MED15 explained

Mediator of RNA polymerase II transcription subunit 15, also known as Gal11, Spt13 in yeast and PCQAP, ARC105, or TIG-1 in humans is a protein encoded by the MED15 gene.^[1]

Function

MED15 is a general transcriptional cofactor of the mediator complex involved in RNA polymerase II dependent transcription, originally called Gal11 and Spt13 and found in yeast as an essential factor for Gal4 dependent transactivation by T.Fukasawa and F.Winston labs. Transcription factors Gcn4, Pho4, Msn2, Ino2, members of the Gal4 family - Gal4, Oaf1, Pdr1, and viral VP16 have been reported to interact with yeast MED15.^[2]

Most of these transcription factors share the same transactivation domain, 9aaTAD, which directly interacts with KIX domain of the MED15.^[3]

Furthermore, human MED15 cooperates in mediator complex (previously known as PC2, ARC, or DRIP) with transcription factors like VP16 and SREBP. Human SREBP regulates sterol responsive gene expression, and this regulatory action is conserved in the genetic model organism C. elegans, a roundworm (homologues MDT-15 and SBP-1). Also in C. elegans, MDT-15 is essential for the response to several stresses (fasting, heavy metal, toxin, and oxidative stress); at least in part the fasting response is conferred by interactions of MDT-15 with nuclear receptors, including NHR-49.

Gene

The MED15 gene contains stretches of trinucleotide repeats and is located in the chromosome 22 region which is deleted in DiGeorge's syndrome. Two transcript variants encoding different isoforms have been found for this gene.^[1]

Further reading

• Taubert S, Hansen M, Van Gilst MR, Cooper SB, Yamamoto KR . The Mediator subunit MDT-15 confers metabolic adaptation to ingested material . PLOS Genetics . 4 . 2 . e1000021 . Feb 2008 . 18454197 . 2265483 . 10.1371/journal.pgen.1000021 . Mango . Susan E. . free .
• Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS, Stine OC, Callahan C, McInnis MG, Ross CA . cDNAs with long CAG trinucleotide repeats from human brain . Human Genetics . 100 . 1 . 114–22 . Jul 1997 . 9225980 . 10.1007/s004390050476 . 25999127 .
• Näär AM, Beaurang PA, Zhou S, Abraham S, Solomon W, Tjian R . Composite co-activator ARC mediates chromatin-directed transcriptional activation . Nature . 398 . 6730 . 828–32 . Apr 1999 . 10235267 . 10.1038/19789 . 1999Natur.398..828N . 23646963 .
• Taubert S, Van Gilst MR, Hansen M, Yamamoto KR . A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans . Genes & Development . 20 . 9 . 1137–49 . May 2006 . 16651656 . 1472473 . 10.1101/gad.1395406 .
• Abraham S, Solomon WB . A novel glutamine-rich putative transcriptional adaptor protein (TIG-1), preferentially expressed in placental and bone-marrow tissues . Gene . 255 . 2 . 389–400 . Sep 2000 . 11024300 . 10.1016/S0378-1119(00)00292-4 .
• Berti L, Mittler G, Przemeck GK, Stelzer G, Günzler B, Amati F, Conti E, Dallapiccola B, Hrabé de Angelis M, Novelli G, Meisterernst M . Isolation and characterization of a novel gene from the DiGeorge chromosomal region that encodes for a mediator subunit . Genomics . 74 . 3 . 320–32 . Jun 2001 . 11414760 . 10.1006/geno.2001.6566 .
• Kato Y, Habas R, Katsuyama Y, Näär AM, He X . A component of the ARC/Mediator complex required for TGF beta/Nodal signalling . Nature . 418 . 6898 . 641–6 . Aug 2002 . 12167862 . 10.1038/nature00969 . 2002Natur.418..641K . 4330754 .
• De Luca A, Conti E, Grifone N, Amati F, Spalletta G, Caltagirone C, Bonaviri G, Pasini A, Gennarelli M, Stefano B, Berti L, Mittler G, Meisterernst M, Dallapiccola B, Novelli G . Association study between CAG trinucleotide repeats in the PCQAP gene (PC2 glutamine/Q-rich-associated protein) and schizophrenia . American Journal of Medical Genetics Part B . 116B . 1 . 32–5 . Jan 2003 . 12497610 . 10.1002/ajmg.b.10008 . 28657663 .
• Zhang J, Liu L, Pfeifer GP . Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene . Oncogene . 23 . 12 . 2241–9 . Mar 2004 . 14691453 . 10.1038/sj.onc.1207328 . free .
• Yang F, DeBeaumont R, Zhou S, Näär AM . The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator . Proceedings of the National Academy of Sciences of the United States of America . 101 . 8 . 2339–44 . Feb 2004 . 14983011 . 356952 . 10.1073/pnas.0308676100 . 2004PNAS..101.2339Y . free .
• Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC . A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology . Molecular Cell . 14 . 5 . 685–91 . Jun 2004 . 15175163 . 10.1016/j.molcel.2004.05.006 . free .
• Sandhu HK, Hollenbeck N, Wassink TH, Philibert RA . An association study of PCQAP polymorphisms and schizophrenia . Psychiatric Genetics . 14 . 3 . 169–72 . Sep 2004 . 15318033 . 10.1097/00041444-200409000-00010 . 45479038 .
• Kwong J, Lo KW, Chow LS, Chan FL, To KF, Huang DP . Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma . International Journal of Cancer . 113 . 3 . 386–92 . Jan 2005 . 15455391 . 10.1002/ijc.20593 . 11628354 .
• Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I . A genome annotation-driven approach to cloning the human ORFeome . Genome Biology . 5 . 10 . R84 . 2005 . 15461802 . 545604 . 10.1186/gb-2004-5-10-r84 . free .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . free .
• 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 . An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis . Nature . 442 . 7103 . 700–4 . Aug 2006 . 16799563 . 10.1038/nature04942 . 2006Natur.442..700Y . 4396081 .
• Ishikawa H, Tachikawa H, Miura Y, Takahashi N . TRIM11 binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105) through the ubiquitin-proteasome system . FEBS Letters . 580 . 20 . 4784–92 . Sep 2006 . 16904669 . 10.1016/j.febslet.2006.07.066 . 33550003 .

