The involvement of coactivators and corepressors, collectively termed as coregulators, increases the complexity of regulation of steroid hormone action. Following the interaction of the steroid hormone-receptor complex with the specific nucleotide sequences of target genes, the coregulators are recruited for activation or suppression of specific genes. The coregulators regulate a number of hormonal events during pregnancy, sex differentiation, development, reproduction and sexual behavior. They also exert equally important functions in non-reproductive tissues like heart, kidney, pancreas, bone and brain. The mutation and/or aberrant expression of these coregulators affect the normal function of steroid hormones and result in physiological abnormalities leading to the development of diseases. Therefore, understanding the role of coregulators in steroid hormone action is important and would help in developing the therapeutic strategy for the treatment of steroid-related diseases. In this review article, we describe the coregulators and their implication in health and pathogenesis of diseases. Furthermore, the possible therapeutic approach has been discussed for the treatment of steroid-related diseases, which will be of future interest in the field of medical sciences.

1.
Evans RM, et al: The steroid and thyroid hormone receptor superfamily. Science 1988;240:889–895.
2.
Kumar R, et al: The clinical relevance of steroid hormone receptor corepressors. Clin Cancer Res 2005;8:2822–2830.
3.
Helmut D, et al: Agonist-antagonist induced coactivator and corepressor interplay on the human androgen receptor. Mol Cell Endocrinol 2003;213:79–85.
4.
McKenna NJ, Malley BWO: Combinatorial control of gene expression by nuclear receptor and coregulators. Cell 2002;108:465–474.
5.
Hong H, et al: GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone-binding domains of the steroid receptors. Proc Natl Acad Sci USA 1996;93:4948–4952.
6.
Breeden L, Nasmyth K: Similarity between cell cycle genes of budding yeast and fission yeast and the notch gene of Drosophila. Nature 1987;329:651–654.
7.
Yoshinaga SK, et al: Roles of SWI1 SWI2, and SWI3 proteins for translational enhancement by steroid receptors. Science 1992;258:1598–1604.
8.
Kwon H, et al: Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 1994;370:477–481.
9.
Chiba H, et al: Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila Brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor. Nucl Acid Res 1994;10:1815–1820.
10.
Peterson CL, et al: Five SWI/SNF gene products are components of a large multisubunit complex required for transcriptional enhancement. Proc Natl Acad Sci USA 1994;8:2905–2908.
11.
Candau R, et al: Histone acetyltransferase activity and interaction with ADA2 are critical for GCN5 function in vivo. EMBO J 1997;16:555–565.
12.
Ogryzko VV, et al: The transcriptional coactivators p300 and CBP are histone acetyltransferase. Cell 1996;87:953–959.
13.
Onate SA, et al: Sequence and characterization of a coactivator for the steroid receptor superfamily. Science 1995;270:1354–1357.
14.
Kalkhoven E, et al: Isoforms of steroid receptor coactivator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J 1998;17:232–243.
15.
McInerney EM, et al: Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor. Proc Natl Acad Sci USA 1996;93:10069–10073.
16.
Rachez C, Freedman LP: Mechanisms of gene regulation by vitamin D3 receptor: a network of coactivator interactions. Gene 2000;246:9–21.
17.
Hirochika K, et al: The chromatin remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell 2003;113:905–917.
18.
Janknecht R: The versatile functions of the transcriptional coactivators p300 and CBP and their roles in disease. Histol Histopathol 2002;17:657–668.
19.
Yeung PL, et al: Nuclear localization of coactivator RAC3 is mediated by a bipartite NLS and importin α3. Biochem Biophys Res Commun 2006;1:13–24.
20.
Balmer NN, et al: Steroid receptor coactivator AIB1 in endometrial carcinoma, hyperplasia and normal endometrium: correlation with clinicopathologic parameters and biomarkers. Mod Pathol 2006;12:1593–1605.
21.
Leader JE, et al: Epigenetics and the estrogen receptor. Ann NY Acad Sci 2006;1089:73–87.
22.
Bertolotti A, et al: hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II. EMBO J 1996;18:5022–5031.
23.
Domanskyi A, et al: Biochemical characterization of androgen receptor-interacting protein 4. Biochem J 2006;3:789–795.
24.
Saether T, et al: The chromatin remodeling factor Mi-2α acts as a novel co-activator for human c-Myb.J Biol Chem 2007;282:13994–14005.
25.
Horwitz KB, et al: Nuclear receptor coactivators and corepressors. Mol Endocrinol 1996;10:1167–1177.
26.
Baniahmad A, et al: A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor. EMBO J 1992;11:1015–1023.
27.
Takahiro I, Lazar MA: The NCoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor. Mol Cell Biol 2003;23:5122–5131.
