Composite co-activator ARC mediates chromatin-directed transcriptional activation

Näär, Anders M.; Beaurang, Pierre A.; Zhou, Shi-Sheng; Abraham, Shaji; Solomon, William B.; Tjian, Robert

doi:10.1038/19789

Cited by 390 publications

(130 citation statements)

References 24 publications

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“…Unlike Mediator, however, TREF does not stimulate GAL4-VP16-dependent transcription in vitro. Together with its cooperativity with Mediator in stimulating transcription from the c-fos promoter and its differing chromatographic behavior from Mediator (30,43), TREF appears to be a novel activity distinct from the well characterized Mediator. Indeed, several steps of chromatography revealed that TREF is separated into three distinct components, one of which, TREF␣, turned out to be hnRNP R. As it is, TREF␣ is also distinct from the reported coactivators for SRF or CREB, including CoS (coactivator for SRF-activated transcription) (44), MRTFs (myocardin-related transcription factors) (45,46), CBP (CREB binding protein)/p300 (47), and TORC (transducer of regulated CREB) (48,49).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein R Enhances Transcription from the Naturally Configured c-fos Promoter in Vitro

Fukuda

Nakadai

Shimada

et al. 2009

Journal of Biological Chemistry

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Transcription of a proto-oncogene c-fos is induced rapidly to high levels by various extracellular stimuli. To explore the molecular mechanism of c-fos gene induction, we established a defined in vitro transcription system for the c-fos promoter that consists of purified activators (SRF, Elk-1, cAMP-responsive element-binding protein, and ATF1), general transcription factors, and RNA polymerase II. In this reconstituted transcription system, activation of c-fos transcription was highly dependent upon coactivators such as PC4 and Mediator, indicating a very weak activation potential of the activators in the context of an unaltered promoter structure. This heightened coactivator dependence, however, allowed us to identify from HeLa nuclear extract a coactivator-like activity termed transcriptional regulator of c-fos (TREF) that enhanced c-fos transcription but not GAL4-VP16-dependent transcription. TREF cooperated with Mediator to enhance c-fos transcription by ϳ60-fold over its basal level and, like Mediator, stimulated activator-independent (basal) transcription as well. Further purification of TREF revealed that it consists of at least three distinct components, one of which was purified to near homogeneity and identified as heterogeneous nuclear ribonucleoprotein R. Recombinant heterogeneous nuclear ribonucleoprotein R enhanced transcription from the c-fos promoter and displayed cooperativity with PC4 and Mediator, thus demonstrating its direct transcriptional activity.

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Section: Discussionmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein R Enhances Transcription from the Naturally Configured c-fos Promoter in Vitro

Fukuda

Nakadai

Shimada

et al. 2009

Journal of Biological Chemistry

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“…The VP16 TAD targets basal Pol II transcription factors, including TFIIA, TFIIB, TFIID, the TFIIH subunit Tfb1/p62 (yeast/human) and the Mediator co-activator [18][19][20][21][22][23] . The VP16 TAD binds the Mediator subunit Med25 (also called Arc92) [24][25][26][27] , which is specific to higher eukaryotes. Med25 consists of two domains, the activator interaction domain (ACID) 24 that binds the VP16 TAD, and a 'von Willebrand factor type A' domain that anchors Med25 to Mediator 24 .…”

mentioning

confidence: 99%

Structure and VP16 binding of the Mediator Med25 activator interaction domain

Vojnic

Mourão

Seizl

et al. 2011

Nat Struct Mol Biol

113

161

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4 0 4 VOLUME 18 NUMBER 4 APRIL 2011 nAture structurAl & moleculAr biologyActivator proteins regulate eukaryotic RNA polymerase II (Pol II) transcription in response to developmental and environmental signals. They bind to the DNA recognition sites of target genes with a sequence-specific DNA-binding domain, and recruit components of the Pol II machinery through a transcriptional activation domain (TAD) 1,2 . Activators have been classified as acidic, glutamine-rich, proline-rich and serine/threonine-rich, depending on the preponderance of amino acids in their TAD 3 . An archetypal acidic activator is the herpes simplex virus protein 16 (VP16), which activates the expression of immediate early viral genes during infection 4-8 . VP16 exerts its activating function through a C-terminal TAD that includes residues 413-490 (refs. 9-13). The VP16 TAD has been intensely used for studying transcriptional activation. Usually, the VP16 TAD is fused with its N terminus to the DNA-binding domain of the yeast transcription factor Gal4. The resulting Gal4-VP16 activator fusion protein stimulates transcription from promoters that contain Gal4-binding sites in the yeast and mammalian transcription systems in vivo 14,15 and in vitro 16,17 . This indicates that basic mechanisms of transcription activation are conserved amongst eukaryotes. The VP16 TAD targets basal Pol II transcription factors, including TFIIA, TFIIB, TFIID, the TFIIH subunit Tfb1/p62 (yeast/human) and the Mediator co-activator [18][19][20][21][22][23] . The VP16 TAD binds the Mediator subunit Med25 (also called Arc92) [24][25][26][27] , which is specific to higher eukaryotes. Med25 consists of two domains, the activator interaction domain (ACID) 24 that binds the VP16 TAD, and a 'von Willebrand factor type A' domain that anchors Med25 to Mediator 24 . Mediator generally conveys regulatory information by forming a bridge between activators and the basal Pol II machinery 28,29 . Whereas information on the core Mediator structure is emerging, structural information about its more peripheral activator-binding domains is limited to the KIX domain in subunit Med15 (or Arc105) 30,31 .The VP16 TAD is intrinsically flexible, whereas the VP16 core domain (residues 49-402) forms a stable structure 23,[32][33][34] . The TAD contains two functional subdomains, H1 (residues 410-452) and H2 (residues 453-490), which activate transcription independently 35,36 . Both H1 and H2 contain acidic amino acids, but specific bulky hydrophobic and aromatic residues are required for their function [36][37][38][39] . H2 has been proposed to adopt an α-helical conformation when bound to TFIIB 40 . NMR analysis revealed a nine-residue amphipathic α-helix in H2 that docks onto a PH fold in Tfb1 21 . On the basis of these and other results it is assumed that acidic TADs are flexible in their free state, but become transiently structured upon interaction with their target proteins.Here we report the NMR structure of the Mediator Med25 ACID and analyze its structural and functional interaction wi...

