Palmitoylation-dependent Estrogen Receptor α Membrane Localization: Regulation by 17β-Estradiol
Tóm tắt
A fraction of the nuclear estrogen receptor α (ERα) is localized to the plasma membrane region of 17β-estradiol (E2) target cells. We previously reported that ERα is a palmitoylated protein. To gain insight into the molecular mechanism of ERα residence at the plasma membrane, we tested both the role of palmitoylation and the impact of E2 stimulation on ERα membrane localization. The cancer cell lines expressing transfected or endogenous human ERα (HeLa and HepG2, respectively) or the ERα nonpalmitoylable Cys447Ala mutant transfected in HeLa cells were used as experimental models. We found that palmitoylation of ERα enacts ERα association with the plasma membrane, interaction with the membrane protein caveolin-1, and nongenomic activities, including activation of signaling pathways and cell proliferation (i.e., ERK and AKT activation, cyclin D1 promoter activity, DNA synthesis). Moreover, E2 reduces both ERα palmitoylation and its interaction with caveolin-1, in a time- and dose-dependent manner. These data point to the physiological role of ERα palmitoylation in the receptor localization to the cell membrane and in the regulation of the E2-induced cell proliferation.
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Tài liệu tham khảo
Acconcia, F., Ascenzi, P., Fabozzi, G., Visca, P., and Marino, M. (2004b). S-Palmitoylation modulates human estrogen receptor-α functions. Biochem. Biophys. Res. Commun. 316, 878-883.
Arvanitis, D. N., Wang, H., Bagshaw, R. D., Callahan, J. W., and Boggs, J. M. (2004). Membrane-associated estrogen receptor and caveolin-1 are present in central nervous system myelin and oligodendrocyte plasma membranes. J. Neurosci. Res. 75, 603-613.
Bijlmakers, M. J., and Marsh, M. (2003). The on-off story of protein palmitoylation. Trends Cell Biol. 13, 32-42.
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 772, 248-254.
Brzozowski, A. M., Pike, A.C.W., Dauter, Z., Hubbard, R. E., Bonn, T., Engstrom, O., Homan, L., Greene, G. F., Gustafsson, J.Å., and Carlquist, M. (1997) Molecular basis of agonism and antagoism in the oestrogen receptor. Nature 389, 753-758.
Castoria, G., Barone, M. V., Di Domenico, M., Bilancio, A., Ametrano, D., Migliaccio, A., and Auricchio, F. (1999). Non-trascriptional action of oestradiol and progestin triggers DNA synthesis. EMBO J. 18, 2500-2510.
Castoria, G., Migliaccio, A., Bilancio, A., Di Domenico, M., de Falco, A., Lombardi, M., Fiorentino, R., Varricchio, L., Barone, M. V., and Auricchio, F. (2001). PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. EMBO J. 20, 6050-6059.
Chambliss, K. L., and Shaul, P. W. (2002). Rapid activation of endothelial NO synthase by estrogen: evidence for a steroid receptor fast-action complex (SRFC) in caveolae. Steroids 67, 413-419.
Chambliss, K .L., Yuhanna, I. S., Anderson, R. G., Mendelsohn, M. E., and Shaul, P. W. (2002). ERβ has nongenomic action in caveolae. Mol. Endocrinol. 16, 938-946.
Coleman, K. M., and Smith, C. L. (2001). Intracellular signaling pathways: nongenomic actions of estrogens and ligand-independent activation of estrogen receptors. Front. Biosci. 6, D1379-D1391.
Dan, P., Cheung, J.C., Scriven, D. R., and Moore, E. D. (2003). Epitope-dependent localization of estrogen receptor-α, but not -β, in en face arterial endothelium. Am. J. Physiol. 284, H1295-H1306.
Deecher, D. C., Swiggard, P., Frail, D. E., and O'Connor, L. T. (2003). Characterization of a membrane-associated estrogen receptor in a rat hypothalamic cell line (D12). Endocrine 22, 211-223.
Hegy, G. B., Shackleton, C. H., Carlquist, M., Bonn, T., Engstrom, O., Sjoholm, P., and Witkowska, H. E. (1996). Carboxymethylation of the human estrogen receptor ligand-binding domain-estradiol complex: HPLC/ESMS peptide mapping shows that cysteine 447 does not react with iodoacetic acid. Steroids 61, 367-373.
Herbert, B., Truss, M., Beato, M., and Müller, R. (1994). Inducibile regulatory elements in the human cyclin D1 promoter. Oncogene 9, 1295-1304.
Jakacka, M., Ito, M., Martinson, F., Ishikawa, T., Lee, E. J., and Jameson, J. L. (2002). An estrogen receptor ERα deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo. Mol. Endocrinol. 16, 2188-2201.
Katzenellenbogen, B. S., Bhardwaj, B., Fang, H., Ince, B. A., Pakdel, F., Reese, J. C., Schodin. D. and Wrenn, C. K. (1993) Hormone binding and transcription activation by estrogen receptors: analyses using mammalian and yeast systems. J. Steroid. Biochem. Mol. Biol. 47, 39-48.
Kelly, M. J., and Levin, E. R. (2001). Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol. Metab. 12, 152-156.
