Mediator (coactivator)

{{Short description|Multiprotein complex involved in transcription in eukaryotes}} {{Use dmy dates|date=October 2020}} thumb|'''Figure 1''': Diagram of Mediator with its cyclin-dependent kinase module attached '''Mediator''' is a multiprotein complex that functions as a transcriptional coactivator in all eukaryotes. It was discovered in 1990 in the lab of Roger D. Kornberg, recipient of the 2006 Nobel Prize in Chemistry.<ref>{{cite journal | vauthors = Kelleher RJ, Flanagan PM, Kornberg RD | title = A novel mediator between activator proteins and the RNA polymerase II transcription apparatus | journal = Cell | volume = 61 | issue = 7 | pages = 1209–15 | date = June 1990 | pmid = 2163759 | doi = 10.1016/0092-8674(90)90685-8 | s2cid = 4971987 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Flanagan PM, Kelleher RJ, Sayre MH, Tschochner H, Kornberg RD | title = A mediator required for activation of RNA polymerase II transcription in vitro | journal = Nature | volume = 350 | issue = 6317 | pages = 436–8 | date = April 1991 | pmid = 2011193 | doi = 10.1038/350436a0 | bibcode = 1991Natur.350..436F | s2cid = 4323957 }}</ref> Mediator{{efn|Mediator is also referred to in scientific literature as the vitamin D receptor interacting protein ('''DRIP''') coactivator complex and the thyroid hormone receptor-associated proteins ('''TRAP''').}} interacts with transcription factors and RNA polymerase II. It mainly functions to transmit signals from the transcription factors to the polymerase.<ref name="allen2015">{{cite journal | vauthors = Allen BL, Taatjes DJ | title = The Mediator complex: a central integrator of transcription | journal = Nature Reviews Molecular Cell Biology | volume = 16 | issue = 3 | pages = 155–66 | date = March 2015 | pmid = 25693131 | doi = 10.1038/nrm3951 | pmc=4963239}}</ref>

Mediator complexes are variable at the evolutionary, compositional and conformational levels.<ref name="allen2015"/> Figure 1 shows only one "snapshot" of what a particular complex might comprise,{{efn|However note that more recently it has been found that the CDK module and MED26 cannot be present concurrently in a complex.<ref name="allen2015"/>}} but it is an inaccurate depiction of the conformation ''in vivo''. During evolution, Mediator has complexified. The yeast ''Saccharomyces cerevisiae'' (a simple eukaryote) is thought to have up to 21 subunits in the core Mediator (exclusive of the CDK module), while mammals have up to 26.

Individual subunits can be absent or replaced by other subunits under different conditions. Also, there are many intrinsically disordered regions in Mediator proteins, which may contribute to the conformational flexibility seen both with and without other bound proteins or protein complexes. A more realistic model of Mediator without the CDK module is shown in Figure 2.<ref name="robinson2015">{{cite journal | vauthors = Robinson PJ, Trnka MJ, Pellarin R, Greenberg CH, Bushnell DA, Davis R, Burlingame AL, Sali A, Kornberg RD | title = Molecular architecture of the yeast Mediator complex | journal = eLife | volume = 4 | article-number = e08719 | date = September 2015 | pmid = 26402457 | doi = 10.7554/eLife.08719|doi-access=free | pmc=4631838}}</ref>

Mediator is required for successful transcription of genes by RNA polymerase II, and contacts the polymerase in the transcription preinitiation complex.<ref name="allen2015"/> A recent model showing the polymerase associating with Mediator without DNA is shown in Figure 3.<ref name=robinson2015/> In addition to RNA polymerase II, Mediator must also associate with transcription factors and DNA; a model of such interactions is shown in Figure 4.<ref>{{cite journal | vauthors = Bernecky C, Grob P, Ebmeier CC, Nogales E, Taatjes DJ | title = Molecular architecture of the human Mediator-RNA polymerase II-TFIIF assembly | journal = PLOS Biology | volume = 9 | issue = 3 | article-number = e1000603 | date = March 2011 | pmid = 21468301 | doi = 10.1371/journal.pbio.1000603|doi-access=free | pmc=3066130}}</ref> Note that the different morphologies of Mediator do not necessarily mean that a particular model is correct; rather those differences may reflect the flexibility of Mediator as it interacts with other molecules.{{efn|The sharp bend in the DNA associated with the transcription bubble is shown in the graphical abstract and first figure of this [http://www.sciencedirect.com/science/article/pii/S1097276515005286 research paper]}} For example, after binding the enhancer and core promoter, the Mediator complex compositionally changes, dissociating the kinase module and associating with RNA polymerase II for transcriptional activation.<ref>{{cite journal |last1=Petrenko |first1=N |last2=Jin |first2=Y |last3=Wong |first3=KH |last4=Struhl |first4=K |title=Mediator Undergoes a Compositional Change during Transcriptional Activation. |journal=Molecular Cell |date=3 November 2016 |volume=64 |issue=3 |pages=443–454 |doi=10.1016/j.molcel.2016.09.015 |pmid=27773675|pmc=5096951 }}</ref>