Notes and References

1. Web site: Entrez Gene: PCQAP PC2 (positive cofactor 2, multiprotein complex) glutamine/Q-rich-associated protein.
2. Suzuki Y, Nogi Y, Abe A, Fukasawa T . GAL11 protein, an auxiliary transcription activator for genes encoding galactose-metabolizing enzymes in Saccharomyces cerevisiae . Molecular and Cellular Biology . 8 . 11 . 4991–9 . Nov 1988 . 3062377 . 365593 . 10.1128/mcb.8.11.4991.

   Fassler JS, Winston F . The Saccharomyces cerevisiae SPT13/GAL11 gene has both positive and negative regulatory roles in transcription . Molecular and Cellular Biology . 9 . 12 . 5602–9 . Dec 1989 . 2685570 . 363730 . 10.1128/mcb.9.12.5602.

   Swanson MJ, Qiu H, Sumibcay L, Krueger A, Kim SJ, Natarajan K, Yoon S, Hinnebusch AG . A multiplicity of coactivators is required by Gcn4p at individual promoters in vivo . Molecular and Cellular Biology . 23 . 8 . 2800–20 . Apr 2003 . 12665580 . 152555 . 10.1128/MCB.23.8.2800-2820.2003 .

   Bryant GO, Ptashne M . Independent recruitment in vivo by Gal4 of two complexes required for transcription . Molecular Cell . 11 . 5 . 1301–9 . May 2003 . 12769853 . 10.1016/S1097-2765(03)00144-8 . free .

   Jedidi I, Zhang F, Qiu H, Stahl SJ, Palmer I, Kaufman JD, Nadaud PS, Mukherjee S, Wingfield PT, Jaroniec CP, Hinnebusch AG . Activator Gcn4 employs multiple segments of Med15/Gal11, including the KIX domain, to recruit mediator to target genes in vivo . The Journal of Biological Chemistry . 285 . 4 . 2438–55 . Jan 2010 . 19940160 . 2807301 . 10.1074/jbc.M109.071589 . free .

   Thakur JK, Arthanari H, Yang F, Chau KH, Wagner G, Näär AM . Mediator subunit Gal11p/MED15 is required for fatty acid-dependent gene activation by yeast transcription factor Oaf1p . The Journal of Biological Chemistry . 284 . 7 . 4422–8 . Feb 2009 . 19056732 . 10.1074/jbc.M808263200 . 3837390 . free .

3. Piskacek S, Gregor M, Nemethova M, Grabner M, Kovarik P, Piskacek M . Nine-amino-acid transactivation domain: establishment and prediction utilities . Genomics . 89 . 6 . 756–68 . Jun 2007 . 17467953 . 10.1016/j.ygeno.2007.02.003 .

   Piskacek M . Common Transactivation Motif 9aaTAD recruits multiple general co-activators TAF9, MED15, CBP and p300 . Nature Precedings . November 2009 . 10.1038/npre.2009.3488.2 . free .

   Thakur JK, Arthanari H, Yang F, Chau KH, Wagner G, Näär AM . Mediator subunit Gal11p/MED15 is required for fatty acid-dependent gene activation by yeast transcription factor Oaf1p . The Journal of Biological Chemistry . 284 . 7 . 4422–8 . Feb 2009 . 19056732 . 10.1074/jbc.M808263200 . 3837390 . free .

   Piskacek M . 9aaTAD Prediction result (2006) . Nature Precedings . November 2009 . 10.1038/npre.2009.3984.1 . free .

   Piskacek M . Common Transactivation Motif 9aaTAD recruits multiple general co-activators TAF9, MED15, CBP and p300 . Nature Precedings . November 2009 . 10.1038/npre.2009.3488.2 . free .

   Piskacek M . 9aaTADs mimic DNA to interact with a pseudo-DNA Binding Domain KIX of Med15 (Molecular Chameleons) . Nature Precedings . November 2009 . 10.1038/npre.2009.3939.1 . free .