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

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). 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.

An architectural perspective of vitamin D responsiveness

“…The multisubunit DRIP (VDR-Interacting Protein) complex also binds to VDR in response to the ligand vitamin D [8,9]. This interaction occurs through the LBD of VDR in the same manner as the p160/SRC coactivators, resulting in transcriptional enhancement [10].…”

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

“…The CDK8-cyclin C complex was subsequently shown to be associated with the RNAP II holoenzyme in yeast (Liao et al, 1995) and in mammalian cells (Ossipow et al, 1995;Maldonado et al, 1996). More recently, CDK8 and cyclin C were also identi®ed as components of mammalian mediator-and SRB protein-containing co-activator complexes that can both positively and negatively affect (activated) RNAP II transcription activation in vitro (Sun et al, 1998;Boyer et al, 1999;Gu et al, 1999;Hampsey and Reinberg, 1999;Na È a È r et al, 1999;Rachez et al, 1999;Ryu et al, 1999;Malik and Roeder, 2000). Overall protein levels and catalytic activity of CDK8-cylin C do not¯uctuate signi®cantly during the cell cycle .…”

Molecular mechanism of a cross‐talk between oestrogen and growth factor signalling pathways

“…Most interestingly, several coactivators (SRC-1/TIF2 family proteins and CBP/p300) themselves are histone acetylases (HATs) that modulate chromatine structure for activating gene expression by the acetylation of histone proteins (Voegel et al 1996;Spencer et al 1997). More recently, another coactivator complex has been identi®ed the DRIP/TRAP complex, which bears no HAT activity (Fondell et al 1996;Freedman 1999;Rachez et al 1999). Therefore, a`two step' model arises, in which the coactivator complex containing the 160 kDa coactivators and CBP/p300 is ®rst recruited to the ligand-bound nuclear receptor following chromosomal DNA rendering the chromatine active for gene induction via the acetylation of histones (Fig.…”