A component of the ARC/Mediator complex required for TGFβ/Nodal signalling

Harvard University, Cambridge, Massachusetts, United States
Nature (Impact Factor: 41.46). 09/2002; 418(6898):641-6. DOI: 10.1038/nature00969
Source: PubMed


The transforming growth factor beta (TGF beta) family of cytokines, including Nodal, Activin and bone morphogenetic protein (BMP), have essential roles in development and tumorigenesis. TGF beta molecules activate the Smad family of signal transducers, which form complexes with specific DNA-binding proteins to regulate gene expression. Two discrete Smad-dependent signalling pathways have been identified: TGF beta, Activin and Nodal signal via the Smad2 (or Smad3)-Smad4 complex, whereas BMP signals via the Smad1-Smad4 complex. How distinct Smad complexes regulate specific gene expression is not fully understood. Here we show that ARC105, a component of the activator-recruited co-factor (ARC) complex or the metazoan Mediator complex, is essential for TGF beta/Activin/Nodal/Smad2/3 signal transduction. Expression of ARC105 stimulates Activin/Nodal/Smad2 signalling in Xenopus laevis embryos, inducing axis duplication and mesendoderm differentiation, and enhances TGF beta response in human cells. Depletion of ARC105 inhibits TGF beta/Activin/Nodal/Smad2/3 signalling and Xenopus axis formation, but not BMP/Smad1 signalling. ARC105 protein binds to Smad2/3-Smad4 in response to TGF beta and is recruited to Activin/Nodal-responsive promoters in chromatin in a Smad2-dependent fashion. Thus ARC105 is a specific and key ARC/Mediator component linking TGF beta/Activin/Nodal/Smad2/3 signalling to transcriptional activation.

