It also interacts with components of the transcription machinery and represses the transcription of a specific gene. The repression of transcription may be due to competition among molecules which bind to DNA or may be due to direct silencing of the basal transcription machinery [ 25 ]. Thus, a particular gene may be repressed through the recruitment of corepressor molecules to the gene and protein-protein interaction.
TR-mediated repression is reversed by cotransfection with either the unliganded retinoic acid receptor RAR or C-terminus of the oncoprotein v-ErbA [ 26 ]. The corepressors are associated with nuclear hormone receptors and recruit histone deacetylase HDAC 3 and other isoforms that mediate histone deacetylation [ 27 ].
These findings strongly support the hypothesis that gene transcription is repressed through nucleosomal condensation caused by deacetylation of histones [ 29 ]. Steroid receptors in combination with their coactivators and corepressors mediate precise gene regulation ranging from the ligand-induced transcriptional activation to repression.
Gene regulation by steroid hormones: Vertebrates and insects 
As studies continue to unfold the role of coregulators in transcriptional regulation by nuclear steroid receptors, it is becoming evident that they are important for understanding the etiology of a variety of diseases such as obesity, diabetes, atherosclerosis, osteoporosis, cancer, neurodegenerative disorders, etc. The coregulators may also be used as therapeutic targets in steroid-related diseases. For example, breast cancer patients show resistance to anticancer drugs, and the majority of them eventually do not respond to tamoxifen therapy [ 31 ].
Mutations in CBP coactivator are involved in embryogenesis and chromosomal translocation of p gene that causes Rubinstein-Taybi syndrome. The loss of one functional copy of the CBP gene leads to the developmental abnormalities in Rubinstein-Taybi syndrome and possibly the propensity for malignancy [ 32 ]. It also causes open neural tube and heart defects in humans, as well as embryonic lethality in mice [ 33 , 34 ]. Knockout studies reveal the effects of two members of the p family on energy homeostasis. In addition, TRAP knockout reveals an early gestational stage with heart failure and exhibits impaired neuronal development with extensive apoptosis [ 40 ].
Mutations in receptor gene also inhibit the binding of coactivators and lead to diseases. For example, androgen-insensitive syndrome is developed due to mutation in the DNA-binding domain of AR which prevents interaction of coactivators to the AF-1 region and transmission of activation signal [ 41 ]. This syndrome shows various degrees of impairment in the genital virilization [ 42 , 43 ].
The transcriptional response to AR coactivator ART is increased by the majority of naturally occurring AR mutations in prostate cancer, but decreased by PL mutation and androgen-insensitive syndrome [ 44 ]. Mutation in the corepressor or change in its interaction with the basal transcription machinery may lead to diseases.
For example, mutations in MeCP-2, RB and DAX-1 result in the loss of corepressor interaction leading to embryonic diseases during development [ 45 , 46 ]. Mutation in MeCP-2, which affects either the methyl-binding domain or the transrepressor domain by deacetylation, causes an X-linked neurodegenerative developmental disorder, Rett syndrome [ 47 ]. These mutations result in the loss of recruitment of the SIN3 corepressor to target genes [ 48 ]. Mutations in MTA metastasis-associated protein 2 are responsible for estrogen-responsive cancer [ 49 ]. The expression of NMH2 decreases with the advancement of atherosclerosis and inflammation in human [ 50 ].
Mutations in receptors also affect their interaction with corepressors and lead to a number of diseases. Similarly, B-cell acute lymphoblastic leukemia involves the chromosomal translocation, which results in the fusion of repression domain of the Ets leukemia protein TEL to the large form of AML. The reduction in HDAC activity and HDAC2 expression causes chronic obstructive pulmonary disease which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 expression may be secondary to the oxidative and nitrative stress as a result of cigarette smoking and severe inflammation.
It occurs to different degrees in severe asthma, smoking asthmatic patients and cystic fibrosis.
Similar mechanisms may also account for the steroid resistance seen in latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, which acts through specific kinases and reverses steroid resistance in chronic obstructive pulmonary disease and other inflammatory lung diseases [ 53 ]. Several histone deacetylase inhibitors have been shown to inhibit tumor growth and now used in clinical trials for the treatment of cancer [ 54 , 55 ]. They are involved in cholesterol transport, glucose metabolism and inflammation.
Thus, synthetic LXR ligands have been designed to treat disorders such as atherosclerosis and diabetes [ 57 ]. Further, statins modulate the sterol-responsive element-binding protein, which targets genes that are involved in cholesterol and fatty acid metabolism, namely hydroxyl-methyl-glutaryl acetyl Coenzyme-A HMG-CoA reductase, HMG-CoA synthase and the low-density lipoprotein receptor [ 58 ]. The expanding number of coregulators has increased the challenge and added the complexity to understanding the transcriptional regulation of steroid hormone action.
One of the future challenges is to determine the specificity of coregulators. In recent years, the studyof corepressor biology has become an area of active research. This has led to substantial progress in the identification ofa number of novel corepressors with critical roles in determiningthe action of NR. Emerging data re-emphasize that the regulation of NRby corepressor is as significant as that by coactivator. Although much more workremains to be done, we have begun to gain a deeper insightinto the transcriptional regulation of steroid receptors, therole played by chromatin modifications, and the contributionof coactivators and corepressors in the development of pathological conditions.
