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Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex

Nature volume 398, pages 824–828 (1999)Cite this article

Abstract

Nuclear receptors modulate the transcription of genes in direct response to small lipophilic ligands. Binding to ligands induces conformational changes in the nuclear receptors that enable the receptors to interact with several types of cofactor that are critical for transcription activation (transactivation)1. We previously described a distinct set of ligand-dependent proteins called DRIPs, which interact with the vitamin D receptor (VDR); together, these proteins constitute a new cofactor complex2. DRIPs bind to several nuclear receptors and mediate ligand-dependent enhancement of transcription by VDR and the thyroid-hormone receptor in cell-free transcription assays2,3. Here we report the identities of thirteen DRIPs that constitute this complex, and show that the complex has a central function in hormone-dependent transactivation by VDR on chromatin templates. The DRIPs are almost indistinguishable from components of another new cofactor complex called ARC, which is recruited by other types of transcription activators to mediate transactivation on chromatin-assembled templates4,5. Several DRIP/ARC subunits are also components of other potentially related cofactors, such as CRSP6, NAT7, SMCC8 and the mouse Mediator9, indicating that unique classes of activators may share common sets or subsets of cofactors. The role of nuclear-receptor ligands may, in part, be to recruit such a cofactor complex to the receptor and, in doing so, to enhance transcription of target genes.

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Figure 1: The VDR ligand-binding domain stably interacts with the DRIP complex in a fully hormone-dependent manner.
Figure 2: A single DRIP subunit binds directly to VDR in a ligand-dependent manner.
Figure 3: A chromatin template and a highly purified DRIP/ARC complex that lacks HAT activity are required for marked ligand-dependent transcription by VDR–RXR in vitro.

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References

  1. Torchia, J., Glass, C. & Rosenfeld, M. G. Co-activators and co-repressors in the integration of transcriptional responses. Curr. Opin. Cell Biol. 10, 373–383 (1998).

    Article  CAS  Google Scholar 

  2. Rachez, C.et al. Anovel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system. Genes Dev. 12, 1787– 1800 (1998).

    Article  CAS  Google Scholar 

  3. Fondell, J. D., Ge, H. & Roeder, R. G. Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc. Natl Acad. Sci. USA 93, 8329–8333 ( 1996).

    Article  ADS  CAS  Google Scholar 

  4. Näär, A. M. et al. Chromatin, TAFs, and a novel multiprotein coactivator are required for synergistic activation by Sp1 and SREBP-1a in vitro. Genes Dev. 12, 3020–3031 (1998).

    Article  Google Scholar 

  5. Näär, A. M. et al. Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398, 828–832 (1999).

    Article  ADS  Google Scholar 

  6. Ryu, S., Zhou, S., Ladurner, A. G. & Tjian, R. The transcriptional co-factor complex CRSP is required for Sp1 activity. Nature 397, 446–450 ( 1999).

    Article  ADS  CAS  Google Scholar 

  7. Sun, X.et al. NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription. Mol. Cell 2, 213–222 (1998).

    Article  CAS  Google Scholar 

  8. Gu, W.et al. Anovel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol. Cell 3, 97– 108 (1999).

    Article  CAS  Google Scholar 

  9. Jiang, Y. W.et al. Mammalian mediator of transcriptional regulation and its possible role as end-point of signal transduction pathways. Proc. Natl Acad. Sci. USA 95, 8538–8543 ( 1998).

    Article  ADS  CAS  Google Scholar 

  10. Moras, D. & Gronemeyer, H. The nuclear receptor ligand-binding domain: structure and function. Curr. Opin. Cell Biol. 10, 384–391 (1998).

    Article  CAS  Google Scholar 

  11. Drane, P., Barel, M., Balbo, M. & Frade, R. Identification of RB18A, a 205 kDa new p53 regulatory protein which shares antigenic and functional properties with p53. Oncogene 15, 3013–3024 (1997).

    Article  CAS  Google Scholar 

  12. Yuan, C. X., Ito, M., Fondell, J. D., Fu, Z. Y. & Roeder, R. G. The TRAP220 component of a thyroid hormone receptor-associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc. Natl Acad. Sci. USA 95, 7939–7944 (1998).

    Article  ADS  CAS  Google Scholar 

  13. Zhu, Y., Qi, C., Jain, S., Rao, M. S. & Reddy, J. K. Isolation and characterization of PBP, a protein that interacts with peroxisome proliferator-activated receptor. J. Biol. Chem. 272, 25500–25506 ( 1997).

    Article  CAS  Google Scholar 

  14. Lee, J. W., Choi, H. S., Gyuris, J., Brent, R. & Moore, D. D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol. Endocrinol. 9, 243– 254 (1995).

    CAS  Google Scholar 

  15. Nagase, T., Seki, N., Tanaka, A., Ishikawa, K. & Nomura, N. Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2, 167–174 ( 1995).

    Article  CAS  Google Scholar 

  16. Li, Y.et al. Yeast global transcriptional regulators Sin4 and Rgr1 are components of mediator complex/RNA polymerase II holoenzyme. Proc. Natl Acad. Sci. USA 92, 10864–10868 ( 1995).

