., Wylie, C., Old, R., Whitman, M., and Heasman, J. (2004). New roles for FoxH1 in patterning the early embryo. Development 131, 5065-5078   DOI   ScienceOn
10 Feng, W., Webb, P., Nguyen, P., Liu, X., Li, J., Karin, M., and Kushner, P.J. (2001). Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway. Mol. Endocrinol. 15, 32-45   DOI   ScienceOn
11 Al-Dhaheri, M.H., and Rowan, B.G. (2007). Protein kinase A exhibits selective modulation of estradiol-dependent transcription in breast cancer cells that is associated with decreased ligand binding, altered estrogen receptor $\alpha$ promoter interaction, and changes in receptor phosphorylation. Mol. Endocrinol. 21, 439-456   DOI   ScienceOn
12 Chen, X., Weisberg, E., Fridmacher, V., Watanabe, M., Naco, G., and Whitman, M. (1997). Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85-89   DOI   ScienceOn
13 Lee, H., and Bai, W. (2002). Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation. Mol. Cell. Biol. 22, 5835-5845
14 Lannigan, D.A. (2003). Estrogen receptor phosphorylation. Steroids 68, 1-9   DOI   PUBMED   ScienceOn
15 Chen, D., Pace, P.E., Coombes, R.C., and Ali, S. (1999). Phosphorylation of human estrogen receptor $\alpha$ by protein kinase A regulates dimerization. Mol. Cell. Biol. 19, 1002-1015   PUBMED
16 Whitman, M. (2001). Nodal signaling in early vertebrate embryos: themes and variations. Dev. Cell 1, 605-617   DOI   PUBMED   ScienceOn
17 Kato, S., Endoh, H., Masuhiro, Y., Kitamoto, T., Uchiyama, S., Sasaki, H., Masushige, S., Gotoh, Y., Nishida, E., Kawashima, H., et al. (1995). Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270, 1491-1494   DOI   PUBMED   ScienceOn
18 Cho, H., and Katzenellenbogen, B.S. (1993). Synergistic activation of estrogen receptor-mediated transcription by estradiol and protein kinase activators. Mol. Endocrinol. 7, 441-452   DOI   ScienceOn
19 Sun, M., Paciga, J.E., Feldman, R.I., Yuan, Z., Coppola, D., Lu, Y.Y., Shelley, S.A., Nicosia, S.V., and Cheng, J.Q. (2001). Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor $\alpha$ (ER$\alpha$) via interaction between ER$\alpha$ and PI3K. Cancer Res. 61, 5985-5991   PUBMED
20 Zhou, S., Zawel, L., Lengauer, C., Kinzler, K.W., and Vogelstein, B. (1998). Characterization of human FAST-1, a TGF $\beta$ and activin signal transducer. Mol. Cell 2, 121-127   DOI   ScienceOn
21 Nilsson, S., Makela, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G., Enmark, E., Pettersson, K., Warner, M., and Gustafsson, J.A. (2001). Mechanisms of estrogen action. Physiol. Rev. 81, 1535-1565   PUBMED
22 McKenna, N.J., Lanz, R.B., and O’Malley, B.W. (1999). Nuclear receptor coregulators: cellular and molecular biology. Endocrine Rev. 20, 321-344   DOI   ScienceOn
23 Pike, M.C., Spicer, D.V., Dahmoush, L., and Press, M.F. (1993). Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol. Rev. 15, 17-35   PUBMED
24 Roessler, E., Ouspenskaia, M.V., Karkera, J.D., Velez, J.I., Kantipong, A., Lacbawan, F., Bowers, P., Belmont, J.W., Towbin, J.A., Goldmuntz, E., et al. (2008). Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am. J. Hum. Genet. 83, 18-29   DOI   ScienceOn
25 Michalides, R., Griekspoor, A., Balkenende, A., Verwoerd, D., Janssen, L., Jalink, K., Floore, A., Velds, A., van’t Veer, L., and Neefjes, J. (2004). Tamoxifen resistance by a conformational arrest of the estrogen receptor $\alpha$ after PKA activation in breast cancer. Cancer Cell 5, 597-605   DOI   PUBMED   ScienceOn
26 Zwart, W., Griekspoor, A., Berno, V., Lakeman, K., Jalink, K., Mancini, M., Neefjes, J., and Michalides, R. (2007). PKA-induced resistance to tamoxifen is associated with an altered orientation of ER$\alpha$ towards co-activator SRC-1. EMBO J. 26, 3534-3544   DOI   PUBMED   ScienceOn
27 Kang, K., Lee, S.B., Jung, S.H., Cha, K.H., Park, W.D., Sohn, Y.C., and Nho, C.W. (2009). Tectoridin, a poor ligand of estrogen receptor alpha, exerts its estrogenic effects via an ERK-dependent pathway. Mol. Cells 27, 351-357   DOI   PUBMED   ScienceOn
28 Xu, J., and Li, Q. (2003). Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol. Endocrinol. 17, 1681-1692