Mediator Complex Recruits Epigenetic Regulators via Its Two Cyclin-dependent Kinase Subunits to Repress Transcription of Immune Response Genes

Tsutsui, Taiki; Fukasawa, Rikiya; Shinmyouzu, Kaori; Nakagawa, Reiko; Tobe, Kazuyuki; Tanaka, Aki; Ohkuma, Yoshiaki

doi:10.1074/jbc.m113.486746

Cited by 64 publications

(43 citation statements)

References 60 publications

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“…CTGF is a secreted signaling molecule, usually crosstalking with the TGF-β signaling pathway, and is reported to regulate the proliferation of pancreatic cancer cells27. Nedd9 is an intracellular scaffolding protein that serves as a downstream gene of the Wnt/β-catenin signaling pathway28, CDK19, a homologous protein of CDK8 (both proteins are components of the mediator complex), uploads the RNA polymerase II transcription machinery and gene-specific transcription factors29. It has been reported that CTGF30, Nedd931, and CDK1931 genes are targets of miR-18a in human cancer cells, and IGF132 is a miR-18a target in deer antler.…”

Section: Resultsmentioning

confidence: 99%

miR-18a counteracts AKT and ERK activation to inhibit the proliferation of pancreatic progenitor cells

Zhang

et al. 2017

Sci Rep

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Activation of endogenous stem/progenitor cells to repair injured tissues is an ideal option for disease treatment. However, adult pancreatic progenitor cells remain in a quiescent state in vivo. Thus, it is difficult to stimulate proliferation and differentiation in these progenitor cells, and the cause remains elusive. miR-17-92 cluster miRNAs are highly conserved in mammals and are expressed in multiple tissue stem/progenitor cells, but their role in pancreatic progenitor cells are less well known. In the present study, we demonstrate that miR-18a, but not the other members of the miR-17-92 gene cluster, inhibits the proliferation of pancreatic progenitor cells in vitro and ex vivo. miR-18a inhibits proliferation of adult pancreatic progenitor cells through arresting the cell cycle at G1 stage, indicating that miR-18a plays a role in keeping the adult pancreatic progenitor cells in quiescence. miR-18a inhibits pancreatic progenitor proliferation by targeting the gene expressions of connective tissue growth factor (CTGF), neural precursor cell expressed, developmentally down-regulated 9 (Nedd9), and cyclin dependent kinase 19 (CDK19), as well as by suppressing activation of the proliferation-related signaling pathways phosphatidylinositol 3-kinase–protein kinase B (PI3K/AKT) and extracellular signal-regulated kinase (ERK).

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Section: Resultsmentioning

confidence: 99%

miR-18a counteracts AKT and ERK activation to inhibit the proliferation of pancreatic progenitor cells

Zhang

et al. 2017

Sci Rep

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“…Furthermore, MED12 mutations found in patients with X-linked intellectual disability attenuated the ability of Mediator to recruit G9a and induced abnormal neuronal gene expression (Ding et al, 2008). In another report, the two kinase subunits of Mediator, CDK8 and CDK19, were shown to interact with the histone arginine methyltransferase PRMT5 and WD-repeat protein 77 (WDR77; also known as MEP50), respectively, both of which are important for further recruitment of the DNA methyltransferase DNMT3A and subsequent repression of C/EBPβ-regulated genes (Tsutsui et al, 2013). Thus, individual Mediator components appear to exhibit specificity for distinct epigenetic events, such as the recruitment of specific histone or DNA modifiers which, in turn, influence specific epigenetic modifications.…”

Section: Mediator and Epigenetic Regulatorsmentioning

confidence: 99%

The Mediator complex: a master coordinator of transcription and cell lineage development

