Mechanisms underlying the induction of the putative human tumor suppressor GPRC5A by Retinoic acid

 Abstract

Retinoic acid regulates the expression of genes involved in cell proliferation,
differentiation, and survival by direct control of gene transcription via activation of
nuclear retinoid receptors bound to response elements in the promoters of target genes
or by indirect mechanisms. Herein, we investigated the mechanism by which retinoic
acid induces the expression of the human tumor suppressor GPRC5A. The proximal 5’
upstream region of the GPRC5A gene was found to contain two potential RAR/RXR
binding sites (RAREs) and one VDR/RXR binding site with direct repeat 5 (DR5) motifs
designated DR5I (-489 to -473), DR5II (-136 to -120), and DR5III (-81 to -65). DR5II and
DR5III but not DR5I were conserved among vertebrates. However, only DR5III (5’-
TGTCCCTCTGCTCACCC-3’) was found to be the functional RARE for mediating
induction of GPRC5A as indicated by electrophoretic mobility shift assay using wild type
and mutated synthetic oligonucleotides representing different fragments of the promoter
for competition with retinoic acid receptor β RARE. Chromatin immunoprecipitation
assay confirmed the binding of retinoic acid receptors α and γ and retinoid X receptors α
and β to DR5III in intact cells. These results demonstrate the importance of functional
analysis for validating the activity of predicted response elements.

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Pages
951 - 962
doi
10.4161/cbt.8.10.8244
Type
Research Paper
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Mechanisms underlying the induction of the putative human tumor suppressor GPRC5A by Retinoic acid