The role of DNA response elements as allosteric modulators of steroid receptor function

Geserick, Christoph; Meyer, Hellmuth-Alexander; Haendler, Bernard

doi:10.1016/j.mce.2005.03.007

Cited by 84 publications

(52 citation statements)

References 57 publications

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“…For example, the effects of sumoylation of the AR-NTD and the role of the polyglutamine stretch in the AR-NTD or NTD-LBD interaction are strikingly different for AR interacting with selective versus nonselective DNA motifs (26)(27)(28). These effects are examples of allosteric influences of the DNA on the functioning of nuclear receptors or transcription factors, similar to what has been described before for the AR (29) and GR (30,31).…”

Section: In Vitro Confirmation Of a Direct Effect Of The Zinc-finger mentioning

confidence: 57%

Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model

Schauwaers

Gendt

Saunders³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

105

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Androgens influence transcription of their target genes through the activation of the androgen receptor (AR) that subsequently interacts with specific DNA motifs in these genes. These DNA motifs, called androgen response elements (AREs), can be classified in two classes: the classical AREs, which are also recognized by the other steroid hormone receptors; and the AR-selective AREs, which display selectivity for the AR. For in vitro interaction with the selective AREs, the androgen receptor DNA-binding domain is dependent on specific residues in its second zinc-finger. To evaluate the physiological relevance of these selective elements, we generated a germ-line knockin mouse model, termed SPARKI (SPecificity-affecting AR KnockIn), in which the second zinc-finger of the AR was replaced with that of the glucocorticoid receptor, resulting in a chimeric protein that retains its ability to bind classical AREs but is unable to bind selective AREs. The reproductive organs of SPARKI males are smaller compared with wild-type animals, and they are also subfertile. Intriguingly, however, they do not display any anabolic phenotype. The expression of two testis-specific, androgen-responsive genes is differentially affected by the SPARKI mutation, which is correlated with the involvement of different types of response elements in their androgen responsiveness. In this report, we present the first in vivo evidence of the existence of two functionally different types of AREs and demonstrate that AR-regulated gene expression can be targeted based on this distinction.DNA-binding domain ͉ fertility ͉ Rhox5 ͉ transcription

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Section: In Vitro Confirmation Of a Direct Effect Of The Zinc-finger mentioning

confidence: 57%

Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model

Schauwaers

Gendt

Saunders³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

105

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“…However, the large size of the mammalian genomes and the general need for more sophisticated control systems to regulate very large numbers of interacting genes require mammalian cells to use rather elaborate control elements to regulate gene transcription. For example, regulation of expression of individual human genes is often controlled by several sets of cis-acting regulatory elements, including promoters, enhancers (Martin 2001), silencers (Pozzoli and Sironi 2005;Boyer et al 2006), insulators (Bell et al 2001;Kuhn and Geyer 2003), and response elements (Geserick et al 2005). In concert with chromatin remodeling, histone modifications such as acetylation and methylation also play an important role in the transcriptional regulatory process (Berger 2002;Turner 2002).…”

mentioning

confidence: 99%

Statistical analysis of the genomic distribution and correlation of regulatory elements in the ENCODE regions

Zhang¹,

Paccanaro²,

Fu³

et al. 2007

Genome Res.

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The comprehensive inventory of functional elements in 44 human genomic regions carried out by the ENCODE Project Consortium enables for the first time a global analysis of the genomic distribution of transcriptional regulatory elements. In this study we developed an intuitive and yet powerful approach to analyze the distribution of regulatory elements found in many different ChIP-chip experiments on a 10∼100-kb scale. First, we focus on the overall chromosomal distribution of regulatory elements in the ENCODE regions and show that it is highly nonuniform. We demonstrate, in fact, that regulatory elements are associated with the location of known genes. Further examination on a local, single-gene scale shows an enrichment of regulatory elements near both transcription start and end sites. Our results indicate that overall these elements are clustered into regulatory rich "islands" and poor "deserts." Next, we examine how consistent the nonuniform distribution is between different transcription factors. We perform on all the factors a multivariate analysis in the framework of a biplot, which enhances biological signals in the experiments. This groups transcription factors into sequence-specific and sequence-nonspecific clusters. Moreover, with experimental variation carefully controlled, detailed correlations show that the distribution of sites was generally reproducible for a specific factor between different laboratories and microarray platforms. Data sets associated with histone modifications have particularly strong correlations. Finally, we show how the correlations between factors change when only regulatory elements far from the transcription start sites are considered.

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“…c The change of dynamics can increase the affinity for the other ligand. d Mutations lead to allosteric diseases by stabilizing an active or inactive conformation and influencing the binding of ligands, signal transmission, and gene expression of the bound transcription factor, more than simply as a docking site for transcription factors [33][34][35]. Recently, a single-molecule study showed that the binding affinity of a second protein separated from the first protein was altered, when a DNA molecule was deformed by specific binding of a protein [36].…”

Section: The Role Of Allosterymentioning

confidence: 99%

Allosteric therapies for lung cancer

Jing

Wang

2015

Cancer Metastasis Rev

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Allostery is a regulation at a distance by conveying information from one site to another and an intrinsic property of dynamic proteins. Allostery plays an essential role in receptor trafficking, signal transmission, controlled catalysis, gene turn on/off, or cell apoptosis. Allosteric mutations are considered as one of causes responsible for cancer development, leading to "allosteric diseases" by stabilizing an active or inactive conformation or changing the dynamic distribution of preexisting propagation pathways. The present article mainly focuses on the potential of allosteric therapies for lung cancer. Allosteric drugs may have several advantages over traditional drugs. The epidermal growth factor receptor mutations and signaling pathways downstream (such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways) were suggested to play a key role in lung cancer and considered as targets of allosteric therapy. Some allosteric inhibitors for lung cancer-specific targets and a series of preclinical trials of allosteric inhibitors for lung cancer have been developed and reported. We expect that allosteric therapies will gain more attentions to develop combinatorial strategies for lung cancer and metastasis.

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The role of DNA response elements as allosteric modulators of steroid receptor function

Cited by 84 publications

References 57 publications

Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model

Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model

Statistical analysis of the genomic distribution and correlation of regulatory elements in the ENCODE regions

Allosteric therapies for lung cancer

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