Mediator is located within the cell nucleus. It is required for successfully transcribing nearly all class II gene promoters in yeast.<ref>{{cite journal | vauthors = Biddick R, Young ET | title = Yeast mediator and its role in transcriptional regulation | journal = Comptes Rendus Biologies | volume = 328 | issue = 9 | pages = 773–82 | date = September 2005 | pmid = 16168358 | doi = 10.1016/j.crvi.2005.03.004 | url = https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2005.03.004/ | url-access = subscription }}</ref> It works similarly in mammals. Mediator functions as a coactivator and binds to the C-terminal domain of RNA polymerase II holoenzyme, bridging this enzyme and transcription factors.<ref>{{cite journal | vauthors = Björklund S, Gustafsson CM | title = The yeast Mediator complex and its regulation | journal = Trends in Biochemical Sciences | volume = 30 | issue = 5 | pages = 240–4 | date = May 2005 | pmid = 15896741 | doi = 10.1016/j.tibs.2005.03.008 }}</ref>

== Structure == thumb|'''Figure 5''': Mediator complex architecture with focus on the disordered "spline" of MED14<ref name="Robinson e08719">{{Cite journal|last1=Robinson|first1=Philip J.|last2=Trnka|first2=Michael J.|last3=Pellarin|first3=Riccardo|last4=Greenberg|first4=Charles H.|last5=Bushnell|first5=David A.|last6=Davis|first6=Ralph|last7=Burlingame|first7=Alma L.|last8=Sali|first8=Andrej|last9=Kornberg|first9=Roger D.|date=2015-09-24|title=Molecular architecture of the yeast Mediator complex|journal=eLife|volume=4|article-number=e08719|doi=10.7554/eLife.08719|issn=2050-084X|pmc=4631838|pmid=26402457 |doi-access=free }}</ref> The yeast Mediator complex is approximately as massive as a small subunit of a eukaryotic ribosome. The yeast Mediator has 25 subunits, while the mammalian Mediator is slightly larger.<ref name=allen2015/> Mediator comprises 4 main parts: the head, middle, tail, and the transiently associated CDK8 kinase module.<ref name=":1">{{Cite journal|last=Soutourina|first=Julie|date=2017-12-06|title=Transcription regulation by the Mediator complex|journal=Nature Reviews Molecular Cell Biology|volume=19|issue=4|pages=262–274|doi=10.1038/nrm.2017.115|pmid=29209056|s2cid=3972303|issn=1471-0072}}</ref>

Mediator subunits have many intrinsically disordered regions called "splines", which may be important to allow the structural changes of Mediator that change the function of the complex.<ref name=allen2015/>{{efn|Some of those changes are diagrammed in [http://www.nature.com/nrm/journal/v16/n3/full/nrm3951.html figure 1 of the review article], which can be viewed in slightly larger form by clicking it at that site.}} Figure 5 shows the splines of the MED14 subunit connecting a large portion of the complex together while still allowing flexibility.<ref name=robinson2015/>{{efn|Note that Med 17 (shown in blue) also has that sort of spline}}

Mediator complexes lacking a subunit have been found or produced. These smaller complexes can still function normally in some activity, but lack other capabilities.<ref name=allen2015/> This indicates a somewhat independent function of some of the subunits while composing the larger complex.

