Retinoic Acid Is a Negative Regulator of the Neuropeptide Y/Peptide YY Y1 Receptor Gene in SK‐N‐MC Cells

: To identify effectors of neuropeptide Y Y1 receptor gene expression predicted by putative regulatory elements in its 5′ flanking region, we examined the effects of several transcriptionally active agents on Y1 receptor mRNA levels and 125I‐peptide YY binding capacity in SK‐N‐MC cells. Phorbol ester caused a rapid, transient 2.6‐fold increase in Y1R mRNA levels. However, all trans‐retinoic acid caused a rapid, sustained decrease in Y1 receptor mRNA levels (to 25% of control). Cycloheximide pretreatment did not attenuate the maximal inhibitory effect of retinoic acid, but it prolonged the time to achieve maximal efficacy. The retinoic acid effect was secondary to both a significant decrease in Y1 receptor mRNA stability and a decreased Y1 receptor gene transcription rate. Y1 receptor binding capacity was also significantly decreased after retinoic acid treatment (368 ± 25 vs. 496 ± 28 fmol/mg of protein for control). These data support a role for retinoic acid as an important agent regulating Y1 receptor gene expression and mediating Y1 receptor down‐regulation.