Abstract
This review focuses on the post-transcriptional regulation of mRNAs that encode steroid hormone receptors, which exert powerful effects on physiology by regulating gene expression. Recent discoveries in the regulation of gene expression indicate that it is not limited to alterations of the rate of gene transcription. On the contrary, stabilities of specific mRNAs are regulated by cellular signals to profoundly alter their steady state concentrations. The mRNAs encoding steroid hormone receptors are post-transcriptionally regulated by their own hormonal ligands to create autoregulatory feedback loops. Negative and positive autoregulatory feedback loops serve to limit or augment hormonal responses, respectively. Studies of the molecular mechanisms of regulated stabilities of mRNAs encoding steroid hormone receptors continue to identify unique and critical mRNA sequence elements, usually within the 3′ untranslated regions. The binding factors for the mRNA sequence elements are either proteins or microRNAs. Several sequence-specific RNA binding proteins have been identified that either stabilize or destabilize mRNAs encoding steroid hormone receptors, while microRNAs usually destabilize mRNAs and/or inhibit translation of the mRNA. These posttranscriptional effects regulate the expression of steroid hormone receptor genes to impact a large population of hormone-responsive genes. Further elucidation of the molecular mechanisms involved in the post-transcriptional regulation of steroid hormone receptor mRNAs may yield novel approaches to the therapeutic control of hormone actions to augment health.
References
Adams BD, Furneaux H, White BA (2007) The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines. Mol Endocrinol 21:1132–1147
Al-Nakhle H, Burns PA, Cummings M, Hanby AM, Hughes TA, Satheesha S, Shaaban AM, Smith L, Speirs V (2010) Estrogen receptor beta 1 expression is regulated by miR-92 in breast cancer. Cancer Res 70:4778–4784
Arao Y, Kikuchi A, Ikeda K, Nomoto S, Horiguchi H, Kayama F (2002) A + U-rich-element RNA binding factor 1/heterogeneous nuclear ribonucleoprotein D gene expression is regulated by oestrogen in the rat uterus. Biochem J 361:125–132
Arao Y, Kikuchi A, Kishida M, Yonekura M, Inoue A, Yasuda S, Wada S, Ikeda K, Kayama F (2004) Stability of A + U-rich element binding factor 1 (AUF1)-binding messenger ribonucleic acid correlates with the subcellular relocalization of AUF1 in the rat uterus upon estrogen treatment. Mol Endocrinol 18:2255–2267
Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP (2008) The impact of microRNAs on protein output. Nature 455:64–71
Balmer LA, Beveridge DJ, Jazayeri JA, Thomson AM, Walker CE, Leedman PJ (2001) Identification of a novel AU-rich element in the 3′ untranslated region of epidermal growth factor receptor mRNA that is the target for regulated RNA-binding proteins. Mol Cell Biol 21:2070–2084
Bevilacqua A, Ceriani MC, Capaccioli S, Nicolin A (2003) Post-transcriptional regulation of gene expression by degradation of messenger RNAs. J Cell Physiol 195:356–372
Boyce-Derricott J, Nagler JJ, Cloud JG (2010) Variation among rainbow trout (Oncorhynchus mykiss) estrogen receptor isoform 3′ untranslated regions and the effect of 17beta-estradiol on mRNA stability in hepatocyte culture. DNA Cell Biol 29:229–234
Brewer G (2001) Messenger RNA, decay during aging and development. Ageing Res Rev 1:607–625