Another example of structural variability is seen in vertebrates, in which 3 paralogues of subunits of the cyclin-dependent kinase (CDK) module have evolved by 3 independent gene duplication events followed by sequence divergence.<ref name=allen2015/> thumb|'''{{Visible anchor|Figure 2}}''': Mediator structural model<ref name="Robinson e08719"/>There is a report that Mediator stably associates with a particular type of non-coding RNA, ncRNA-a.<ref name="lai2013">{{cite journal|last1=Lai|first1=F |display-authors=etal|title=Activating RNAs associate with mediator to enhance chromatin architecture and transcription|journal=Nature|date=2013|volume=494|issue=7438|pages=497–501|doi=10.1038/nature11884|pmid=23417068|pmc=4109059|url=http://pubman.mpdl.mpg.de/pubman/item/escidoc:2019856/component/escidoc:2019946/Lai.pdf|bibcode=2013Natur.494..497L |hdl=11858/00-001M-0000-0019-1122-4 }}</ref>{{efn|These non-coding '''a'''ctivating RNAs have not been mentioned yet in the ncRNA article as of 16 February 2017}} These stable associations regulate gene expression ''in vivo'', and are prevented by mutations in MED12 that produce the human disease FG syndrome.<ref name="lai2013"/> Thus, the structure of a Mediator complex can be augmented by RNA as well as proteinaceous transcription factors.<ref name=allen2015/>

== Function == thumb|'''{{Visible anchor|Figure 3}}''': Structural model of Mediator's tail and middle bound to RNA polymerase II<ref name="Robinson e08719"/> Mediator was originally discovered because it was important for RNA polymerase II function, but it has many more functions than just interactions at the transcription start site.<ref name=allen2015/>

=== RNA polymerase II–Mediator core initiation complex === thumb|'''{{Visible anchor|Figure 4}}''': Model of Mediator with some transcription factors, Pol II and DNA Mediator is a crucial component for transcription initiation. Mediator interacts with the pre-initiation complex, composed of RNA Polymerase II and general transcription factors TFIIB, TFIID, TFIIE, TFIIF, and TFIIH to stabilize and initiate transcription.<ref name=":0">{{Cite journal|last1=Plaschka|first1=C.|last2=Larivière|first2=L.|last3=Wenzeck|first3=L.|last4=Seizl|first4=M.|last5=Hemann|first5=M.|last6=Tegunov|first6=D.|last7=Petrotchenko|first7=E. V.|last8=Borchers|first8=C. H.|last9=Baumeister|first9=W.|date=February 2015|title=Architecture of the RNA polymerase II–Mediator core initiation complex|journal=Nature|volume=518|issue=7539|pages=376–380|doi=10.1038/nature14229|pmid=25652824|issn=0028-0836|bibcode=2015Natur.518..376P|s2cid=4450934|url=https://resolver.sub.uni-goettingen.de/purl?gro-2/2924 |hdl=11858/00-001M-0000-0024-CED0-5|hdl-access=free}}</ref> Studies of Mediator–RNA Pol II contacts in budding yeast showed the importance of TFIIB-Mediator contacts in the formation of the complex. Interactions of Mediator with TFIID in the initiation complex has been shown.<ref name=":1" />

The structure of a core Mediator (cMed) while associated with a core pre-initiation complex was elucidated.<ref name=":0" />

===RNA synthesis=== The preinitiation complex, which contains Mediator, transcription factors, a nucleosome<ref>{{cite journal|vauthors=Nagai S, Davis RE, Mattei PJ, Eagen KP, Kornberg RD |title=Chromatin potentiates transcription|journal=Proc Natl Acad Sci U S A|date=2017|volume=114|issue=7|pages=1536–154|doi=10.1073/pnas.1620312114|pmid=28137832|pmc=5320956|doi-access=free|bibcode=2017PNAS..114.1536N }}</ref><ref>{{cite web|last1=Kornberg|first1=RD|title=The Molecular Basis of Eukaryotic Transcription|url=https://www.youtube.com/watch?v=QZIj062Pd1E&t=1414s |archive-url=https://ghostarchive.org/varchive/youtube/20211215/QZIj062Pd1E |archive-date=2021-12-15 |url-status=live|website=YouTube|date=14 January 2016 |publisher=Israel Institute for Advanced Studies|access-date=17 February 2017}}{{cbignore}}</ref>{{efn|This is the +1 nucleosome, which "covers" the transcription start site during the preinitiation phase. }} and RNA polymerase II, is important for positioning the polymerase for the start of transcription. Before RNA synthesis starts, the polymerase dissociates from Mediator. This is seemingly via phosphorylation of the polymerase by a kinase. Importantly, Mediator and transcription factors do not dissociate from the DNA when the polymerase begins transcription. Rather, the complex remains at the promoter to recruit another RNA polymerase to begin another round of transcription.<ref name="allen2015"/>{{efn|This is diagrammed in [http://www.nature.com/nrm/journal/v16/n3/full/nrm3951.html figure 2 of the review article], which can be viewed in slightly larger form by clicking it at that site.}}

