Title

Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3

UMMS Affiliation

Department of Pharmacology

Publication Date

2-22-2000

Document Type

Article

Subjects

Amino Acids; Binding, Competitive; Blotting, Western; Cell Line; Dose-Response Relationship, Drug; Estrogen Receptor beta; Humans; Mutagenesis, Site-Directed; Mutation; Nuclear Proteins; Peptides; Protein Structure, Tertiary; Receptors, Calcitriol; Receptors, Cytoplasmic and Nuclear; Receptors, Estrogen; Recombinant Fusion Proteins; Trans-Activators; *Transcription Factors

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Steroid and nuclear receptor coactivators (NCoAs) have been implicated in the regulation of nuclear receptor function by enhancing ligand-dependent transcriptional activation of target gene expression. We have previously isolated receptor-associated coactivator 3 (RAC3), which belongs to the steroid receptor coactivator family. In this study, we investigated the differential mechanisms by which RAC3 interacts with and modulates the transcriptional activity of different nuclear receptors. We found that the vitamin D receptor (VDR) and estrogen receptor beta interact with different alpha-helical LXXLL motifs of RAC3. Peptides corresponding to these motifs have diverse affinities for the VDR and estrogen receptor beta, and mutation of specific motifs differentially impairs the ability of RAC3 to interact with these receptors in vitro. Consequently, these mutations inhibit the enhancement of transcriptional activation by these receptors in vivo. Furthermore, we found that the activation function-2 (AF-2) domain of the retinoid X receptor interferes with RAC3 binding to a DNA-bound VDR/retinoid X receptor (RXR) heterodimer, whereas the VDR AF-2 domain is required for this interaction. These results suggest a receptor-specific binding preference for the different LXXLL motifs of RAC3, which may provide flexibility for RAC3 to differentially regulate the function of different nuclear receptors.

Rights and Permissions

Citation: J Biol Chem. 2000 Feb 25;275(8):5976-82.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of biological chemistry

PubMed ID

10681591