Chen CY, Gherzi R, Ong SE, Chan EL, Raijmakers R, Pruijn GJ, Stoecklin G, Moroni C, Mann M, Karin M (2001) AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell 107:451–464
Cochrane DR, Spoelstra NS, Richer JK (2012) The role of miRNAs in progesterone action. Mol Cell Endocrinol 357:50–59
Coulis CM, Lee C, Nardone V, Prokipcak RD (2000) Inhibition of c-myc expression in cells by targeting an RNA-protein interaction using antisense oligonucleotides. Mol Pharmacol 57:485–494
Cuadrado A, Navarro-Yubero C, Furneaux H, Munoz A (2003) Neuronal HuD gene encoding a mRNA stability regulator is transcriptionally repressed by thyroid hormone. J Neurochem 86:763–773
Cui W, Li Q, Feng L, Ding W (2011) MiR-126-3p regulates progesterone receptors and involves development and lactation of mouse mammary gland. Mol Cell Biochem 355:17–25
DeJong ES, Luy B, Marino JP (2002) RNA and RNA-protein complexes as targets for therapeutic intervention. Curr Top Med Chem 2:289–302
Derijk RH, Schaaf MJ, Turner G, Datson NA, Vreugdenhil E, Cidlowski J, de Kloet ER, Emery P, Sternberg EM, Detera-Wadleigh SD (2001) A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis. J Rheumatol 28:2383–2388
Dodson RE, Shapiro DJ (2002) Regulation of pathways of mRNA destabilization and stabilization. Prog Nucleic Acids Res 72:129–164
Esau CC, Monia BP (2007) Therapeutic potential for microRNAs. Adv Drug Deliv Rev 59:101–114
Flouriot G, Pakdel F, Valotaire Y (1996) Transcriptional and post-transcriptional regulation of rainbow trout estrogen receptor and vitellogenin gene expression. Mol Cell Endocrinol 124:173–183
Ford LP, Cheng A (2008) Using synthetic precursor and inhibitor miRNAs to understand miRNA function. Methods Mol Biol 419:289–301
Gruber AR, Fallmann J, Kratochvill F, Kovarik P, Hofacker IL (2011) AREsite: a database for the comprehensive investigation of AU-rich elements. Nucleic Acids Res 39:D66–D69
Guhaniyogi J, Brewer G (2001) Regulation of mRNA stability in mammalian cells. Gene 265:11–23
Haraguchi H, Saito-Fujita T, Hirota Y, Egashira M, Matsumoto L, Matsuo M, Hiraoka T, Koga K, Yamauchi N, Fukayama M, Bartos A, Cha J, Dey SK, Fujii T, Osuga Y (2014) MicroRNA-200a locally attenuates progesterone signaling in the cervix, preventing embryo implantation. Mol Endocrinol 28:1108–1117
Hargrove JL, Schmidt FH (1989) The role of mRNA and protein stability in gene expression. FASEB J 3:2360–2370
Hargrove JL, Hulsey MG, Beale EG (1991) The kinetics of mammalian gene expression. Bioessays 13:667–674
Herman JP, Watson SJ (1995) Stress regulation of mineralocorticoid receptor heteronuclear RNA in rat hippocampus. Brain Res 677:243–249
Hollams EM, Giles KM, Thomson AM, Leedman PJ (2002) mRNA stability and the control of gene expression: implications for human disease. Neurochem Res 27:957–980
Hossain A, Kuo MT, Saunders GF (2006) Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol Cell Biol 26:8191–8201
Ing NH (2005) Steroid hormones regulate gene expression post-transcriptionally by altering the stabilities of messenger RNAs. Biol Reprod 72:1290–1296
Ing NH (2009) Post-transcriptional effects of estrogens on gene expression: messenger RNA stability and translation regulated by microRNAs and other factors. In: Berhardt LV (ed) Advances in Medicine and Biology. Nova, Hauppauge
Ing NH (2010) Estradiol up-regulates expression of the A + U-rich binding factor 1 (AUF1) gene in the sheep uterus. J Steroid Biochem Mol Biol 122:172–179
