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Chemical Compound Review

Mediator     2-[1-[3-(trifluoromethyl) phenyl]propan-2...

Synonyms: Mediaxal, Balans, Lipophoral, Benfluorex HCl, Prestwick_911, ...
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Disease relevance of Benfluramate

  • Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein [1].
  • This human Srb/Mediator complex stimulates transcription in vitro in response to both the E1A zinc-finger and the herpes simplex virus VP16 activation domains [1].
  • Yeast Mediator proteins interacting with Med17(Srb4) have been expressed at a high level with the use of recombinant baculoviruses and recovered in homogeneous form as a seven subunit, 223 kDa complex [2].
  • Surprisingly, the HIV promoter in unactivated Jurkat T cells is partially occupied and carries Mediator containing the CDK8 repressive module, TFIID and RNAP II that is hypophosphorylated and confined to the promoter region [3].
  • Here we demonstrate that KSHV RTA recruits CBP, the SWI/SNF chromatin remodeling complex, and the TRAP/Mediator coactivator into viral promoters through interactions with a short acidic sequence in the carboxyl region and that this recruitment is essential for RTA-dependent viral gene expression [4].

Psychiatry related information on Benfluramate


High impact information on Benfluramate

  • Additional outstanding questions include the patterns of promoter-specificity of the various Mediator subunits, the possible cell-type-specificity of Mediator subunit composition, and the full structures of both free Mediator and RNA polymerase II holoenzyme [6].
  • We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex [7].
  • Essential components of the eukaryotic transcription apparatus include RNA polymerase II, a common set of initiation factors, and a Mediator complex that transmits regulatory information to the enzyme [8].
  • The TRAP (thyroid hormone receptor-associated proteins) transcription coactivator complex (also known as Mediator) was first isolated as a group of proteins that facilitate the function of the thyroid hormone receptor [9].
  • A component of the ARC/Mediator complex required for TGF beta/Nodal signalling [10].

Chemical compound and disease context of Benfluramate


Biological context of Benfluramate

  • Here we show that the E1A zinc-finger domain that is required to activate transcription of viral early genes binds to a host-cell multiprotein complex containing homologues of yeast Srb/Mediator proteins [1].
  • Here we have used RNA interference (RNAi) in Drosophila cells to selectively deplete subunits of the MED and TFIID complexes to dissect the contribution of each of these complexes in modulating activated transcription [13].
  • Experiments examining the kinetics of binding show that Mediator binds to HO promoter elements 1.5 kb upstream of the transcription start site in early G1, but this binding occurs without RNA Pol II [14].
  • Swi/Snf is required for Mediator binding, and genetic suppression experiments suggest that Swi/Snf and Mediator act in the same genetic pathway of HO activation [14].
  • Here we report that the Mediator protein Mrc1, which is required for normal DNA replication and for activation of Rad53, is present at replication forks [15].

Anatomical context of Benfluramate

  • All these events are abolished in Med1/Trap220 null cells, indicating a key role for TRAP/Mediator in these processes [16].
  • These findings support the idea of Mediator as a primary conduit of regulatory information from enhancers to promoters in eukaryotic cells [17].
  • The physiological relevance of the in vitro interaction is documented further by the isolation of an ERalpha-TRAP/Mediator complex from cultured cells expressing an epitope-tagged ERalpha [18].
  • Studies with extracts from TRAP220(-/-) fibroblasts reveal that these interactions depend on TRAP220, a TRAP/Mediator subunit previously shown to interact with ER and other nuclear receptors in a ligand-dependent manner [18].
  • Quantitative immunoblotting indicated that there are about 3 x 10(5) to 6 x 10(5) molecules of hSur2 Mediator subunit per HeLa cell, i.e., the same order of magnitude as RNA polymerase II and general transcription factors [19].

