Determinants of Cell- and Gene-Specific Transcriptional Regulation by the Glucocorticoid Receptor

So, Alex Yick-Lun; Chaivorapol, Christina; Bolton, Eric; Li, Hao; Yamamoto, Keith R.

doi:10.1371/journal.pgen.0030094

Cited by 273 publications

(304 citation statements)

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“…In general, we were struck by the remarkable degree of cell and gene specificity inherent in androgen regulation, as 182 (89%) of the 205 ARGs we identified were apparently androgen-unresponsive in LNCaP cells (DePrimo et al 2002;Nelson et al 2002). Similarly, comparisons of glucocorticoid-responsive genes in different cell types (Rogatsky et al 2003;Wang et al 2004;Phuc Le et al 2005;So et al 2007) revealed little overlap. It will be important in future work to assemble expression and response data from multiple androgen-responsive cell types to better define and understand tissue-specific transcriptional networks radiating outward from AR.…”

Section: Figure 6 Distribution Analysis Of Ares Located Near Args (A)mentioning

confidence: 94%

“…We interrogated ∼104 kb genomic regions centered on the transcription start sites of 548 candidate hormone-responsive genes to identify AREs and to determine the distribution of AREs at promoter proximal, distal, and intragenic regions. These human candidate genes included our 157 putative and validated ARGs identified in HPr-1AR cells, 241 putative and validated glucocorticoid receptor-(GR) responsive genes identified in A549 lung adenocarcinoma cells and U2OS-GR osteosarcoma cells (Rogatsky et al 2003;Wang et al 2004;So et al 2007), and 150 genes potentially hormone-responsive in other cell types (e.g., 35 ARGs from LNCaP cells; DePrimo et al 2002;Nelson et al 2002). GR, which is closely related to AR, binds in vitro with similar affinity as AR to consensus sequences in the elementary halfsites GGTACAnnnTGTTCT (Claessens et al 2001).…”

Section: Identification Of Ar Binding Regionsmentioning

confidence: 99%

“…We employed unbiased searches using BioProspector or MobyDick (Bussemaker et al 2000;So et al 2007) to identify recurring sequence motifs among our 524 AREs (500-bp sequences centered at the AR binding peak) (Fig. 7).…”

Section: Potential Composite Aresmentioning

confidence: 99%

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Cell- and gene-specific regulation of primary target genes by the androgen receptor

Bolton¹,

So²,

Chaivorapol³

et al. 2007

Genes Dev.

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312

273

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The androgen receptor (AR) mediates the physiologic and pathophysiologic effects of androgens including sexual differentiation, prostate development, and cancer progression by binding to genomic androgen response elements (AREs), which influence transcription of AR target genes. The composition and context of AREs differ between genes, thus enabling AR to confer multiple regulatory functions within a single nucleus. We used expression profiling of an immortalized human prostate epithelial cell line to identify 205 androgen-responsive genes (ARGs), most of them novel. In addition, we performed chromatin immunoprecipitation to identify 524 AR binding regions and validated in reporter assays the ARE activities of several such regions. Interestingly, 67% of our AREs resided within ∼50 kb of the transcription start sites of 84% of our ARGs. Indeed, most ARGs were associated with two or more AREs, and ARGs were sometimes themselves linked in gene clusters containing up to 13 AREs and 12 ARGs. AREs appeared typically to be composite elements, containing AR binding sequences adjacent to binding motifs for other transcriptional regulators. Functionally, ARGs were commonly involved in prostate cell proliferation, communication, differentiation, and possibly cancer progression. Our results provide new insights into cell-and gene-specific mechanisms of transcriptional regulation of androgen-responsive gene networks.[Keywords: Androgen receptor (AR); androgen response element (ARE); transcription; steroid receptor; chromatin immunoprecipitation (ChIP); prostate cancer] Supplemental material is available at http://www.genesdev.org.

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Section: Figure 6 Distribution Analysis Of Ares Located Near Args (A)mentioning

confidence: 94%

Section: Identification Of Ar Binding Regionsmentioning

confidence: 99%

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Cell- and gene-specific regulation of primary target genes by the androgen receptor

Bolton¹,

So²,

Chaivorapol³

et al. 2007

Genes Dev.

Self Cite

312

273

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“…GRs can bind to DNA as heterodimers with many other transcription factors, such as members of the signal transducer and activator of transcription (STAT) family, the ETS transcription factors and the vitamin D3 receptor [5,6] leading to the recruitment of distinct coactivator (e.g. GRIP-1) or corepressor (e.g.…”

Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Chung

Caramori

Adcock

2009

Eur J Clin Pharmacol

123

106

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International audienceInhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting β-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 μg daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 μg daily, and addition of the LABA formoterol to budesonide (800 μg) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV and the rate of exacerbations. A reduction in the rate of decline in FEV of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases

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“…(32)(33)(34)(35)(36) A comprehensive review of the mechanisms known for non-Mendelian inheritance is provided by Heyningen and Yeyati (1) and Zlotogora. (2) The factors that affect gene product levels include genespecific transcription (37,38) and translation regulators. (39) Therefore, a monogenic disease could be under the influence of gene-specific interacting partners that are referred to as modifier genes.…”

Section: Molecular Basis Of Ip-vementioning

confidence: 99%

Incomplete penetrance and variable expressivity: is there a microRNA connection?

et al. 2009

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Incomplete penetrance and variable expressivity are non‐Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in fine‐tuning gene expression at translational level, we propose miRNA‐mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3′ UTR, co‐expression of target gene–miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles.

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Determinants of Cell- and Gene-Specific Transcriptional Regulation by the Glucocorticoid Receptor

Cited by 273 publications

References 60 publications

Cell- and gene-specific regulation of primary target genes by the androgen receptor

Cell- and gene-specific regulation of primary target genes by the androgen receptor

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Incomplete penetrance and variable expressivity: is there a microRNA connection?

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