Inhibition of mammary carcinoma cell growth by RXR is mediated by the receptor's oligomeric switch
Abstract
Ligands that activate the nuclear receptor retinoid X 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 element. 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, it can alter gene expression by modulating the DNA architecture.
Here, we show that inhibition of mammary carcinoma cell growth by RXR ligands stems 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 anticarcinogenic agents.
See also All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives).