Cited by 386Genomics and Chromatin DynamicsNuclear Structure and FunctionChromatin Remodeling and Cancer

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A mediator required for activation of RNA polymerase II transcription in vitro

Flanagan, Peter M., Kelleher, Raymond J., Sayre, Michael H., Tschochner, Herbert, Kornberg, Roger D.·1991·Nature

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Abstract

Activator proteins bind to enhancer DNA elements and stimulate the initiation of transcription. It has been proposed that activators contact general initiation factors at a promoter, and evidence for such direct interaction has been obtained. Studies of transcription in vitro, however, have suggested that activators might function through an intermediary molecule(s) distinct from the general factors. In the first of these studies, we exploited the finding that one activator could inhibit transcription stimulated by a second activator (activator interference or 'squelching'). This inhibition, which is attributed to competition between the activators for a common target factor, could not be relieved by addition of a large excess of general initiation factors, suggesting that the target for which activators compete is distinct from these factors. Similar conclusions came from the observation that TFIID's expressed from cloned genes fail to replace partially purified 'natural' TFIID fractions in supporting activation, evidently because they lacked some component present in the impure fractions. While these lines of evidence for a novel 'mediator' of activation were negative, we also showed that a partially purified fraction from yeast would reverse activator interference. This positive effect of a presumptive mediator provided an assay for its activity, but its role in activation was still only inferred. We now present direct evidence for a mediator which is required for stimulation of transcription in vitro by the activators GAL4-VP16 and GCN4, but which has no effect on transcription in the absence of activator protein.