28.
Lopez-Garcia J, et al: ZNF366 is an estrogen receptor corepressor that acts through CtBP and histone deacetylases. Nucleic Acid Res 2006;21:6126–6136.
29.
Wolffe AP, Pruss D: Targeting chromatin disruption: transcription regulators that acetylate histones. Cell 1996;84:817–819.
30.
Li J, et al: Both corepressor proteins SMRT and NCoR exist in large protein complexes containing HDAC3. EMBO J 2000;19:4342–4350.
31.
Wang LH, et al: Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer. Cancer Cell 2006;6:4874–4899.
32.
Fred P, et al: Rubinstein-Taybi syndrome caused by mutations in the transcriptional coactivator CBP. Nature 2002;376:348–351.
33.
Yao TP, et al: Gene dosage-dependent embryronic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 1998;93:361–372.
34.
Kung AL, et al: Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Gen Dev 2000;14:272–277.
35.
Neri C: New light on polyglutamine neurodegenerative disorders: inference with transcription. Trend Mol Med 2001;7:283–284.
36.
Kobayashi S, et al: FHL2, UBC9 and PIAS1 are novel estrogen receptor α-interacting proteins. Endocr Res 2004;4:617–621.
37.
Den Hollander P, et al: Ciz1, a novel DNA-binding coactivator of the estrogen receptor α confers hypersensitivity to estrogen action. Cancer Res 2006;22:11021–11029.
38.
Glass CK: Going nuclear in metabolic and cardiovascular disease. J Clin Invest 2006;3:556–560.
39.
Frederic P, et al: SRC-1 and TIF2 control energy balance white and brown adipose tissues.Cell 2002;111:931–941.
40.
Ito M, et al: Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action. Mol Cell 2000;5:683–693.
41.
Imasaki K, et al: Androgen insensitivity syndrome due to new mutations in the DNA-binding domain of the androgen receptor. Mol Cell Endocrinol 1996;120:15–24.
42.
Eli YA, Jon DH: Single-gene mutations resulting in reproductive dysfunction in women. N Engl J Med 1999;340:709–718.
43.
Zoppi S, et al: Complete testicular feminization caused by amino-terminal truncation of the androgen receptor with downstream initiation. J Clin Invest 1993;91:1105–1112.
44.
Li W, et al: Androgen receptor mutations identified in prostate cancer and androgen insensitivity syndrome display aberrant ART-27 coactivator function. Mol Endocrinol 2005;9:2273–2282.
45.
Nan X, et al: Transcriptional repressions by methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998;393:386–389.
46.
Batsche E, et al: Rb enhances p160/SRC coactivator-dependent activity of nuclear receptors and hormone responsiveness. J Biol Chem 2005;280:19746–19756.
47.
Kouzarides T: Histone acetylases and deacetylases in cell proliferation. Curr Opin Gen Dev 1999;9:140–148.
48.
Wong CW, Privalsky ML: Transcriptional repression by the SMRT-mSin3 corepressor: multiple interactions, multiple mechanisms, and a potential role for TFIIB. Mol Cell Biol 1998;18:5500–5510.
49.
Cui Y, et al: Metastasis-associated protein 2 is a repressor of estrogen receptor α whose overexpression leads to estrogen-independent growth of human breast cancer cells. Mol Endocrinol 2006;9:2020–2035.
50.
Rayner K, et al: NM23-H2, an estrogen receptor β-associated protein, shows diminished expression with progression of atherosclerosis. Am J Physiol 2007;292:R743–R750.
51.
Fenrick R, et al: Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein. Mol Cell Biol 1999;10:6566–6574.
52.
Lutterbach B, et al: A target of t(8;21) in acute leukemia interacts with the NCoR and mSin3 corepressors. Mol Cell Biol 1988;18:7176–7184.
53.
Adcock IM, et al: Histone deacetylation: an important mechanism in inflammatory lung diseases. J Chron Obstruct Pulmon Dis 2005;4:445–455.
54.
Secrist JP, et al: HDAC inhibitors for the treatment of cancer. Curr Opin Invest Drugs 2003;4:1422–1427.
55.
Bicaku E, et al: Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling. Cancer Res 2008;68:1513–1519.
56.
Wang J, et al: Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res 1999;12:2766–2769.
57.
Michael LF, et al: The pharmacology of LXR. Med Chem 2005;8:729–740.
58.
De Nigris F, et al: Coregulators new insights in the transcriptional activity and coregulator molecules in the arterial wall. Int J Cardiol 2002;2–3:153–168.
59.
Tanaka T, et al: Ligands for peroxisome proliferator-activated receptors and inhibit chemically induced colitis and formation of aberrant crypt foci in rats. Cancer Res2001;61:2424–2428.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.