Inhibition of Mammary Carcinoma Cell Growth by RXR is Mediated by the Receptor's Oligomeric Switch

Abstract

Ligands that activate the nuclear receptor RXR display potent anticarcinogenic activities but the mechanisms by which these compounds inhibit carcinoma cell growth are poorly understood. While RXR can regulate gene expression due to its intrinsic ligand-activated transcription function, this receptor can also regulate transcription by functioning as a ligand-controlled DNA architectural factor. It was thus reported that apo-RXR self-associates into tetramers and that each dimer within these tetramers can separately bind to an RXR response elements. Hence, DNA-binding by RXR tetramers may bring distant genomic regions into close physical proximity. As ligand-binding induces the dissociation of RXR tetramers into dimers, can alter gene expression by modulating DNA architecture. Here we show that inhibition of mammary carcinoma cell growth by RXR ligands stem from the ability of these compounds to regulate the oligomeric state of RXR and is independent of the direct intrinsic transcriptional activity of the receptor. The data suggest that compounds that trigger dissociation of RXR tetramers may comprise a novel class of anti-carcinogenic agents.

Defining the Communication between Agonist and Coactivator Binding in the Retinoid X Receptor α Ligand Binding Domain

“…Tetramers dissociate into dimers upon ligand binding (63,64). An mRXR⌬H12 mutant does not have transcriptional activity, but it displays WT oligomeric activity (tetramer-dimer association), and cancer-relevant genes are up-regulated (65). Each of the regions of RXR LBD identified by their differential HDX MS profiles here (H3, H11, and H12) are important for RXR tetramer formation.…”

The Function of Retinoid X Receptor α in Cancer Cells

“…Ligands that activate the nuclear RXRα display potent anti-carcinogenic activities through the mechanisms by which these ligands inhibit carcinoma cell growth and promote apoptosis. The case that RXRα ligands inhibit mammary carcinoma cell growth stems from the ability of these ligands to regulate the state of RXRα and is independent of the direct intrinsic transcriptional activity of the receptor [104]. Some combined compounds that target RAR/RXR, RXR/TR3, PPAR/RXR, VDR/RXR, RXR/LXR, RXR/FXR, etc.…”

The retinoid X receptors and their ligands

“…In addition to its role as a conventional dimeric NR transcription factor, Noy and collaborators presented evidence that RXR can function as a DNA architectural switch through its ability to interconvert from nonliganded homotetramers to homodimers [91,92]. Because the RXR homotetramers have their DBDs exposed, they retained the ability to complex with RXREs.…”

“…1D) [93]. The RXR ligands caused the homotetramer to dissociate into ligand-bound homodimers [91]. Using a transcriptionally inactive RXRα mutant lacking the LBD H12 (RXRΔH12), which formed homotetramers, bound DNA, and dissociated into homodimers on agonist or antagonist binding, but was transcriptionally inactive by being unable to bind CoAs, they established that the mutant homotetramer induced DNA looping.…”