There is some evidence to suggest that Mediator in ''Schizosaccharomyces pombe'' helps regulate RNA polymerase III (Pol III) transcripts of tRNAs.<ref>{{cite journal|last1=Carlsten|first1=JO|last2=Zhu X, López MD, Samuelsson T, Gustafsson CM|title=Loss of the Mediator subunit Med20 affects transcription of tRNA and other non-coding RNA genes in fission yeast|journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms|date=February 2016|volume=1859|issue=2|pages=339–347|doi=10.1016/j.bbagrm.2015.11.007|pmid=26608234}}</ref> An independent report confirmed Mediator specifically associating with Pol III in ''Saccharomyces cerevisiae''.<ref name="uthe2017">{{cite journal|vauthors=Uthe H, Vanselow JT, Schlosser A |title=Proteomic Analysis of the Mediator Complex Interactome in Saccharomyces cerevisiae|journal=Sci Rep|date=2017|volume=7|article-number=43584|doi=10.1038/srep43584|doi-access=free|pmid=28240253|pmc=5327418|bibcode=2017NatSR...743584U}}</ref> Those authors also reported specific associations with RNA polymerase I and proteins involved in transcription elongation and RNA processing, supporting other evidence of Mediator's involvement in elongation and processing.<ref name=uthe2017/>

===Chromatin organization=== Mediator is involved in chromatin looping, which brings distant regions of a chromosome into closer physical proximity.<ref name="allen2015"/> The ncRNA-a mentioned above<ref name="lai2013"/> is involved in such looping.{{efn|This is diagrammed in [http://www.nature.com/nrm/journal/v16/n3/full/nrm3951.html figure 3 of the review article], which can be viewed in slightly larger form by clicking it at that site. That figure also shows Pol II disengaged from mediator, ''etc'', which remains on the DNA}} Enhancer RNAs (eRNAs) can function similarly.<ref name="allen2015"/>

In addition to euchromatin looping, Mediator helps form or maintain heterochromatin at centromeres and telomeres.<ref name="allen2015"/>