Associations of Benfluramate with other chemical compounds


Gene context of Benfluramate

  • The cdk8/cyclin C protein complex is also found in a number of mammalian Mediator-like protein complexes, which repress activated transcription independently of the CTD in vitro [25].
  • Human TRAP/Mediator is a key coactivator for many transcription factors that act through direct interactions with distinct subunits, and MED1/TRAP220 is the main subunit target for various nuclear receptors [26].
  • Targeting of Swi/Snf to the yeast GAL1 UAS G requires the Mediator, TAF IIs, and RNA polymerase II [27].
  • Combined with previous studies on the effects of SRB10/SRB11 deletions, our data suggest that posttranslational modifications of Mediator subunits are important for regulation of gene expression [28].
  • The Mediator complex is composed of two subcomplexes, the Rgr1 and Srb4 subcomplexes, which appear to function in the reception of activator signals and the subsequent modulation of Pol II activity, respectively [29].

Analytical, diagnostic and therapeutic context of Benfluramate


  1. Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein. Boyer, T.G., Martin, M.E., Lees, E., Ricciardi, R.P., Berk, A.J. Nature (1999) [Pubmed]
  2. Head module control of mediator interactions. Takagi, Y., Calero, G., Komori, H., Brown, J.A., Ehrensberger, A.H., Hudmon, A., Asturias, F., Kornberg, R.D. Mol. Cell (2006) [Pubmed]
  3. Recruitment of TFIIH to the HIV LTR is a rate-limiting step in the emergence of HIV from latency. Kim, Y.K., Bourgeois, C.F., Pearson, R., Tyagi, M., West, M.J., Wong, J., Wu, S.Y., Chiang, C.M., Karn, J. EMBO J. (2006) [Pubmed]
  4. Principal role of TRAP/mediator and SWI/SNF complexes in Kaposi's sarcoma-associated herpesvirus RTA-mediated lytic reactivation. Gwack, Y., Baek, H.J., Nakamura, H., Lee, S.H., Meisterernst, M., Roeder, R.G., Jung, J.U. Mol. Cell. Biol. (2003) [Pubmed]
  5. Gambling Control Self-efficacy as a Mediator of the Effects of Low Emotional Intelligence on Problem Gambling. Kaur, I., Schutte, N.S., Thorsteinsson, E.B. Journal of gambling studies / co-sponsored by the National Council on Problem Gambling and Institute for the Study of Gambling and Commercial Gaming (2006) [Pubmed]
  6. Mediator of transcriptional regulation. Myers, L.C., Kornberg, R.D. Annu. Rev. Biochem. (2000) [Pubmed]
  7. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Risheg, H., Graham, J.M., Clark, R.D., Rogers, R.C., Opitz, J.M., Moeschler, J.B., Peiffer, A.P., May, M., Joseph, S.M., Jones, J.R., Stevenson, R.E., Schwartz, C.E., Friez, M.J. Nat. Genet. (2007) [Pubmed]
  8. The RNA polymerase II machinery: structure illuminates function. Woychik, N.A., Hampsey, M. Cell (2002) [Pubmed]
  9. Transcription coactivator TRAP220 is required for PPAR gamma 2-stimulated adipogenesis. Ge, K., Guermah, M., Yuan, C.X., Ito, M., Wallberg, A.E., Spiegelman, B.M., Roeder, R.G. Nature (2002) [Pubmed]
  10. A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Kato, Y., Habas, R., Katsuyama, Y., Näär, A.M., He, X. Nature (2002) [Pubmed]
  11. The Role of Decay-accelerating Factor as a Receptor for Helicobacter pylori and a Mediator of Gastric Inflammation. O'brien, D.P., Israel, D.A., Krishna, U., Romero-Gallo, J., Nedrud, J., Medof, M.E., Lin, F., Redline, R., Lublin, D.M., Nowicki, B.J., Franco, A.T., Ogden, S., Williams, A.D., Polk, D.B., Peek, R.M. J. Biol. Chem. (2006) [Pubmed]
  12. Histamine, But Not Leukotriene C4, is an Essential Mediator in Cold Urticaria Wheals. Nuutinen, P., Harvima, I.T., Ackermann, L. Acta Derm. Venereol. (2007) [Pubmed]
  13. Coactivator cross-talk specifies transcriptional output. Marr, M.T., Isogai, Y., Wright, K.J., Tjian, R. Genes Dev. (2006) [Pubmed]
  14. The Swi5 activator recruits the Mediator complex to the HO promoter without RNA polymerase II. Bhoite, L.T., Yu, Y., Stillman, D.J. Genes Dev. (2001) [Pubmed]