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Background
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Background
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BackgroundMethodInfluential
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BackgroundMethodInfluentialSelf-citation
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Background
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Background
Specific functions for Mediator complex subunits from different modules in the transcriptional response of Arabidopsis thaliana to abiotic stress
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Background
Transcriptional activation by herpes simplex virus type 1 VP16 in vitro and its inhibition by oligopeptides
Wu, T.-J., Monokian, G., Mark, D., & Wobbe, C. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.5.3484-3493.1994 · Cited by 42
“Despite such intensive study, the mechanism of action of this prototypic activation domain-whether it acts directly on a basal transcription factor (27, 39, 40, 57), indirectly on basal factors via an intermediary molecule (4, 5, 18, 30, 63), or via displacement of histones (15, 36)-remains hotly debated.”
Background
A comprehensive insight on the recent development of Cyclic Dependent Kinase inhibitors as anticancer agents
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“A pure yeast in vitro transcription system consisting of pol II and all the general transcription factors (GTFs) cannot be stimulated by activators in the absence of Mediator (2,3).”
Background
Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells
Rahman, S., Jones, M. V., & Jallepalli, P. V. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505323112 · Cited by 50
“This dominant-negative effect is analogous to “squelching” by transcriptional activators (43, 44) and suggests that these mutants competitively titrate or displace a limiting corepressor from Esco1 target genes.”
Med1 Subunit of the Mediator Complex in Nuclear Receptor-Regulated Energy Metabolism, Liver Regeneration, and Hepatocarcinogenesis
Jia, Y., Viswakarma, N., & Reddy, J. K. (2014) · Gene Expression · doi:10.3727/105221614x13919976902219 · Cited by 54
The molecular basis of eucaryotic transcription
Kornberg, R. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402251 · Cited by 38
Self-citation
The classical srb4-138 mutant allele causes dissociation of yeast Mediator.
Linder, T., Zhu, X., Baraznenok, V., & Gustafsson, C. (2006) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2006.08.099 · Cited by 38
Functional interplay between Mediator and TFIIB in preinitiation complex assembly in relation to promoter architecturePreprint
Eychenne, T., Novikova, E., Barrault, M., Alibert, O., Boschiero, C., Peixeiro, N., Cornu, D., Redeker, V., Kuras, L., Nicolas, P., et al. (2016) · Genes & Development · doi:10.1101/gad.285775.116 · Cited by 44
Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types
Syring, I., Klümper, N., Offermann, A., Braun, M., Deng, M., Boehm, D., Queisser, A., von Mässenhausen, A., Brägelmann, J., Vogel, W., et al. (2016) · OncoTarget · doi:10.18632/oncotarget.8469 · Cited by 36
“While the head, middle and tail modules form a stable core complex [3], the kinase module, consisting of the Mediator subunits MED12 and MED13, the cyclindependent kinase 8 (CDK8) and Cyclin C, associates reversibly with the core complex [4].”
Background
Genetic evidence for the interaction of the yeast transcriptional co-activator proteins GCN5 and ADA2
Georgakopoulos, T., Gounalaki, N., & Thireos, G. (1995) · Molecular and General Genetics MGG · doi:10.1007/bf00290718 · Cited by 36
“The existence of such factors, termed mediators or adaptors, which confer the ability to respond to activator proteins in reconstituted systems, has been shown in both yeast and mammalian systems (Kelleher et al. 1990; Flanagan et al. 1991; Kretzschmer et al. 1993).”
Background
Mechanistic advances in eukaryotic gene activation.
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The Structures of Eukaryotic Transcription Pre-initiation Complexes and Their Functional Implications
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“Mediator integrates the signals from transcriptional activators and repressors for regulated transcription initiation (Borggrefe and Yue 2011; Brzovic et al. 2011; Flanagan et al. 1991; Subcell Biochem.”
Background
Molecular architecture of enhancer–promoter interaction
Hamamoto, K., & Fukaya, T. (2022) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2022.01.003 · Cited by 58
Emerging functions of multi-protein complex Mediator with special emphasis on plants
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Recent developments in hepatitis delta virus research.
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The tail-module of yeast Mediator complex is required for telomere heterochromatin maintenance
Peng, J., & Zhou, J. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr757 · Cited by 34
Properties of initiator-associated transcription mediated by GAL4-VP16
Chang, C., & Gralla, J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.12.7469-7475.1993 · Cited by 33
“and GAL4-p53(1-73) produces about half of the GAL4-VP16 activity (data not shown).”
BackgroundInfluential
MED29, a component of the mediator complex, possesses both oncogenic and tumor suppressive characteristics in pancreatic cancer
Kuuselo, R., Savinainen, K., Sandström, S., Autio, R., & Kallioniemi, A. H. (2011) · International Journal of Cancer · doi:10.1002/ijc.25924 · Cited by 37
“The Mediator complex is a large multiprotein coactivator that was originally identified in Saccharomyces cerevisiae when it was discovered that activators and the general transcription machinery alone were not sufficient to activate transcription in vitro.(5) Mediator acts as a link between transcriptional activators…”
Background
Interaction map of Arabidopsis Mediator complex expounding its topology
Maji, S., Dahiya, P., Waseem, M., Dwivedi, N., Bhat, D. S., Dar, T. U. H., & Thakur, J. K. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz122 · Cited by 39
“Mediator is a multi-subunit protein complex originally discovered in yeast as a molecular bridge between enhancerbound transcription factors (TFs) and RNA pol II (1,2).”
Background
Sequence and expression analyses of KIX domain proteins suggest their importance in seed development and determination of seed size in rice, and genome stability in Arabidopsis
Thakur, J. K., Agarwal, P., Parida, S. K., Bajaj, D., & Pasrija, R. (2013) · Molecular Genetics and Genomics · doi:10.1007/s00438-013-0753-9 · Cited by 44
The Eukaryotic Gene Transcription Machinery
Kornberg, R. (2001) · Biological chemistry · doi:10.1515/bc.2001.140 · Cited by 31
“We and others cloned and sequenced genes for all 25 subunits of the GTFs.”
BackgroundInfluentialSelf-citation
Regulation of SREBP-Mediated Gene Expression
Zhao, X.-P., & Yang, F.-J. (2012) · Sheng Wu Wu Li Hsueh Bao · doi:10.3724/sp.j.1260.2012.20034 · Cited by 31
Intrinsic Disorder in Plant Transcription Factor Systems: Functional Implications
