Nuclear Receptor Coregulators: Judges, Juries, and Executioners of Cellular Regulation

Lonard, David M.; O’Malley, Bert W.

doi:10.1016/j.molcel.2007.08.012

Cited by 427 publications

(331 citation statements)

References 104 publications

(102 reference statements)

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“…For ligand-dependent transcriptional controls by nuclear steroid/vitamin receptors, several distinct classes of transcriptional co-regulators-co-regulator complexes are indispensable in addition to basic transcription machinery to reorganize chromatin state (4). Transcriptional co-regulators for NRs can be divided into two classes in terms of chromatin reorganization (5-7).…”

mentioning

confidence: 99%

Double PHD Fingers Protein DPF2 Recognizes Acetylated Histones and Suppresses the Function of Estrogen-related Receptor α through Histone Deacetylase 1

Matsuyama

Takada

Yokoyama

et al. 2010

Journal of Biological Chemistry

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Estrogen-related receptor ␣ (ERR␣) is a member of the nuclear receptor superfamily and regulates many physiological functions, including mitochondrial biogenesis and lipid metabolism. ERR␣ enhances the transactivation function without endogenous ligand by associating with coactivators such as peroxisome proliferator-activated receptor ␥ coactivator 1 ␣ and ␤ (PGC-1␣ and -␤) and members of the steroid receptor coactivator family. However, the molecular mechanism by which the transactivation function of ERR␣ is converted from a repressive state to an active state is poorly understood. Here we used biochemical purification techniques to identify ERR␣-associated proteins in HeLa cells stably expressing ERR␣. Interestingly, we found that double PHD fingers protein DPF2/BAF45d suppressed PGC-1␣-dependent transactivation of ERR␣ by recognizing acetylated histone H3 and associating with HDAC1. DPF2 directly bound to ERR␣ and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERR␣. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERR␣ by associating with both acetylated histone H3 and HDAC1.Nuclear receptors (NRs) 3 play pivotal roles during the development of vertebrates and in diverse physiological events in adults (1, 2). NRs constitute a gene superfamily and act as transcription factors. For most members of the NR superfamily, the transcriptional function is dependent on binding of lipophilic ligands such as steroid hormones and fat-soluble vitamins. The other subset of NRs is considered an orphan receptor, as physiologically relevant ligands remain to be identified. Orphan receptors are constitutively active or repressive transcription factors; however, their potency in transcriptional regulation appears to be dependent on cell types and the promoter context (3).For ligand-dependent transcriptional controls by nuclear steroid/vitamin receptors, several distinct classes of transcriptional co-regulators-co-regulator complexes are indispensable in addition to basic transcription machinery to reorganize chromatin state (4). Transcriptional co-regulators for NRs can be divided into two classes in terms of chromatin reorganization (5-7). One class consists of histone-modifying enzymes that reversibly modify the N-terminal tails of histone proteins (8, 9). For example, acetylation and methylation at histone H3K4 and H3K36 are chromatin-activating modifications and support transcriptional activation by NRs (8, 10, 11). In contrast, transcriptional repression by NRs is coupled with inactivating modifications like deacetylation and methylation at histone H3K9 and H3K27. Accordingly, cognate histone modifying enzymes serve as NR co-regulators.The other class of transcriptional co-regulators are chromatin remodeling factors that directly reorganize nucleosomal arrays through ATP hydrolysis (11). Chromatin remod...

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confidence: 99%

Double PHD Fingers Protein DPF2 Recognizes Acetylated Histones and Suppresses the Function of Estrogen-related Receptor α through Histone Deacetylase 1

Matsuyama

Takada

Yokoyama

et al. 2010

Journal of Biological Chemistry

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“…3D). Transcription coregulators (CoRs) cooperate with TFs to integrate diverse cellular signals and thereby mediate a coordinated transcriptional response (11). Although many CoRs do not directly bind to DNA, they can be recruited to TFREs through interaction with TFs.…”

Section: Label-free and Stable Isotope Labeling By Amino Acids In Celmentioning

confidence: 99%

Proteome-wide profiling of activated transcription factors with a concatenated tandem array of transcription factor response elements