===Signal transduction=== TGFβ signaling at the cell membrane involves two different intracellular pathways. Only one depends on MED15.{{efn|Also known as ARC105 in ''Xenopus laevis,'' the model species in which the work was done.}}<ref>{{cite journal|vauthors=Kato Y, Habas R, Katsuyama Y, Näär AM, He X |title=A component of the ARC/Mediator complex required for TGF beta/Nodal signalling|journal=Nature|date=2002|volume=418|issue=6898|pages=641–6|doi=10.1038/nature00969|pmid=12167862|bibcode=2002Natur.418..641K|s2cid=4330754}}</ref> In both human cells and ''Caenorhabditis elegans'', MED15 helps lipid homeostasis through the SREBP-containing pathway.<ref>{{cite journal|vauthors=Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, Macol C, Iyer L, Tjian R, van den Heuvel S, Hart AC, Wagner G, Näär AM |title=An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis|journal=Nature|date=2006|volume=442|issue=7103|pages=700–4|doi=10.1038/nature04942|pmid=16799563|bibcode=2006Natur.442..700Y|s2cid=4396081}}</ref> In the model plant ''Arabidopsis thaliana'', the ortholog of MED15 is required for signaling by the plant hormone salicylic acid,<ref>{{cite journal|vauthors=Canet JV, Dobón A, Tornero P |title=Non-recognition-of-BTH4, an Arabidopsis mediator subunit homolog, is necessary for development and response to salicylic acid|journal=Plant Cell|date=2012|volume=24|issue=10|pages=4220–35|doi=10.1105/tpc.112.103028|doi-access=free|pmid=23064321|pmc=3517246 |bibcode=2012PlanC..24.4220C }}</ref> while MED25 is required for the transcriptional activation of responses to hypoxia, jasmonate and shade signalling.<ref>{{cite journal |last1=Chen |first1=Rong |last2=Jiang |first2=Hongling |last3=Li |first3=Lin |last4=Zhai |first4=Qingzhe |last5=Qi |first5=Linlin |last6=Zhou |first6=Wenkun |last7=Liu |first7=Xiaoqiang |last8=Li |first8=Hongmei |last9=Zheng |first9=Wenguang |last10=Sun |first10=Jiaqiang |last11=Li |first11=Chuanyou |title=The Arabidopsis Mediator Subunit MED25 Differentially Regulates Jasmonate and Abscisic Acid Signaling through Interacting with the MYC2 and ABI5 Transcription Factors |journal=The Plant Cell |date=July 2012 |volume=24 |issue=7 |pages=2898–2916 |doi=10.1105/tpc.112.098277|pmid=22822206 |pmc=3426122 |bibcode=2012PlanC..24.2898C |doi-access=free }}</ref><ref>{{cite journal |last1=Sun |first1=Wenjing |last2=Han |first2=Hongyu |last3=Deng |first3=Lei |last4=Sun |first4=Chuanlong |last5=Xu |first5=Yiran |last6=Lin |first6=Lihao |last7=Ren |first7=Panrong |last8=Zhao |first8=Jiuhai |last9=Zhai |first9=Qingzhe |last10=Li |first10=Chuanyou |title=Mediator Subunit MED25 Physically Interacts with PHYTOCHROME INTERACTING FACTOR4 to Regulate Shade-Induced Hypocotyl Elongation in Tomato |journal=Plant Physiology |date=November 2020 |volume=184 |issue=3 |pages=1549–1562 |doi=10.1104/pp.20.00587|pmid=32938743 |pmc=7608172 |doi-access=free }}</ref><ref>{{cite journal |last1=Hartman |first1=Sjon |title=MED25 Mediates Shade-Induced Hypocotyl Elongation in Tomato |journal=Plant Physiology |date=November 2020 |volume=184 |issue=3 |pages=1217–1218 |doi=10.1104/pp.20.01324|pmid=33139486 |pmc=7608160 |doi-access=free }}</ref><ref>{{cite journal |last1=Schippers |first1=Jos H. M. |last2=von Bongartz |first2=Kira |last3=Laritzki |first3=Lisa |last4=Frohn |first4=Stephanie |last5=Frings |first5=Stephanie |last6=Renziehausen |first6=Tilo |last7=Augstein |first7=Frauke |last8=Winkels |first8=Katharina |last9=Sprangers |first9=Katrien |last10=Sasidharan |first10=Rashmi |last11=Vertommen |first11=Didier |last12=Van Breusegem |first12=Frank |last13=Hartman |first13=Sjon |last14=Beemster |first14=Gerrit T. S. |last15=Mhamdi |first15=Amna |last16=van Dongen |first16=Joost T. |last17=Schmidt-Schippers |first17=Romy R. |title=ERFVII -controlled hypoxia responses are in part facilitated by MEDIATOR SUBUNIT 25 in Arabidopsis thaliana |journal=The Plant Journal |date=11 September 2024 |volume=120 |issue=2 |pages=748–768 |doi=10.1111/tpj.17018 |pmid=39259461 |bibcode=2024PlJ...120..748S |doi-access=free |hdl=2078.1/291364 |hdl-access=free }}</ref> Two components of the CDK module (MED12 and MED13) are involved in the Wnt signaling pathway.<ref name =allen2015/> MED23 is involved in the RAS/MAPK/ERK pathway.<ref name =allen2015/> This abbreviated review shows the versatility of individual Mediator subunits, and leads to the idea that Mediator is an end-point of signaling pathways.<ref name =allen2015/>