Salladini, E., Jørgensen, M. L. M., Theisen, F. F., & Skriver, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249755 · Cited by 34
“The gigantic multi-subunit complex Mediator (MED) is a key transcriptional co-activator in eukaryotic cells, which links information from TFs with the central transcriptional machinery, thereby fine- tuning transcriptional reprogramming [152,153].”
Background
Molecular determinants of MED1 interaction with the DNA bound VDR–RXR heterodimer
Belorusova, A. Y., Bourguet, M., Hessmann, S., Chalhoub, S., Kieffer, B., Cianférani, S., & Rochel, N. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa775 · Cited by 40
“It was discovered as a group of factors needed for the yeast RNA polymerase II activity (6,7), and subsequently various mammalian Mediator subcomplexes have been isolated through association with NRs, such as TRAP complex associated with thyroid receptor (TR), (8) and DRIP complex associated with vitamin D receptor (V…”
Background
Mediating lipid biosynthesis: Implications for cardiovascular disease
Xiaoli, & Yang, F. (2013) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2013.03.002 · Cited by 27
Maize transcription factor Zmdof1 involves in the regulation of Zm401 gene
Chen, X., Wang, D.-X., Liu, C., Wang, M.-Z., Wang, T., Zhao, Q., & Yu, J.-J. (2012) · Plant growth regulation (Print) · doi:10.1007/s10725-011-9651-5 · Cited by 28
“Mediator was first found in yeast as a co-regulator required for transcriptional activation (Flanagan et al. 1991) and was recently identified within the plant kingdom in Arabidopsis thaliana (Bäckström et al.”
Background
Functional Interactions within Yeast Mediator and Evidence of Differential Subunit Modifications*
Balčiūnas, D., Hallberg, M., Björklund, S., & Ronne, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m206946200 · Cited by 28
Yeast RNA polymerase II holoenzyme.
Li, Y. I., Björklund, S., Kim, Y.-J., & Kornberg, R. (1996) · Methods in Enzymology · doi:10.1016/s0076-6879(96)73017-3 · Cited by 28
Self-citation
Identification of the Hypoxia-inducible Factor 2α Nuclear Interactome in Melanoma Cells Reveals Master Proteins Involved in Melanoma Development
Steunou, A., Ducoux‐Petit, M., Lazar, I., Monsarrat, B., Érard, M., Muller, C., Clottes, E., Burlet‐Schiltz, O., & Nieto, L. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m112.020727 · Cited by 35
“Almost all of the subunits thought to be part of the mediator complex were identified, which is remarkable, as these proteins are usually found in small amounts in cells (28).”
The molecular basis of eukaryotic transcription (Nobel Lecture).
Kornberg, R. (2007) · Angewandte Chemie · doi:10.1002/anie.200701832 · Cited by 27
Self-citation
Med15: Glutamine-Rich Mediator Subunit with Potential for Plasticity
Cooper, D. G., & Fassler, J. S. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.03.008 · Cited by 31
Replication of human hepatitis delta virus: influence of studies on subviral plant pathogens.
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Origin and evolution of jasmonate signaling
Schluttenhofer, C. M. (2020) · Plant Science · doi:10.1016/j.plantsci.2020.110542 · Cited by 23
VP16 fusion induces the multiple‐knockout phenotype of redundant transcriptional repressors partly by Med25‐independent mechanisms in Arabidopsis
Fujiwara, S., Sakamoto, S., Kigoshi, K., Suzuki, K., & Ohme‐Takagi, M. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.08.010 · Cited by 29
“Mediator, first identified in Saccharomyces cerevisiae [18,8], is the central coactivator of transcription in eukaryotes ranging from yeast to humans [37].”
Background
Yeast transcription factors
Struhl, K. (1993) · Current Opinion in Cell Biology · doi:10.1016/0955-0674(93)90018-l · Cited by 24
The Mediator complex subunit MED25 interacts with HDA9 and PIF4 to regulate thermomorphogenesis
Shapulatov, U., van Zanten, M., van Hoogdalem, M., Meisenburg, M., van Hall, A., Kappers, I., Fasano, C., Facella, P., Loh, C. C., Perrella, G., et al. (2022) · Plant Physiology · doi:10.1093/plphys/kiac581 · Cited by 24
“Mediator of RNA polymerase II transcription (Mediator) is a multi-subunit protein complex originally discovered in yeast ( Saccharomyces cerevisiae ) that functions as a co-regulator of transcription (Flanagan et al., 1991; Kim et al., 1994).”
Crosstalk of promoter and terminator during RNA polymerase II transcription cycle
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MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression
Donnio, L.-M., Bidon, B., Hashimoto, S., May, M., Epanchintsev, A., Ryan, C. M., Allen, W., Hackett, A., Gécz, J., Skinner, C., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx099 · Cited by 24
Regulation of transcription in eukaryotes by DNA-binding proteins
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High-throughput affinity measurements of direct interactions between activation domains and co-activatorsPreprint
DelRosso, N. V., Suzuki, P., Griffith, D., Lotthammer, J. M., Novak, B., Kocalar, S., Sheth, M. U., Holehouse, A. S., Bintu, L., & Fordyce, P. M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.19.608698 · Cited by 23
“…P300 14 ), recruiting and/or regulating RNA Polymerase II activity ( e.g. the TATA-binding protein complex TFIID 15 and the Mediator complex 16 , which is recruited by the majority of yeast ADs 17 ), or by regulating transcriptional elongation ( e.g. bromodomain-containing proteins 18,19 ).”
Background
Mediator Complex Dependent Regulation of Cardiac Development and Disease
Grueter, C. E. (2013) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2013.05.002 · Cited by 20
Heterogeneous Nuclear Ribonucleoprotein R Enhances Transcription from the Naturally Configured c-fos Promoter in Vitro*
Fukuda, A., Nakadai, T., Shimada, M., & Hisatake, K. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.013656 · Cited by 23

Authors: Flanagan, P. M., Kelleher, R. J., Sayre, M. H., Tschochner, H., & Kornberg, R. D.
Affiliations: Stanford Medicine (US)
ORCID: Tschochner, Herbert
Kornberg, Roger D.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1991-04
Volume: 350
Issue: 6317
Pages: 436-438
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/350436a0
OpenAlex: W2062439115
Cited by: 386
References: 0
Citations by year: 2026: 1 · 2025: 8 · 2024: 9 · 2023: 3 · 2022: 10 · 2021: 13 · 2020: 21 · 2019: 11 · 2018: 9 · 2017: 11 · 2016: 11 · 2015: 8 · 2014: 5 · 2013: 15 · 2012: 9
FWCI: 11.51
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords: RNA polymerase II transcription, transcriptional activator, Mediator complex, TFIID, GAL4-VP16, GCN4, enhancers, transcriptional activation, yeast
MeSH terms: DNA-Binding Proteins, Enzyme Activation, Fungal Proteins, Nuclear Proteins, Recombinant Proteins, RNA Polymerase II, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Saccharomyces cerevisiae Proteins, Transcription Factor TFIID, In Vitro Techniques

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A mediator required for activation of RNA polymerase II transcription in vitro

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