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    • "Growing evidence supports the notion that the Mediator subunits control diverse development processes with subunit specificity (Kato et al., 2002; Wang et al., 2006; Yang et al., 2006; Lin et al., 2007; Chen 473 RESEARCH ARTICLE Development (2015) 142, 465-476 doi:10.1242/dev.112946 DEVELOPMENT et al., 2010). "
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    ABSTRACT: Unraveling the mechanisms underlying early neural differentiation of embryonic stem cells (ESCs) is crucial to developing cell-based therapies of neurodegenerative diseases. Neural fate acquisition is proposed to be controlled by a 'default' mechanism, for which the molecular regulation is not well understood. In this study, we investigated the functional roles of Mediator Med23 in pluripotency and lineage commitment of murine ESCs. Unexpectedly, we found that, despite the largely unchanged pluripotency and self-renewal of ESCs, Med23 depletion rendered the cells prone to neural differentiation in different differentiation assays. Knockdown of two other Mediator subunits, Med1 and Med15, did not alter the neural differentiation of ESCs. Med15 knockdown selectively inhibited endoderm differentiation, suggesting the specificity of cell fate control by distinctive Mediator subunits. Gene profiling revealed that Med23 depletion attenuated BMP signaling in ESCs. Mechanistically, MED23 modulated Bmp4 expression by controlling the activity of ETS1, which is involved in Bmp4 promoter-enhancer communication. Interestingly, med23 knockdown in zebrafish embryos also enhanced neural development at early embryogenesis, which could be reversed by co-injection of bmp4 mRNA. Taken together, our study reveals an intrinsic, restrictive role of MED23 in early neural development, thus providing new molecular insights for neural fate determination. © 2015. Published by The Company of Biologists Ltd.
    Development 01/2015; 142(3). DOI:10.1242/dev.112946 · 6.46 Impact Factor
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    • "Recent studies have demonstrated that Mediators exert their functions largely through interacting with and coordinating the action of many transcriptional co-activators or co-repressors [52]. For example, MED15 has been shown to be targeted by the Smad2/4 transcriptional activators to control the TGF-β signaling [55] and participate in the SREBP signaling [56] as well. Similarly, MED14 is required for Mediator-dependent activation of genes regulated by the glucocorticoid receptor [57], HNF4 (Hepatocyte nuclear factor 4) [58], and PPARγ (Peroxisome proliferator-activated receptor gamma) [59]. "
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    ABSTRACT: FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c- Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anti-cancer therapeutic strategy.
    Oncotarget 04/2014; 5(8):2000-2015. DOI:10.18632/oncotarget.1859 · 6.36 Impact Factor
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    • "Table 3. DNA-binding TFs and their identified Mediator subunit target(s)*. Gene TF Reference Organism Gene TF Reference Organism MED1 TRa Fondell et al., 1996 MED15 Smad2/4 Kato et al., 2002 Yuan et al., 1998 Smad3/4 Kato et al., 2002 Malik et al., 2004 NHR-49 Taubert et al., 2006 C. elegans TRb Yuan et al., 1998 Oaf1 Thakur et al., 2009 Yeast Zhu et al., 1997 Pdr1 Thakur et al., 2008 Yeast VDR Yuan et al., 1998 Pdr3 Thakur et al., 2008 Yeast Rachez et al., 1999 VP16 Park et al., 2000 Yeast RARa Yuan et al., 1998 Gal4 Park et al., 2000 Yeast Zhu et al., 1997 Gcn4 Park et al., 2000 Yeast Shao et al., 2000 Swanson et al., 2003 Yeast Lee et al., 2007 Zhang et al., 2004 RXRa Yuan et al., 1998 SREBP-1a Yang et al., 2006 Zhu et al., 1997 MED16 Dif Kim et al., 2004 PPARa Yuan et al., 1998 Gcn4 Swanson et al., 2003 Yeast Zhu et al., 1997 MED17 VP16 Ito et al., 1999 PPARg Yuan et al., 1998 Park et al., 2003 Drosophila Ge et al., 2002 p53 Ito et al., 1999 Ge et al., 2008 Meyer et al., 2010 ER Kang et al., 2002 ER Burakov et al., 2000 Zhang et al., 2005 Hsf Park et al., 2001b Drosophila Burakov et al., 2000 Park et al., 2003 Drosophila Kim et al., 2008 Kim et al., 2004 Warnmark et al., 2001 Dif Park et al., 2003 Drosophila AR Wang et al., 2002 Kim et al., 2004 GR Hittelman et al., 1999 STAT2 Lau et al., 2003 Chen et al., 2006 Gal4 Koh et al., 1998 Yeast Chen & Roeder, 2007 RXR Park et al., 2003 Drosophila Kim et al., 2008 p65 van Essen et al., 2009 HNF4 Malik et al., 2002 MED19 REST Ding et al., 2009 p53 Ito et al., 1999 MED21 TRa Nevado et al., 2004 Yeast Frade et al., 2000 Tup1 Hallberg et al., 2006 Yeast Drane et al., 1997 MED22 GCN4 Swanson et al., 2003 Yeast Meyer et al., 2010 MED23 "
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    ABSTRACT: Abstract The Mediator complex is a multi-subunit assembly that appears to be required for regulating expression of most RNA polymerase II (pol II) transcripts, which include protein-coding and most non-coding RNA genes. Mediator and pol II function within the pre-initiation complex (PIC), which consists of Mediator, pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa in size. Mediator serves as a central scaffold within the PIC and helps regulate pol II activity in ways that remain poorly understood. Mediator is also generally targeted by sequence-specific, DNA-binding transcription factors (TFs) that work to control gene expression programs in response to developmental or environmental cues. At a basic level, Mediator functions by relaying signals from TFs directly to the pol II enzyme, thereby facilitating TF-dependent regulation of gene expression. Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression). In this review, we summarize an expansive body of research on the Mediator complex, with an emphasis on yeast and mammalian complexes. We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing. We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module.
    Critical Reviews in Biochemistry and Molecular Biology 10/2013; 48(6). DOI:10.3109/10409238.2013.840259 · 7.71 Impact Factor
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