Ing NH, Massuto DA, Jaeger LA (2008) Estradiol up-regulates AUF1p45 binding to stabilizing regions within the 3′-untranslated region of estrogen receptor alpha mRNA. J Biol Chem 283:1764–1772
Ing NH, Ott TL (1999) Estradiol up-regulates estrogen receptor-alpha messenger ribonucleic acid in sheep endometrium by increasing its stability. Biol Reprod 60:134–139
Ing NH, Spencer TE, Bazer FW (1996) Estrogen enhances expression of the estrogen receptor gene in endometrium by a posttranscriptional mechanism. Biol Reprod 54:591–599
Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070
Jing Q, Huang S, Guth S, Zarubin T, Motoyama A, Chen J, Di Padova F, Lin SC, Gram H, Han J (2005) Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120:623–634
Keene JD, Tenenbaum SA (2002) Eukaryotic mRNPs may represent posttranscriptional operons. Mol Cell 9:1161–1167
Kenealy M-R, Flouriot G, Sonntag-Buck V, Dandekar T, Brand H, Gannon F (2000) The 3′ untranslated region of the human estrogen receptor-α gene mediates rapid messenger ribonucleic acid turnover. Endocrinology 141:2805–2813
Klinge CM (2012) miRNAs and estrogen action. Trends Endocrinol Metab 23:223–233
Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438:685–689
Lal A, Abdelmohsen K, Pullmann R, Kawai T, Galban S, Yang X, Brewer G, Gorospe M (2006) Posttranscriptional derepression of GADD45alpha by genotoxic stress. Mol Cell 22:117–128
Ledderose C, Mohnle P, Limbeck E, Schutz S, Weis F, Rink J, Briegel J, Kreth S (2012) Corticosteroid resistance in sepsis is influenced by microRNA-124-induced downregulation of glucocorticoid receptor-alpha. Crit Care Med 40:2745–2753
Lee MT, Ouyang B, Ho SM, Leung YK (2013) Differential expression of estrogen receptor beta isoforms in prostate cancer through interplay between transcriptional and translational regulation. Mol Cell Endocrinol 376:125–135
Loflin P, Chen CY, Shyu AB (1999) Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element. Genes Dev 13:1884–1897
Lu J-Y, Schneider RJ (2004) Tissue distribution of AU-rich mRNA-binding proteins involved in regulation of mRNA decay. J Biol Chem 279:12974–12979
Lv M, Zhang X, Jia H, Li D, Zhang B, Zhang H, Hong M, Jiang T, Jiang Q, Lu J, Huang X, Huang B (2012) An oncogenic role of miR-142-3p in human T-cell acute lymphoblastic leukemia (T-ALL) by targeting glucocorticoid receptor-alpha and cAMP/PKA pathways. Leukemia 26:769–777
Maillot G, Lacroix-Triki M, Pierredon S, Gratadou L, Schmidt S, Benes V, Roche H, Dalenc F, Auboeuf D, Millevoi S, Vagner S (2009) Widespread estrogen-dependent repression of microRNAs involved in breast tumor cell growth. Cancer Res 69:8332–8340
Makeyev AV, Eastmond DL, Liebhaber SA (2002) Targeting a KH-domain protein with RNA decoys. RNA 8:1160–1173
Manavathi B, Dey O, Gajulapalli VN, Bhatia RS, Bugide S, Kumar R (2013) Derailed estrogen signaling and breast cancer: an authentic couple. Endocr Rev 34:1–32
Maniatis T, Reed R (2002) An extensive network of coupling among gene expression machines. Nature 416:499–506
Manjithaya RR, Dighe RR (2004) The 3′untranslated region of bovine follicle-stimulating hormone β messenger RNA downregulates reporter expression: involvement of AU-rich elements and transfactors. Biol Reprod 71:1158–1166
Mattick JS (2001) The evolution of controlled multitasked gene networks: the role of introns and other noncoding RNAs in the development of complex organisms. Mol Biol Evol 18:1611–1630