===Human disease=== Involvement of Mediator in various human diseases has been reviewed.<ref>{{cite journal|vauthors=Clark AD, Oldenbroek M, Boyer TG |pmc=4928375|title=Mediator kinase module and human tumorigenesis|journal=Crit Rev Biochem Mol Biol|date=2015|volume=50|issue=5|pages=393–426|pmid=26182352|doi=10.3109/10409238.2015.1064854|doi-broken-date=12 July 2025}}</ref><ref>{{cite journal|vauthors=Croce S, Chibon F |title=MED12 and uterine smooth muscle oncogenesis: State of the art and perspectives|journal=Eur J Cancer|date=2015|volume=51|issue=12|pages=1603–10|doi=10.1016/j.ejca.2015.04.023|pmid=26037152}}</ref><ref>{{cite journal|vauthors=Schiano C, Casamassimi A, Rienzo M, de Nigris F, Sommese L, Napoli C |title=Involvement of Mediator complex in malignancy|journal=Biochim Biophys Acta|date=2014|volume=1845|issue=1|pages=66–83|doi=10.1016/j.bbcan.2013.12.001|pmid=24342527}}</ref><ref>{{cite journal|vauthors=Schiano C, Casamassimi A, Vietri MT, Rienzo M, Napoli C |title=The roles of mediator complex in cardiovascular diseases|journal=Biochim Biophys Acta|date=2014|volume=1839|issue=6|pages=444–51|doi=10.1016/j.bbagrm.2014.04.012|pmid=24751643}}</ref><ref>{{cite journal|vauthors=Utami KH, Winata CL, Hillmer AM, Aksoy I, Long HT, Liany H, Chew EG, Mathavan S, Tay SK, Korzh V, Sarda P, Davila S, Cacheux V |title=Impaired development of neural-crest cell-derived organs and intellectual disability caused by MED13L haploinsufficiency|journal=Hum Mutat|date=2014|volume=35|issue=11|pages=1311–20|doi=10.1002/humu.22636|pmid=25137640|s2cid=42336634|doi-access=free}}</ref><ref>{{cite journal|last1=Grueter CE|title=Mediator complex dependent regulation of cardiac development and disease|journal=Genomics Proteomics Bioinformatics|date=2013|volume=11|issue=3|pages=151–7|doi=10.1016/j.gpb.2013.05.002 |doi-access=free|pmid=23727265|pmc=4357813}}</ref><ref>{{cite journal|last1=Yang X and Yang F|title=Mediating Lipid Biosynthesis: Implications for Cardiovascular Disease|journal=Trends Cardiovasc Med|date=2013|volume=23|issue=7|pages=269–273|doi=10.1016/j.tcm.2013.03.002|pmc=3744615|pmid=23562092}}</ref><ref>{{cite journal|vauthors=Napoli C, Sessa M, Infante T, Casamassimi A |title=Unraveling framework of the ancestral Mediator complex in human diseases|journal=Biochimie|date=2012|volume=94|issue=3|pages=579–87|doi=10.1016/j.biochi.2011.09.016|pmid=21983542}}</ref><ref>{{cite journal|vauthors=Xu W, Ji JY |title=Dysregulation of CDK8 and Cyclin C in tumorigenesis|journal=J Genet Genomics|date=2011|volume=38|issue=10|pages=439–52|doi=10.1016/j.jgg.2011.09.002|pmid=22035865|pmc=9792140 }}</ref><ref>{{cite journal|vauthors=Spaeth JM, Kim NH, Boyer TG |title=Mediator and human disease|journal=Semin Cell Dev Biol|date=2011|volume=22|issue=7|pages=776–87|doi=10.1016/j.semcdb.2011.07.024|pmid=21840410|pmc=4100472}}</ref><ref>{{cite book|last1=Lyons MJ|title=MED12-Related Disorders|date=2008 |edition=08/11/2016|url=https://www.ncbi.nlm.nih.gov/books/NBK1676/|publisher=University of Washington, Seattle|pmid=20301719}}</ref>{{Excessive citations inline|date=July 2025}} Since inhibiting one interaction of a disease-causing signaling pathway with a subunit of Mediator may not inhibit general transcription needed for normal function, Mediator subunits are attractive candidates for therapeutic drugs.<ref name=allen2015/>

==Interactions== thumb|Mediator interactome in Saccharomyces cerevisiae<ref name=uthe2017/> Very gentle cell lysis in yeast followed by co-immunoprecipitation with an antibody to a MED17 has confirmed almost all previously reported or predicted interactions and revealed many previously unsuspected specific interactions of various proteins with Mediator.<ref name=uthe2017/>

== MED1 == {{Main|MED1}} [[File:BioPlexMed1c.jpg|thumb|The interaction network of MED1 protein from BioPlex 2.0]] Details of the first subunit are illustrative of the types of information that may be gathered for other subunits. See {{Section link||Subunit composition}} for them.