Kousteni, S. et al. (2001). Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104, 719-790.
Levin, E. R. (2001). Cell localization, physiology, and nongenomic actions of estrogen receptors. J. Appl. Physiol. 91, 1860-1867.
Li, L., Haynes, M. P., and Bender, J. R. (2003). Plasma membrane localization and function of the estrogen receptor α variant (ER46) in human endothelial cells. Proc. Natl. Acad. Sci. USA 100, 4807-4812.
Lobenhofer, E. K., Huper, G., Iglehart, J. D., and Marks, J. R. (2000). Inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase activity in MCF-7 cells prevents estrogen-induced mitogenesis. Cell Growth Differ. 11, 99-110.
Mardones, G., and Gonzalez, A. (2003). Selective plasma membrane permeabilization by freeze-thawing and immunofluorescence epitope access to determine the topology of intracellular membrane proteins. J. Immunol. Methods 275, 169-177.
Marino, M., Pallottini, V., and Trentalance, A. (1998). Estrogens cause rapid activation of IP3-PKC-α signal transduction pathway in HEPG2 cells. Biochem. Biophys. Res. Commun. 245, 254-258.
Marino, M., Distefano, E., Pallottini, V., Caporali, S., Ceracchi, G., and Trentalance, A. (2001a). β-Estradiol stimulation of DNA synthesis requires different PKC isoforms in HepG2 and MCF7 cells. J. Cell Physiol. 188, 170-177.
Marino, M., Distefano, E., Trentalance, A., and Smith, C. L. (2001b). Estradiol-induced IP3 mediate the estrogen receptor activity expressed in human cells. Mol. Cell. Endocrinol. 182, 19-26.
Migliaccio, A., Castoria, G., Di Domenico, M., de Falco, A., Bilancio, A., and Auricchio, F. (2002). Src is an initial target of sex steroid hormone action. Ann. N.Y. Acad. Sci. 963, 185-190.
Neff, S., Sadowski, C., and Miksicek, R. J. (1994). Mutational analysis of cysteine residues within the hormone-binding domain of the human estrogen receptor identifies mutants that are defective in both DNA-binding and subcellular distribution. Mol. Endocrinol. 8, 1215-1223.
Norfleet, A. M., Thomas, M. L., Gametchu, B., and Watson, C. S. (1999). Estrogen receptor-α detected on the plasma membrane of aldehyde-fixed GH3/B6/F10 rat pituitary tumor cells by enzyme-linked immunocytochemistry. Endocrinology 140, 3805-3814.
Pappas, T. C., Gametchu, B., and Watson, C. S. (1995). Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J. 9, 404-410.
Razandi, M., Pedram, A., Greene, G. L., and Levin, E. R. (1999). Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERα and ERβ expressed in Chinese hamster ovary cells. Mol. Endocrinol. 13, 307-319.
Razandi, M., Pedram, A., and Levin, E. R. (2000). Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Mol. Endocrinol. 14, 1434-1447.
Razandi, M., Oh, P., Pedram, A., Schnitzer, J., and Levin, E. R. (2002). ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol. Endocrinol. 16, 100-115.
Razandi, M., Alton, G., Pedram, A., Ghonshani, S., Webb, P., and Levin, E. R. (2003). Identification of a structural determinant necessary for the localization and function of estrogen receptor α at the plasma membrane. Mol. Cell. Biol. 23, 1633-1646.
Reid, G., Hubner, M. R., Metivier, R., Brand, H., Denger, S., Manu, D., Beaudouin, J., Ellenberg, J., and Gannon, F. (2003). Cyclic, proteasome-mediated turnover of unliganded and liganded ERα on responsive promoters is an integral feature of estrogen signaling. Mol. Cell 11, 695-707.
Resh, M. D. (1999). Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim. Biophys. Acta 1451, 1-16.
Ropero, A. B., Soria, B., and Nadal, A. (2002). A nonclassical estrogen membrane receptor triggers rapid differential actions in the endocrine pancreas. Mol. Endocrinol. 16, 497-505.
Simoncini, T., Hafezi-Moghadam, A., Brazil, D. P., Ley, K., Chin, W. W., and Liao, J. K. (2000). Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538-541.
Song, R. X., McPherson, R. A., Adam, L., Bao, Y., Shupnik, M., Kumar, R., and Santen, R. J. (2002). Linkage of rapid estrogen action to MAPK activation by ERα-Shc association and Shc pathway activation. Mol. Endocrinol. 16, 116-127.
Song, R. X., Barnes, C. J., Zhang, Z., Bao, Y., Kumar, R., and Santen, R. J. (2004). The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane. Proc. Natl. Acad. Sci. USA 101, 2076-2081.
Toran-Allerand, C. D., Guan, X., MacLusky, N. J., Horvath, T. L., Diano, S., Singh, M., Connolly, E. S., Jr., Nethrapalli, I. S., and Tinnikov, A. A. (2002). ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J. Neurosci. 22, 8391-8401.
Varner, A. S., Ducker, C. E., Xia, Z., Zhuang, Y., De Vos, M. L., and Smith, C. D. (2003). Characterization of human palmitoyl-acyl transferase activity using peptides that mimic distinct palmitoylation motifs. Biochem. J. 373, 91-99.