McGlincy NJ, Smith CW (2008) Alternative splicing resulting in nonsense-mediated mRNA decay: what is the meaning of nonsense? Trends Biochem Sci 33:385–393
McKnight GS, Palmiter RD (1979) Transcriptional regulation of the ovalbumin and conalbumin genes by steroid hormones in chick oviduct. J Biol Chem 254:9050–9058
Menon KMJ, Munshi UM, Clouser CL, Nair AK (2004) Regulation of luteinizing hormone/human chorionic gonadotropin receptor expression: a perspective. Biol Reprod 70:861–866
Mitchell DC, Ing NH (2003) Estradiol stabilizes estrogen receptor mRNA in sheep endometrium via discrete sequence elements in its 3′ untranslated region. Mol Endocrinol 17:562–574
Mukherjee D, Gao M, O'Connor JP, Raijmakers R, Pruijn G, Lutz CS, Wilusz J (2002) The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. EMBO J 21:165–174
Ni JZ, Grate L, Donohue JP, Preston C, Nobida N, O'Brien G, Shiue L, Clark TA, Blume JE, Ares M Jr (2007) Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev 21:708–718
Östling P, Leivonen SK, Aakula A, Kohonen P, Makela R, Hagman Z, Edsjo A, Kangaspeska S, Edgren H, Nicorici D, Bjartell A, Ceder Y, Perala M, Kallioniemi O (2011) Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Res 71:1956–1967
Pandey DP, Picard D (2010) Multidirectional interplay between nuclear receptors and microRNAs. Curr Opin Pharmacol 10:637–642
Piva R, Spandidos DA, Gambari R (2013) From microRNA functions to microRNA therapeutics: novel targets and novel drugs in breast cancer research and treatment. Int J Oncol 43:985–994
Ramamoorthy S, Cidlowski JA (2013) Ligand-induced repression of the glucocorticoid receptor gene is mediated by an NCoR1 repression complex formed by long-range chromatin interactions with intragenic glucocorticoid response elements. Mol Cell Biol 33:1711–1722
Riester A, Issler O, Spyroglou A, Rodrig SH, Chen A, Beuschlein F (2012) ACTH-dependent regulation of microRNA as endogenous modulators of glucocorticoid receptor expression in the adrenal gland. Endocrinology 153:212–222
Saceda M, Lindsey RK, Solomon H, Angeloni SV, Martin MB (1998) Estradiol regulates estrogen receptor mRNA stability. J Steroid Biochem Mol Biol 66:113–120
Saltzman AL, Kim YK, Pan Q, Fagnani MM, Maquat LE, Blencowe BJ (2008) Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay. Mol Cell Biol 28:4320–4330
Sarkar B, Xi Q, He C, Schneider RJ (2003) Selective degradation of AU-rich mRNAs promoted by the p37 AUF1 protein isoform. Mol Cell Biol 23:6685–6693
Sato S, Shirato K, Tachiyashiki K, Imaizumi K (2011) Synthesized glucocorticoid, dexamethasone regulates the expressions of beta(2)-adrenoceptor and glucocorticoid receptor mRNAs but not proteins in slow-twitch soleus muscle of rats. J Toxicol Sci 36:479–486
Schaaf MJ, Cidlowski JA (2002) AUUUA motifs in the 3′UTR of human glucocorticoid receptor alpha and beta mRNA destabilize mRNA and decrease receptor protein expression. Steroids 67:627–636
Schaaf MJM, Cidlowski JA (2003) Molecular mechanisms of glucocorticoid action and resistance. J Steroid Biochem Mol Biol 83:37–48
Shim J, Karin M (2002) The control of mRNA stability in response to extracellular stimuli. Mol Cells 14:323–331
Smith L, Coleman LJ, Cummings M, Satheesha S, Shaw SO, Speirs V, Hughes TA (2010) Expression of oestrogen receptor beta isoforms is regulated by transcriptional and post-transcriptional mechanisms. Biochem J 429:283–290
