The Regulation and Function of Nuclear Receptor Corepressor SMRT in Human Breast Cancer Cells
Annual summary rept. 1 May 2000-30 Apr 2001
MASSACHUSETTS UNIV MEDICAL CENTER WORCESTER
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Members of the steroid receptor coactivator family have been implicated in the regulation of nuclear receptor function by enhancing ligand-dependent transcriptional activation of target genes. We have previously isolated the third member of the SRC family, receptor-associated coactivator 3 RAC3. In this study, we investigated the mechanisms by which RAC3 may interact with and modulate the transcriptional activity of nuclear receptors. We found that VDR, ERBeta, and retinoid receptors interact with different a-helical LXXLL motifs of RAC3. Peptides corresponding to these motifs have diverse affinities for the VDR and ERBeta and mutation of specific motifs differentially impairs the ability of RAC3 to interact with 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 RXR interferes with RAC3 binding to DNA-bound VDRRXR or RARRXR heterodimers, while the VDR or RAR AF-2 domains are required for this interaction. Finally, we demonstrated that RAR and RXR differentially contribute to coactivator recruitment and transcriptional regulation by the RARRXR heterodimer. These results suggest a receptor-specific binding preference for the different LXXLL motifs of RAC3, which may provide flexibility for RAC3 to regulate the function of different receptors.
- Medicine and Medical Research