Further study of key coregulators in physiologically relevantanimal models and human subjects combined withcell culture models will help to elucidate the detailed mechanism of steroid hormone action and develop the therapeutic strategies for the hormone-related diseases. 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.
Hormone-control regions mediate steroid receptor–dependent genome organization
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Forgot Password? This enzyme sometimes called phosphorylase a phosphatase, synthase phosphatase, or kinase phosphatase to indicate its substrate specificity is regulated by another protein, phosphoprotein phosphatase inhibitor. This inhibitor, when phosphorylated by protein kinase A, inhibits phosphoprotein phosphatase A rise in the concentration of cAMP therefore stimulates phosphorylation of certain regulated proteins such as glycogen phosphorylase and also slows dephosphorylation of these proteins, prolonging the effect of phosphorylation. Cells contain a family of phosphoprotein phosphatases that hydrolyze specific phosphoserine, phosphothreonine, and phosphotyrosine esters, releasing P i.
Although this class of enzymes is not yet as thoroughly studied as the protein kinases, it is very likely that these phosphatases will turn out to be just as important as the protein kinases in regulating cellular processes and metabolism. The known phosphoprotein phosphatases show substrate specificity, acting on only a subset of phosphoproteins, and they are in some cases regulated by a second messenger or an extracellular signal. Some protein phosphatases are transmembrane proteins of the plasma membrane, with extracellular receptorlike domains and intracellular phosphatase domains; they may well prove to be regulated by extracellular signals in a fashion similar to regulation of the tyrosine kinase of the insulin receptor.
The complexity and the subtlety of the regulatory mechanisms achieved by evolution strain the imagination, and the experimental challenges of discovering the full range of regulatory mechanisms remain to be met.
Gene regulation by steroid hormones: Vertebrates and insects
The DNA sequences HREs to which hormone-receptor complexes bind are similar in length and arrangement, but different in sequence, for the various steroid hormones. The HRE sequences recognized by a given receptor are very similar but not identical; for each receptor there is a "consensus sequence" Table , which the hormonereceptor complex binds at least as well as it binds the natural HREs.
Each HRE consensus sequence consists of two six-nucleotide sequences, either contiguous or separated by three nucleotides. The two hexameric sequences occur either in tandem or in a palindromic arrangement Fig. The hormone-receptor complex binds to the DNA as a dimer, with each monomer recognizing one of the six-nucleotide sequences. The ability of a given hormone to alter the expression of a specific gene depends upon the HRE element's exact sequence and on its position relative to the gene and the number of HREs associated with the gene.
Figure The general mechanism by which steroid and thyroid hormones, retinoids and vitamin D act to regulate gene expression.
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Hormone H carried to the target tissue on serum binding proteins diffuses across the plasma membrane and binds to its specific receptor protein Rec in the nucleus. Hormone binding changes the conformation of the receptor, allowing it to form dimers in the nucleus with other hormone-receptor complexes of the same type and to bind to specific regulatory regions, hormone response elements HREs , in the DNA adjacent to specific genes.
This binding somehow facilitates transcription of the adjacent gene s by RNA polymerase Chapter 25 , increasing the rate of messenger RNA formation and 4. The changed level of the newly synthesized protein produces the cellular response to the hormone. The details of protein synthesis are discussed in Chapter Comparison of the amino acid sequences of receptors for several steroid hormones as well as receptors for thyroid hormone, vitamin D, and retinoids has revealed several highly conserved sequences and some regions in which the sequences differ considerably with receptor type Fig.
Retinoids are compounds related to retinoate, the carboxylate form of vitamin Al see Fig. A centrally located sequence of 66 to 68 residues is very similar in all of the receptors; this is the DNA-binding region, which resembles regions of other proteins known to bind DNA. All of these DNA-binding regions share the "zinc finger" structure see Fig. Figure The DNA-binding domain common to a number of steroid hormone receptor proteins. These proteins have a binding site for the hormone, a DNA-binding domain, and a region that activates the transcription of the regulated gene.
The DNAbinding region is highly conserved. The sequence shown here see Table for amino acid abbreviations is that for the estrogen receptor, but the residues in bold type are common to all such receptors. The regulation of gene expression is described in more detail in Chapter The region of the hormone receptor responsible for hormone bmding the ligand-binding region, always at the carboxyl terminus is quite different in different members of the hormone receptor family. In the vitamin D receptor, the ligand-binding region consists of only 25 residues, whereas it has residues in the mineralocorticoid receptor.
The different sequences are reflected in different specificities for hormone binding. Mutations that change one amino acid residue in this region result in loss of responsiveness to a specific hormone; some humans unable to respond to cortisol, testosterone, vitamin D, or thyroxine have been shown to have such mutations in the corresponding hormone receptor. The specificity of the ligand-binding site is exploited in the use of a drug, tamoxifen , in the treatment of breast cancer in humans.
In some types of breast cancer, division of the cancerous cells depends on the continued presence of the hormone estrogen.