    Article  ADS  CAS  Google Scholar 

  17. Yoshikawa, H., Fujiyama, A., Nakai, K., Inazawa, J. & Matsubara, K. Detection and isolation of a novel human gene located on Xp11.2-p11.4 that escapes X-inactivation using a two-dimensional DNA mapping method. Genomics 49, 237– 246 (1998).

    Article  CAS  Google Scholar 

  18. McInerney, E. M.et al . Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes Dev. 12, 3357–3368 (1998).

    Article  CAS  Google Scholar 

  19. Darimont, B. D.et al . Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev. 12, 3343– 3356 (1998).

    Article  CAS  Google Scholar 

  20. Heery, D. M., Kalkhoven, E., Hoare, S. & Parker, M. G. Asignature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 ( 1997).

    Article  ADS  CAS  Google Scholar 

  21. Torchia, J.et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677 –686 (1997).

    Article  ADS  CAS  Google Scholar 

  22. Le Douarin, B.et al . Apossible involvement of IF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors. EMBO J. 15, 6701–6715 ( 1996).

    Article  CAS  Google Scholar 

  23. Lemon, B. D., Fondell, J. D. & Freedman, L. P. Retinoid X receptor:vitamin D3 receptor heterodimers promote stable preinitiation complex formation and direct 1,25-dihydroxyvitamin D3-dependent cell-free transcription. Mol. Cell. Biol. 17, 1923–1937 (1997).

    Article  CAS  Google Scholar 

  24. Kraus, W. L. & Kadonaga, J. T. p300 and estrogen receptor cooperatively activate transcription via differential enhancement of initiation and reinitiation. Genes Dev. 12, 331–342 (1998).

    Article  CAS  Google Scholar 

  25. Lui, M., Tempst, P. & Erdjument-Bromage, H. Methodical analysis of protein-nitrocellulose interactions to design a refined digestion protocol. Analyt. Biochem. 241, 156–166 (1996).

    Article  CAS  Google Scholar 

  26. Erdjument-Bromage, H. et al. Examination of micro-tip reversed-phase liquid chromatographic extraction of peptide pools for mass spectrometric analysis. J. Chromatogr. 826, 167–181 (1998).

    Article  CAS  Google Scholar 

  27. Geromanos, S., Philip, J., Freckleton, G. & Tempst, P. Injection adaptable fine ionization source (‘JaFIS’) for continuous flow nano-electrospray. Rapid Commun. Mass Spectrom. 12, 551–556 (1998).

    Article  ADS  CAS  Google Scholar 

  28. Mann, M. & Wilm, M. Error-tolerant identification of peptides in sequence databases by peptide sequence tags. Analyt. Chem. 66, 4390–4399 (1994).

    Article  CAS  Google Scholar 

  29. Kamakaka, R. T., Bulger, M. & Kadonaga, J. T. Potentiation of RNA polymerase II transcription by Gal4-VP16 during but not after DNA replication and chromatin assembly. Genes Dev. 7, 1779–1795 (1993).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank L. Lacomis, M. Lui, A. Grewal and S. Geromanos for help with sequencing and mass-spectrometric analysis; M. Mann for the PeptideSearch and SequenceTag programs; J. Lee for the B-cell cDNA library; D. Reinberg and H. Cho for human Med6 antibody; R. Kornberg for human Med7 antibody; C. Glass and M. G. Rosenfeld for NCoA-1 and NCoA-2 antibodies; H. Yoshikawa for EXLM1 cDNA; T. Nagase and the Kazusa DNA Research Institute for KIAA 0593, 0192, and 0130 cDNAs; C.-P. Chang and K. Bark for technical assistance; M. Haggart for DNA sequencing; and C. Inouye for purified recombinant human basal factors TFIIA, -E, and -F. This work was supported by grants from the NIH and the Human Frontiers Science Program (to L.P.F.); B.D.L. is a recipient of a National Research Service Award. Z.S. was supported by the Robert Wood Johnson Jr Charitable Trust.

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Author notes

  1. Christophe Rachez, Bryan D. Lemon, Hediye Erdjument-Bromage and Paul Tempst: These authors contributed equally to this work

Authors and Affiliations

  1. Sloan-Kettering Division, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences Cornell University, 1275 York Avenue, New York , 10021, New York, USA

    Christophe Rachez, Zalman Suldan, Virginia Bromleigh, Matthew Gamble & Leonard P. Freedman

  2. Sloan-Kettering Division, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences, Cornell University, 1275 York Avenue, New York, 10021, New York, USA

    Hediye Erdjument-Bromage & Paul Tempst

  3. Howard Hughes Medical Institute Department of Molecular Biology and Cell Biology, University of California, Berkeley, 94720, California, USA

    Bryan D. Lemon & Anders M. Näär

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Correspondence to Leonard P. Freedman.

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Rachez, C., Lemon, B., Suldan, Z. et al. Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398, 824–828 (1999). https://doi.org/10.1038/19783

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