2014

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Mediator is a multiprotein complex that is required for gene transcription by RNA polymerase II. Multiple subunits of the complex show specificity in relaying information from signals and transcription factors to the RNA polymerase II machinery, thus enabling control of the expression of specific genes. Recent studies have also provided novel mechanistic insights into the roles of Mediator in epigenetic regulation, transcriptional elongation, termination, mRNA processing, noncoding RNA activation and super enhancer formation. Based on these specific roles in gene regulation, Mediator has emerged as a master coordinator of development and cell lineage determination. Here, we describe the most recent advances in understanding the mechanisms of Mediator function, with an emphasis on its role during development and disease. KEY WORDS: Mediator complex, Transcription, Cell fate, Lineage development, Disease IntroductionMediator is a large, multisubunit complex that was discovered following efforts to understand how RNA polymerase II (Pol II)-mediated transcription is regulated by transcription factors in yeast (Nonet and Young, 1989;Kelleher et al., 1990;Thompson et al., 1993;Kim et al., 1994). The complex, which consists of ~30 polypeptides ( Fig. 1), shows conservation from yeast to humans and plays an indispensable role in regulating transcription. Multiple laboratories then used a variety of procedures to isolate mammalian Mediator complexes, which were named TRAP/SMCC, NAT, ARC, DRIP, Srb/MED, PC2, CRSP and mouse Mediator (Jiang et al., 1998;Sun et al., 1998; Boyer et al., 1999;Ito et al., 1999;Kingston, 1999;Näär et al., 1999;Rachez et al., 1999;Ryu et al., 1999;Malik et al., 2000). In 2004, a unified nomenclature for Mediator was established, consisting of MED1 to MED31, together with the cyclin-dependent kinase (CDK) 8-cyclin C pair and several paralogs such as MED1-like (MED1L), MED12L, MED13L and CDK19 (Bourbon et al., 2004). The Mediator complex can be divided into four distinct modules termed the head, middle, tail and CDK8 kinase module, which contains CDK8 (or its paralog CDK19), cyclin C, MED12 (or MED12L) and MED13 (or MED13L) subunits (Malik and Roeder, 2010;Taatjes, 2010). Importantly, the subunit composition of Mediator can vary and is not restricted to a single isoform. For example, immunodepletion of the Mediator complex from HeLa nuclear extracts with an anti-CDK8 antibody revealed that Mediator exists as at least two main isoforms, distinguished by the presence or absence of the CDK8 submodule (Wang et al., 2001). In addition, MED1 and MED26 are not present in all isolated isoforms (Malik and Roeder, 2010).After the initial discovery of Mediator, research mainly focused on how the Mediator complex conveys signals from transcription factors to the Pol II machinery and general transcription factors (GTFs). These studies led to the formulation of the 'bridge' model, in which Mediator connects the transcription factor and Pol II machineries and promotes formation of the pre-initiation compl...

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“…Several other proteins have been previously identified (9) but remain to be confirmed, including those of the Mediator complex (10,11), a large multisubunit complex that regulates RNAP II transcribed genes. In humans, MED is composed of 28 proteins assembled in four distinct modules as follows: the "Head," which contacts the RNAP II; the "Middle" and "Tail" that transfer regulatory signals after interacting with transcription factors to the Head; and the "CDK8 module," including MED12 and MED13 that associate less stably to the whole complex and have activating and repressing functions (12)(13)(14). These different subunits can contact various transcriptional regulators and act together as an adaptor to convey transcription signals from activators to the general transcription machinery, helping the initiation of transcription by RNAP II (15)(16)(17).…”

mentioning

confidence: 99%

Characterization of the Influence of Mediator Complex in HIV-1 Transcription

Ruiz

Pauls

Badía

et al. 2014

Journal of Biological Chemistry

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Mediator Complex Recruits Epigenetic Regulators via Its Two Cyclin-dependent Kinase Subunits to Repress Transcription of Immune Response Genes

Cited by 64 publications

References 60 publications

miR-18a counteracts AKT and ERK activation to inhibit the proliferation of pancreatic progenitor cells

miR-18a counteracts AKT and ERK activation to inhibit the proliferation of pancreatic progenitor cells

The Mediator complex: a master coordinator of transcription and cell lineage development

Characterization of the Influence of Mediator Complex in HIV-1 Transcription

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