Chen

Chan

Liu

et al. 2013

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

111

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Transcription factors (TFs) are families of proteins that bind to specific DNA sequences, or TF response elements (TFREs), and function as regulators of many cellular processes. Because of the low abundance of TFs, direct quantitative measurement of TFs on a proteome scale remains a challenge. In this study, we report the development of an affinity reagent that permits identification of endogenous TFs at the proteome scale. The affinity reagent is composed of a synthetic DNA containing a concatenated tandem array of the consensus TFREs (catTFRE) for the majority of TF families. By using catTFRE to enrich TFs from cells, we were able to identify as many as 400 TFs from a single cell line and a total of 878 TFs from 11 cell types, covering more than 50% of the gene products that code for the DNA-binding TFs in the genome. We further demonstrated that catTFRE pull-downs could quantitatively measure proteome-wide changes in DNA binding activity of TFs in response to exogenous stimulation by using a labelfree MS-based quantification approach. Applying catTFRE on the evaluation of drug effects, we described a panoramic view of TF activations and provided candidates for the elucidation of molecular mechanisms of drug actions. We anticipate that the catTFRE affinity strategy will find widespread applications in biomedical research.TF activity profiling | transcriptional coregulator | drug effects screening A lmost all biological processes, ranging from cell cycle regulation to organ development, are controlled by the transcriptional regulatory system (1). In the classic cell membraneto-nucleus signal transduction paradigm, transcription factors (TFs) are the final effectors. They are activated and bind to consensus DNA sequences to execute specific transcriptional programs in response to the signal. Thus, the ability to monitor TF activity is important for the delineation of signal transduction pathways when the cells are perturbed (e.g., treated with a drug), or when organs are under the influence of developmental cues.Approximately 1,500 TF coding genes are reported to be in the human genome (2). TFs can be grouped into different families depending on the structure of their DNA binding domains. There are approximately 50 TF families (2), and each family prefers to bind a specific DNA consensus sequence. For example, nuclear receptors (NRs) are ligand-modulated TFs that recognize one or two hormone response element sequences such as 5′-AGAACA-3′ or 5′-AGGTCA-3′ (3). Previous studies have demonstrated the importance of linking an extracellular signaling event to the activation of TFs. For example, assigning Forkhead box (Fox) P3 to a signaling module that is crucial for regulatory T-cell development has accelerated our understanding of signal transductions and gene functions (4).The abundance of TFs in the cells is currently inferred from mRNA profiling. Yang et al. identified 45 of 49 known NRs from several tissues in mice and linked NR expression to the circadian clock (5). Bookout et al. surveyed the expression of al...

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“…The nuclear receptor superfamily, the largest family of transcription factors, is responsible for the sensing of hormonal, environmental and dietary-derived factors, and the translation of these signals into appropriate transcriptional responses (30)(31)(32)(33)(34)(35) . Often working co-operatively, nuclear receptors converge on common gene targets to give tight regulation of gene expression and repression.…”

Section: The Nuclear Receptor Superfamilymentioning

confidence: 99%

The vitamin D receptor in cancer

2008

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Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1a,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics. The cancer burdenThe impact of cancer continues to be one of the greatest burdens in the developed world and is also increasingly impacting on the developing world. Approximately 1 . 5 million individuals will die from breast, colon or prostate cancer this year, and the total number of deaths from cancer accounts for 13 % of all deaths worldwide and for one in every four deaths in the UK and USA (1) . The impact is also economic; $280 · 10 9 is spent annually worldwide on the treatment of patients. Many cancers are however preventable, and through lifestyle choices such as smoking, diet and exercise the worldwide incidence of cancer could be cut by 40 % (2,3) . Major risk factors for cancer DietRecently, the appreciation of the impact of diet on cancer has come to the fore, with a number of studies establishing unequivocal relationships between diet and cancer initiation and progression. Reflecting the accumulation of these data, the WHO has now stated that diet forms the secondmost preventable cause of cancer (after smoking) (3) . This impact will rise further as a result of demographic factors, and quite possibly because of changing dietary habits worldwide, which will contribute further to the projected increase in cancer incidence in developing nations. Highprofile malignancies such as breast, prostate, and colon cancer typify this scenario, in which the aetiology of the disease reflects the cumulative impact of dietary factors over an individual's lifetime (4)(5)(6) . The relationship between diet and disease is already exploited clinically, e.g. in the Selenium and Vitamin E Cancer Prevention Trial to assess the chemoprevention potential of vitamin E ...

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Nuclear Receptor Coregulators: Judges, Juries, and Executioners of Cellular Regulation

Cited by 427 publications

References 104 publications

Double PHD Fingers Protein DPF2 Recognizes Acetylated Histones and Suppresses the Function of Estrogen-related Receptor α through Histone Deacetylase 1

Double PHD Fingers Protein DPF2 Recognizes Acetylated Histones and Suppresses the Function of Estrogen-related Receptor α through Histone Deacetylase 1

Proteome-wide profiling of activated transcription factors with a concatenated tandem array of transcription factor response elements

The vitamin D receptor in cancer

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