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

Nuclear receptors modulate the transcription of genes in direct response to small, lipophilic ligands. Binding to ligands induces conformational chang es in the nuclear receptors that enable the receptors to interact with seve ral types of cofactor that are critical for transcription activation (trans activation)(1). We previously described a distinct set of ligand-dependent proteins called DRIPs, which interact with the vitamin D receptor (VDR); to gether, these proteins constitute a new cofactor complex(2). DRIPs bind to several nuclear receptors and mediate ligand-dependent enhancement of trans cription by VDR and the thyroid-hormone receptor in cell-free transcription assays(2,3). Here we report the identities of thirteen DRIPs that constitu te this complex, and show that the complex has a central function in hormon e-dependent transactivation by VDR on chromatin templates. The DRIPs are al most indistinguishable from components of another new cofactor complex call ed ARC, which is recruited by other types of transcription activators to me diate transactivation on chromatin-assembled templates(4,5). Several DRIP/A RC subunits are also components of other potentially related cofactors, suc h as CRSP6, NAT(7), SMCC8 and the mouse Mediator(9), indicating that unique classes of activators may share common sets or subsets of cofactors. The r ole 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 targ et genes.