Abstract
The mouse kappa opioid receptor (KOR) gene is constitutively expressed in mouse embryonal carcinoma P19 stem cells and suppressed by retinoic acid (RA) in cells undergoing neuronal differentiation. A negative regulatory element is located within intron 1 of the KOR gene, which contains an Ikaros (Ik)-binding site (GGGAAgGGGAT). This sequence is an Ik-1 respondive, functionally negative element as demonstrated in the context of both natural KOR and heterologous promoters. The two underlined G residues of the second half-site are critical for Ik-1 binding and Ik-mediated repression of the KOR gene. RA induces Ik-1 expression within 1 day of treatment and suppresses KOR expression between 2 and 3 days. Overexpression of Ik-1 in P19 suppresses endogenous KOR gene expression, accompanied by increased binding of Ik-1 to the Ik-binding site and chromatin histone deacetylation on KOR promoters. It is proposed that in an RA-induced P19 differentiation model, RA elevates Ik-1 expression, which recruits histone deacetylase to intron 1 of the KOR gene and silences KOR gene promoters.
Highlights
Opioid receptors are expressed in the central nervous system in the adult, primarily in the areas associated with pain sensation and behavior changes, but how they are expressed in these tissues/cells is not understood
retinoic acid (RA) Suppresses kappa opioid receptor (KOR) Gene Expression, Mediated by a Putative Ik-binding Sequence in Intron 1—Previously, we showed that three mouse KOR isoform mRNA species could be generated as a result of using dual promoters and alternative splicing [19, 22]
In an attempt to examine the KOR gene expression pattern in RA-induced P19 cell differentiation model, we found that RA suppressed total KOR gene expression in P19
Summary
Opioid receptors are expressed in the central nervous system in the adult, primarily in the areas associated with pain sensation and behavior changes, but how they are expressed in these tissues/cells is not understood. We have demonstrated the expression of opioid receptors in early developing animals [18]. To understand how the KOR gene is regulated for specific expression in developing animals, we have tested various hormones and opioid compounds in developing animals as well as an embryonal carcinoma cell model, P19, which constitutively expresses the KOR gene [18]. This study aims at understanding the mechanism of RA suppression of KOR gene expression. Ik-1 is induced by RA in P19, and its overexpression in P19 results in suppressed KOR mRNA expression, accompanied by chromatin histone deacetylation on the KOR promoters. This study proposes a novel mechanism of targeted suppression of the opioid receptor gene by RA through Ik-1 binding to an intronic silencer, which renders histone deacetylation of the promoters
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
