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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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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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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DOI: https://doi.org/10.1038/19783
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