Söber S, Laan M, Annilo T (2010) MicroRNAs miR-124 and miR-135a are potential regulators of the mineralocorticoid receptor gene (NR3C2) expression. Biochem Biophys Res Commun 391:727–732
Staton JM, Thomson AM, Leedman PJ (2000) Hormonal regulation of mRNA stability and RNA-protein interactions in the pituitary. J Mol Endocrinol 25:17–34
Stellato C (2004) Post-transcriptional and nongenomic effects of glucocorticoids. Proc Am Thorac Soc 1:255–263
Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R (2008) Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol Cancer Ther 7:464–473
Tessel MA, Benham AL, Krett NL, Rosen ST, Gunaratne PH (2011) Role for microRNAs in regulating glucocorticoid response and resistance in multiple myeloma. Horm Cancer 2:182–189
Tolnay M, Vereshchagina LA, Tsokos GC (1999) Heterogeneous nuclear ribonucleoprotein D0B is a sequence-specific DNA-binding protein. Biochem J 338:417–425
Tseng L, Zhu HH (1997) Regulation of progesterone receptor messenger ribonucleic acid by progestin in human endometrial stromal cells. Biol Reprod 57:1360–1366
Uchida S, Nishida A, Hara K, Kamemoto T, Suetsugi M, Fujimoto M, Watanuki T, Wakabayashi Y, Otsuki K, McEwen BS, Watanabe Y (2008) Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor. Eur J Neurosci 27:2250–2261
Vandevyver S, Dejager L, Libert C (2014) Comprehensive overview of the structure and regulation of the glucocorticoid receptor. Endocr Rev 35:671–693
Vreugdenhil E, Verissimo CS, Mariman R, Kamphorst JT, Barbosa JS, Zweers T, Champagne DL, Schouten T, Meijer OC, de Kloet ER, Fitzsimons CP (2009) MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. Endocrinology 150(5):2220–2228
Wagner BJ, DeMaria CT, Sun Y, Wilson GM, Brewer G (1998) Structure and genomic organization of the human AUF1 gene: alternative pre-mRNA splicing generates four protein isoforms. Genomics 48:195–202
Yeap BB, Krueger RG, Leedman PJ (1999) Differential posttranscriptional regulation of androgen receptor gene expression by androgen in prostate and breast cancer cells. Endocrinology 140:3282–3291
Yeap BB, Wilce JA, Leedman PJ (2004) Novel binding of HuR and poly(C) binding protein to a conserved UC-rich motif within the 3′-untranslated region of the androgen receptor mRNA. Bioessays 26:672–682
Zhang T, Kruyus V, Huez G, Gueydan C (2002) AU-rich element-mediated translational control: complexity and multiple activities of trans-acting factors. Biochem Soc Trans 30:952–958
Zhao JJ, Lin J, Yang H, Kong W, He L, Ma X, Coppola D, Cheng JQ (2008) MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem 283:31079–31086
Zhou H, Mazan-Mamczarz K, Martindale JL, Barker A, Liu Z, Gorospe M, Leedman PJ, Gartenhaus RB, Hamburger AW, Zhang Y (2010) Post-transcriptional regulation of androgen receptor mRNA by an ErbB3 binding protein 1 in prostate cancer. Nucleic Acids Res 38:3619–3631
Zhu KC, Lu JJ, Xu XL, Sun JM (2013) MicroRNAs in androgen-dependent PCa. Front Biosci 18:748–755
Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31:3406–3415
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Ing, N.H. (2016). Post-transcriptional Regulation of Steroid Hormone Receptors. In: Menon, PhD, K., Goldstrohm, PhD, A. (eds) Post-transcriptional Mechanisms in Endocrine Regulation. Springer, Cham. https://doi.org/10.1007/978-3-319-25124-0_5
Download citation
DOI: https://doi.org/10.1007/978-3-319-25124-0_5
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-25122-6
Online ISBN: 978-3-319-25124-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)