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“…SRCs and cointegrators such as p300/CBP and p300/CBP-associated factor (PCAF), which enhance transcriptional activation of NRs, also exhibit histone acetyltransferase activity, which may also contribute to interactions of NRs with their cognate response elements and the basal transcriptional machinery (38 -41). In addition, members of a complex group of related proteins that include vitamin D receptor-interacting proteins (DRIP), cofactors required for Sp1 (CRSP), activated recruited cofactors, and thyroid hormone-associated proteins (TRAP) also coactivate ER and other NRs (42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52). In contrast, these proteins do not exhibit histone acetyltransferase activity, and a recent study using a chromatin immunoprecipitation assay showed that both SRC-3 and DRIP205 are recruited to the estrogen-responsive region of the cathepsin D gene promoter after treatment of MCF-7 cells with 17␤-estradiol (E2) (53).…”

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confidence: 99%

Cooperative Coactivation of Estrogen Receptor α in ZR-75 Human Breast Cancer Cells by SNURF and TATA-binding Protein

Saville

Poukka

Wormke

et al. 2002

Journal of Biological Chemistry

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SNURF is a small RING finger protein that binds the zinc finger region of steroid hormone receptors and enhances Sp1-and androgen receptor-mediated transcription in COS and CV-1 cells. In this study, we show that SNURF coactivates both wild-type estrogen receptor ␣ (ER␣) (4-fold)-and HE19 (ER␣ deletion of activation function 1 (AF1)) (210-fold)-mediated activation of an estrogen-responsive element promoter in ZR-75 cells. In mammalian two-hybrid assays in ZR-75 cells SNURF interactions were estrogen (E2)-dependent and were not observed with the antiestrogen ICI 182,780. ER␣ interacted with multiple regions of SNURF; SNURF interactions with ER␣ were dependent on AF2, and D538N, E542Q, and D545N mutations in helix 12 abrogated both SNURF-ER␣ binding and coactivation. Moreover, peptide fusion proteins that inhibit interactions between helix 12 of ER␣ with LXXLL box-containing proteins also blocked ER␣ coactivation by SNURF. However, cotransfection of SNURF with prototypical steroid receptor coactivators 1, 2, and 3 that contain LXXLL box motifs did not enhance E2 responsiveness, whereas TATA-binding protein (TBP) and SNURF cooperatively coactivated ER␣-mediated transactivation. The results are consistent with a unique model for cooperative coactivation of ER␣ that requires ligand binding, repositioning of helix 12, recruitment of TBP, and interaction with SNURF, which binds both ER␣ and TBP. The nuclear receptor (NR)1 superfamily of transcription factors includes the steroid/thyroid hormone, retinoid, and vitamin D receptors and a growing number of orphan receptors for which endogenous ligands have not yet been identified (1-6). The orphan pregnane (steroid) X receptor, constitutive androstane receptor, and peroxisome proliferator-activated receptor ␣ bind structurally diverse steroidal compounds, drugs, and xenobiotics and induce members of the CYP2, CYP3, and CYP4 family of P450 isoenzymes (7-19). NRs share common structural features or domains, and these have been extensively characterized for most ligand-activated NRs (1-6). For example, the two forms of the estrogen receptor (ER␣ and ER␤) contain a highly conserved DNA binding domain C (DBD) (97% homology for human ERs) in the central portion of both proteins (20 -23). Similarities between the DBDs of NRs are due to their zinc finger motifs, which directly bind DNA; however, despite these similarities, subtle structural differences are important for sequence-specific interactions of these transcription factors (2). The N-terminal and C-terminal domains (A/B and E/F for the ER) of NRs contain activation function 1 (AF1) and AF2, respectively, and the ligand binding domain is also located in AF2. The expression and functions of AF1/AF2 are highly variable among NRs; however, for some NRs, such as the androgen receptor (AR), both domains interact to enhance transcriptional activation.Several different classes of proteins interact with NRs to enhance or inhibit their activity as trans-acting factors, and these interacting proteins include coactivators, cointegrato...

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Composite co-activator ARC mediates chromatin-directed transcriptional activation

Cited by 390 publications

References 24 publications

Heterogeneous Nuclear Ribonucleoprotein R Enhances Transcription from the Naturally Configured c-fos Promoter in Vitro

Heterogeneous Nuclear Ribonucleoprotein R Enhances Transcription from the Naturally Configured c-fos Promoter in Vitro

Structure and VP16 binding of the Mediator Med25 activator interaction domain

Cooperative Coactivation of Estrogen Receptor α in ZR-75 Human Breast Cancer Cells by SNURF and TATA-binding Protein

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