PubMed · 10979788
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K Washenik, L Clark-Loeser, A Friedman-Kien. 2000-08-24. Kaposi's sarcoma.. https://pubmed.ncbi.nlm.nih.gov/10979788/
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The constitutive androstane receptor (CAR) enhances transcription of specific target genes that regulate several metabolic pathways. CAR functions as an obligate heterodimer (CAR-RXR) with the retinoid X receptor (RXR). Also part of the active receptor complex is the steroid receptor coactivator-1 (SRC-1) which interacts with the receptor complex via specific receptor interaction domains (RIDs). A peptide derived from SRC-1 RID2 is used to study the thermodynamic properties of the interaction with the CAR-RXR ligand binding domain (LBD) complex. In the absence of ligands for both CAR and RXR, binding of coactivator peptide to the CAR-RXR heterodimer is characterized by a favorable enthalpy change and an unfavorable entropy change. The addition of the CAR agonist, TCPOBOP, increases the affinity for coactivator by decreasing the unfavorable entropy and increasing the favorable intrinsic enthalpy of the interaction. The RXR ligand, 9-cis-RA, generates a second SRC-1 site and increases the affinity by improving the entropic component of binding. There is an additional increase in affinity for one of the two sites in the presence of both ligands. The change in heat capacity (deltaCp) is also investigated. A 2-fold difference in deltaCp is observed between liganded and unliganded CAR-RXR. The observed thermodynamic parameters for binding of SRC-1 peptide to liganded and apo CAR-RXR as well as the difference in the deltaCp data provide evidence that the apo CAR-RXR heterodimer is conformationally mobile. The more favorable enthalpic contribution for TCPOBOP-bound CAR-RXR indicates that preformation of the binding site improves the complementarity of the coactivator-receptor interaction.
It is assumed that the retinoid X receptor (RXR) acts as a silent partner to the vitamin D receptor (VDR) with its only function to increase affinity of VDR/RXR to its DNA recognition site. In this study, we show that the RXR ligand 9-cis-retinoic acid (9-cis-RA) induces recruitment of coactivators by the DNA-bound heterodimer and potentiates vitamin D-dependent transcriptional responses. The presence of 9-cis-RA increases induction of cyp24 transcripts and differentiation of colon cancer cells by vitamin D, confers significant agonistic activity to a VDR ligand with very low agonistic activity and can even restore transcriptional activity of an AF-2 mutant VDR that causes hereditary rickets. This study shows that, in VDR/RXR heterodimers, allosteric communication triggered by the RXR ligand has a previously unrecognized role in vitamin D signalling, with important physiological and therapeutic implications.
Retinoic acids, which have shown potential chemopreventive and therapeutic activities for several neoplastic diseases in vitro, modulate the growth-promoting and anti-apoptotic activities of insulin-like growth factors (IGFs), in part by influencing the expression of insulin-like growth factor binding protein-3 (IGFBP-3). This study sought to investigate the effect of 9-cis retinoic acid (9cRA) on the expression of IGFBP-3 and the underlying mechanisms involving retinoic acid receptor-beta (RAR-beta). The pharmacologic activity of 9cRA was characterized by monitoring target modulation as well as by evaluating the underlying mechanisms in NSCLC cells. Treatment of 9cRA inhibited proliferation of a part of NSCLC cell lines including H460 cells in clinically-achievable concentrations and induced IGFBP-3 expression in dose- and time-dependent manners. Transient transfection with a reporter constructs driven by the human IGFBP-3 gene promoter indicated that 9cRA induces gene expression via the -534 to -445 region (relative to translation start site) of the IGFBP-3 promoter. Unilateral deletion and site-directed mutagenesis identified a retinoic acid responsive element (RARE), a direct repeat of two GGGTCA-related hexanucleotides separated by just 8 bp (DR-8-type response element). A cotransfection assay with a RAR-beta expression vector potentiated (and with siRNA for RAR-beta, diminished) the effect of 9cRA on IGFBP-3 expression. IGFBP-3 gene expression by 9cRA is mediated by a distinct DR-8 RARE located in the proximal region of the IGFBP promoter and involves the RAR-beta, a putative tumor suppressor in NSCLC.