The human uncoupling protein-3 gene promoter requires MyoD and is induced by retinoic acid in muscle cells.

The uncoupling protein-3 (UCP-3) gene encodes for a mitochondrial protein expressed preferentially in skeletal muscle. UCP-3 mRNA is expressed in cultured muscle cells (C2C12 or L6E9) only when differentiated, at which stage UCP-3 is highly induced by all-trans retinoic acid (RA). Here we report that human UCP-3 promoter activity is dependent on MyoD and inducible by all trans-RA. The action of all trans-RA is increased by co-transfection with RA receptor (RAR). We have characterized the RA response element that controls the induction by RA in the 5' noncoding region of the UCP-3 gene. Deletion and point-mutation analysis of the hUCP-3 promoter led us to identify a direct-repeat element with one base-pair spacing (DR1) at position -71/-59 responsible for the induction by RA of the activity of the promoter. This DR1 element bound a nuclear protein complex from muscle cells that contain RAR and retinoid X receptor (RXR). In the absence of this element, the promoter became unresponsive to RA, but it was still dependent on MyoD. In conclusion, it has been established that UCP-3 gene promoter activity is dependent on MyoD, and the first regulatory pathway for UCP-3 gene promoter regulation has been recognized by identifying RA as a transcriptional activator of the gene.