RAR-GAMMA-2 EXPRESSION IS REGULATED THROUGH A RETINOIC ACID RESPONSE ELEMENT EMBEDDED IN SP1-SITES

At the level of transcription, all signals of the vitamin A derivative retinoic acid (RA) are mediated by the RA receptors (Rewires) as well as the retinoid REWIRES receptors (RXRs). The control of expression of the various receptor subtypes and their specific isoforms appears to be strictly regulated and can be assumed to play a pivotal role during development and in the adult tissue. It has previously been shown that the RAR-beta-2 isoform can regulate its own synthesis through an RA response element (RARE) in its promoter. Recent evidence suggests that the expression of other RAR isoforms, including that of RAR-gamma-2, are also regulated by RA. We present evidence that expression of the RAR-gamma-2 isoform can be regulated through the RARE in its own promoter region. Similar to the beta-2RARE, the gamma-2RARE consists of a 6-bp direct repeat with a 5-nucleotide spacer, but it has different functional features, including receptor specificity, basal-level activity, and affinity for RAR. In agreement with recent observations, this response element is bound most effectively by RAR/RXR heterodimers. Single-base-pair mutations had different effects on the activity of this RARE. The gamma-2RARE is surrounded by several binding sites for the transcription factor Spl. Cotransfected Spl enhanced strongly the activity of gamma-2 promoter reporter constructs in Drosophila cells. Our data suggest an important role for RAR-containing heterodimers and Sp1 in the regulation of RAR-gamma-2 expression.