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). 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 complex. DRIPs bind to several nuclear receptors and mediate ligand-dependent enhancement of transcription by VDR and the thyroid-hormone receptor in cell-free transcription assays. 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 templates. Several DRIP/ARC subunits are also components of other potentially related cofactors, such as CRSP, NAT, SMCC and the mouse Mediator, 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.

Steroid, retinoid, vitamin D 3 , and thyroid hormones signal through ligand-dependent transcription factors that collectively comprise a superfamily of intracellular, soluble receptors (hereafter collectively called nuclear receptors) that reside in the nucleus or translocate there in response to hormonal signals. As the largest known family of eukaryotic transcriptional regulators, nuclear receptors are implicated via the target genes they modulate in the control of cell growth and differentiation, homeostasis, development, and several physiological processes (for review, see Freedman 1997 and references therein). Moreover, because they are regulated tightly by small lipophilic molecules, they are extremely attractive as pharmacologic targets.Nuclear receptors all share a common organization in functional domains and extensive homologies in structure. A DNA-binding domain allows the receptors to bind as homodimers, or heterodimers with a common partner, retinoid X receptor (RXR), to specific DNA response elements typically composed of two hexameric half-sites organized as direct or inverted repeats. The carboxy-terminal half of the prototype nuclear receptor includes a ligand-binding domain (LBD) with a superimposed dimerization surface, and a ligand-dependent transcriptional activation function called AF-2, located at the extreme carboxyl terminus of the receptor (Danielian et al. 1992;Barettino et al. 1994;Durand et al. 1994). Crystallographic analyses have revealed that binding of a specific ligand, all-trans retinoic acid (ATRA), to retinoic acid receptor ␥ (RAR␥) induces a conformational change in its structure that modifies the orientation of the AF-2 core motif, contained within the last of 12 ␣-helices that

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