The Regulation and Function of Nuclear Receptor Corepressor SMRT in Human Breast Cancer Cells
Abstract
Steroid and nuclear receptor coactivators 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 cactivator 3 (RAC3), which belongs to the steroid receptor (SRC) family. In the current study, we have 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 (Erb) interact with different alpha-helical LXXLL motifs of RAC3. Peptides corresponding to these motifs have diverse affinities for the VDR and Erb 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 receptors in vivo. Furthermore, we found enhancement of transcriptional activation by receptors in vivo. Furthermore, we found that the activation function-2 (AF-2) domain of the retinoid X receptor (RxR) interferes with RAC3 binding to a DNA-bound vDR/RxR heterodimer, while 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2000
- Accession Number
- ADA386935
Entities
People
- Christopher Leo
Organizations
- University of Massachusetts