===Regulation by MicroRNAs=== MicroRNAs help regulate the expression of many proteins. MED1 is targeted by miR-1, which is important in gene regulation in cancers.<ref>{{cite journal|vauthors=Jiang C, Chen H, Shao L, Wang Q |title=MicroRNA-1 functions as a potential tumor suppressor in osteosarcoma by targeting Med1 and Med31|journal=Oncol Rep|date=2014|volume=32|issue=3|pages=1249–56|doi=10.3892/or.2014.3274|pmid=24969180|doi-access=free}}</ref> The tumor suppressor miR-137 also regulates MED1.<ref>{{cite journal|vauthors=Nilsson EM, Laursen KB, Whitchurch J, McWilliam A, Ødum N, Persson JL, Heery DM, Gudas LJ, Mongan NP |title=MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators|journal=Oncotarget|date=2015|volume=6|issue=34|pages=35710–25|doi=10.18632/oncotarget.5958|pmid=26461474|pmc=4742136}}</ref>

===Mouse embryonic development=== Null mutants die early (embryonic day 11.5).<ref>{{cite journal|vauthors=Ito M, Yuan CX, Okano HJ, Darnell RB, Roeder RG |title=Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action|journal=Mol Cell|date=2000|volume=5|issue=4|pages=683–93|doi=10.1016/S1097-2765(00)80247-6|pmid=10882104|doi-access=free}}</ref><ref name="land2003">{{cite journal|last1=Landles C, Chalk S, Steel JH, Rosewell I, Spencer-Dene B, Lalani el-N, Parker MG|title=The thyroid hormone receptor-associated protein TRAP220 is required at distinct embryonic stages in placental, cardiac, and hepatic development|journal=Mol Endocrinol|date=2003|volume=17|issue=12|pages=2418–35|doi=10.1210/me.2003-0097|pmid=14500757|doi-access=free}}</ref> Investigating hypomorphic mutants (which survive 2 days longer) found that placental defects were primarily lethal and that there were also defects in cardiac and hepatic development, but many other organs were normal.<ref name=land2003/>

===Mouse cells and tissues=== thumb|A Mediator mutation causes hairy teeth in mice In mice, conditional mutations can be produced to affect only specific cells or tissues at specific times, so that the mouse can develop to adulthood to have its adult phenotype studied. In one case, MED1 was found to participate in controlling the timing of events of meiosis in male mice.<ref>{{cite journal|vauthors=Huszar JM, Jia Y, Reddy JK, Payne CJ |title=Med1 regulates meiotic progression during spermatogenesis in mice|journal=Reproduction|date=2015|volume=149|issue=6|pages=597–604|doi=10.1530/REP-14-0483|pmid=25778538|pmc=4417004}}</ref> Conditional mutants in keratinocytes differ in skin wound healing.<ref>{{cite journal|vauthors=Noguchi F, Nakajima T, Inui S, Reddy JK, Itami S |title=Alteration of skin wound healing in keratinocyte-specific mediator complex subunit 1 null mice|journal=PLOS ONE|date=2014|volume=9|issue=8|article-number=e102271|doi=10.1371/journal.pone.0102271|doi-access=free|pmid=25122137|pmc=4133190|bibcode=2014PLoSO...9j2271N}}</ref> A conditional mutation in mice changed dental epithelium into epidermal epithelium, which caused hair to grow beside the incisors.<ref>{{cite journal|vauthors=Yoshizaki K, Hu L, Nguyen T, Sakai K, He B, Fong C, Yamada Y, Bikle DD, Oda Y |title=Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair|journal=PLOS ONE|date=2014|volume=9|issue=6|article-number=e99991|doi=10.1371/journal.pone.0099991|doi-access=free|pmid=24949995|pmc=4065011|bibcode=2014PLoSO...999991Y}}</ref>

== Subunit composition ==

The Mediator complex is composed of at least 31 subunits in all eukaryotes studied: MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED28, MED29, MED30, MED31, CCNC, and CDK8. There are three fungal-specific components, referred to as MED2, MED3 and MED5.<ref name="Bourbon_2004">{{cite journal | vauthors = Bourbon HM, Aguilera A, Ansari AZ, Asturias FJ, Berk AJ, Bjorklund S, Blackwell TK, Borggrefe T, Carey M, Carlson M, Conaway JW, Conaway RC, Emmons SW, Fondell JD, Freedman LP, Fukasawa T, Gustafsson CM, Han M, He X, Herman PK, Hinnebusch AG, Holmberg S, Holstege FC, Jaehning JA, Kim YJ, Kuras L, Leutz A, Lis JT, Meisterernest M, Naar AM, Nasmyth K, Parvin JD, Ptashne M, Reinberg D, Ronne H, Sadowski I, Sakurai H, Sipiczki M, Sternberg PW, Stillman DJ, Strich R, Struhl K, Svejstrup JQ, Tuck S, Winston F, Roeder RG, Kornberg RD | display-authors = 6 | title = A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II | journal = Molecular Cell | volume = 14 | issue = 5 | pages = 553–7 | year = 2004 | pmid = 15175151 | doi = 10.1016/j.molcel.2004.05.011 | doi-access = free }}</ref>

The subunits form at least three structurally distinct submodules. The head and the middle modules interact directly with RNA polymerase II, whereas the elongated tail module interacts with gene-specific regulatory proteins. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation.