  15. Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53. Osborn, A.J., Elledge, S.J. Genes Dev. (2003) [Pubmed]
  16. Thyroid hormone-induced juxtaposition of regulatory elements/factors and chromatin remodeling of Crabp1 dependent on MED1/TRAP220. Park, S.W., Li, G., Lin, Y.P., Barrero, M.J., Ge, K., Roeder, R.G., Wei, L.N. Mol. Cell (2005) [Pubmed]
  17. Association of the Mediator complex with enhancers of active genes. Kuras, L., Borggrefe, T., Kornberg, R.D. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  18. The TRAP/Mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro. Kang, Y.K., Guermah, M., Yuan, C.X., Roeder, R.G. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  19. Characterization of mediator complexes from HeLa cell nuclear extract. Wang, G., Cantin, G.T., Stevens, J.L., Berk, A.J. Mol. Cell. Biol. (2001) [Pubmed]
  20. A role for cofactor-cofactor and cofactor-histone interactions in targeting p300, SWI/SNF and Mediator for transcription. Huang, Z.Q., Li, J., Sachs, L.M., Cole, P.A., Wong, J. EMBO J. (2003) [Pubmed]
  21. Ordered recruitment of histone acetyltransferases and the TRAP/Mediator complex to thyroid hormone-responsive promoters in vivo. Sharma, D., Fondell, J.D. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  22. Independent recruitment of mediator and SAGA by the activator Met4. Leroy, C., Cormier, L., Kuras, L. Mol. Cell. Biol. (2006) [Pubmed]
  23. ChREBP*Mlx Is the Principal Mediator of Glucose-induced Gene Expression in the Liver. Ma, L., Robinson, L.N., Towle, H.C. J. Biol. Chem. (2006) [Pubmed]
  24. Evidence against Calcium as a Mediator of Mitochondrial Dysfunction during Apoptosis Induced by Arachidonic Acid and Other Free Fatty Acids. Maia, R.C., Culver, C.A., Laster, S.M. J. Immunol. (2006) [Pubmed]
  25. TFIIH is negatively regulated by cdk8-containing mediator complexes. Akoulitchev, S., Chuikov, S., Reinberg, D. Nature (2000) [Pubmed]
  26. MED1/TRAP220 exists predominantly in a TRAP/ Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription. Zhang, X., Krutchinsky, A., Fukuda, A., Chen, W., Yamamura, S., Chait, B.T., Roeder, R.G. Mol. Cell (2005) [Pubmed]
  27. Targeting of Swi/Snf to the yeast GAL1 UAS G requires the Mediator, TAF IIs, and RNA polymerase II. Lemieux, K., Gaudreau, L. EMBO J. (2004) [Pubmed]
  28. Site-specific Srb10-dependent phosphorylation of the yeast Mediator subunit Med2 regulates gene expression from the 2-microm plasmid. Hallberg, M., Polozkov, G.V., Hu, G.Z., Beve, J., Gustafsson, C.M., Ronne, H., Björklund, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  29. Activator-specific requirement of yeast mediator proteins for RNA polymerase II transcriptional activation. Han, S.J., Lee, Y.C., Gim, B.S., Ryu, G.H., Park, S.J., Lane, W.S., Kim, Y.J. Mol. Cell. Biol. (1999) [Pubmed]
  30. Conserved structures of mediator and RNA polymerase II holoenzyme. Asturias, F.J., Jiang, Y.W., Myers, L.C., Gustafsson, C.M., Kornberg, R.D. Science (1999) [Pubmed]
  31. In vivo target of a transcriptional activator revealed by fluorescence resonance energy transfer. Bhaumik, S.R., Raha, T., Aiello, D.P., Green, M.R. Genes Dev. (2004) [Pubmed]
  32. Genome-wide occupancy profile of mediator and the Srb8-11 module reveals interactions with coding regions. Zhu, X., Wirén, M., Sinha, I., Rasmussen, N.N., Linder, T., Holmberg, S., Ekwall, K., Gustafsson, C.M. Mol. Cell (2006) [Pubmed]
  33. RNA polymerase II structure, and organization of the preinitiation complex. Asturias, F.J. Curr. Opin. Struct. Biol. (2004) [Pubmed]
  34. The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator. Yang, F., DeBeaumont, R., Zhou, S., Näär, A.M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
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