The Regulation and Function of Nuclear Receptor Corepressor SMRT in Human Breast Cancer Cells
Annual summary 1 May 1999-30 Apr 2000
MASSACHUSETTS UNIV MEDICAL CENTER WORCESTER
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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 vDRRxR 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.
- Anatomy and Physiology
- Medicine and Medical Research