*The head module contains: MED6, MED8, MED11, SRB4/MED17, SRB5/MED18, ROX3/MED19, SRB2/MED20 and SRB6/MED22. *The middle module contains: MED1, MED4, NUT1/MED5, MED7, CSE2/MED9, NUT2/MED10, SRB7/MED21 and SOH1/MED31. CSE2/MED9 interacts directly with MED4. *The tail module contains: MED2, PGD1/MED3, RGR1/MED14, GAL11/MED15 and SIN4/MED16. *The CDK8 module contains: MED12, MED13, CCNC and CDK8. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.

== In other species ==

Below is a cross-species comparison of Mediator complex subunits.<ref name="Bourbon_2004" /><ref>Gene names derived from {{cite web | title = UniProtKB | url = https://www.uniprot.org/uniprot/ | access-date = 12 October 2012 }}</ref>

{| class="wikitable sortable" border="1"

!'''Subunit No.''' !Human gene !''C. elegans'' gene !''D. melanogaster'' gene !''S. cerevisiae'' gene !''Sch. pombe'' gene

|- | MED1 || MED1 || Sop3/mdt-1.1, 1.2 ||MED1 ||MED1 ||med1

|-

| MED2{{efn|name=Fungal|Fungal-specific}} || || || ||MED2 ||

|-

| MED3{{efn|name=Fungal}}|| || || ||PGD1 ||

|-

| MED4 || MED4 || || MED4|| MED4|| med4

|-

| MED5{{efn|name=Fungal}}|| || || || NUT1|| |-

| MED6 || MED6 || MDT-6 || MED6|| MED6||med6 |-

| MED7 || MED7 ||MDT-7/let-49 || MED7||MED7 ||med7 |-

|MED8 || MED8 || MDT-8 || MED8||MED8||med8 |-

|MED9 || MED9 || || MED9|| CSE2|| |-

|MED10 || MED10 || MDT-10 || ||NUT2 ||med10 |-

|MED11|| MED11 || MDT-11 || MED11||MED11 ||med11 |-

|MED12|| MED12 || MDT-12/dpy-22 ||MED12 || SRB8||srb8 |-

|MED12L|| MED12L || || || || |-

|MED13|| MED13 || MDT-13/let-19 ||MED13 ||SSN2 || srb9 |-

|MED14 || MED14 || MDT-14/rgr-1 || MED14||RGR1||med14 |-

|MED15|| MED15 || mdt-15|| MED15|| GAL11||YN91_SCHPO{{efn|name=spb|Protein-name in ''Sch. pombe''}} |-

|MED16 || MED16 || || MED16||SIN4|| |-

|MED17 || MED17|| MDT-17 || MED17||SRB4 ||med17 |-

|MED18 || MED18 || MDT-18 || MED18||SRB5 ||med18 |-

|MED19 || MED19|| MDT-19 || MED19|| ROX3<ref name="Bourbon_2004" /> | med19 |-

|MED20 || MED20 || MDT-20 || MED20||SRB2 ||med20 |-

|MED21 || MED21 || MDT-21 || MED21||SRB7 ||med21 |-

|MED22 || MED22 || MDT-22 || MED22||SRB6 ||med22 |-

|MED23 || MED23 ||MDT-23/sur-2 || MED23|| || |-

|MED24 || MED24 || || MED24|| || |-

|MED25 || MED25 || || MED25|| || |-

|MED26 || MED26 || || MED26|| || |-

|MED27 || MED27 || || MED27|| ||med27 |-

|MED28 || MED28 || || MED28|| || |-

|MED29 || MED29 || MDT-19 || MED29|| || |-

|MED30|| MED30 || || MED30|| || |-

|MED31 ||MED31 || MDT-31|| MED31||SOH1 ||med31 |-

| CCNC||CCNC || cic-1||CycC ||SSN8 ||pch1 |-

| CDK8||CDK8 ||cdk-8|| Cdk8||SSN3 || srb10 |-

|}

==Notes== {{notelist|35em}}

== References == {{reflist|35em}}

{{Transcription coregulators}}

Category:Protein complexes Category:Gene expression