Signal transduction by retinoid receptors.

Vitamin A derivatives (retinoids) affect a large variety of fundamental biological processes. Understanding of the signaling mechanism has been greatly advanced by the cloning of specific retinoid receptors. These regulatory proteins belong to the steroid/thyroid hormone nuclear receptor superfamily. Two types of retinoid receptors have been identified, the retinoic acid receptors (RAR alpha, beta and gamma) and the retinoid X receptors (RXR alpha, beta, and gamma). Similar to the steroid hormone receptors, the retinoid receptors bind to specific DNA sequences that have diad symmetries. However, the RARs require heterodimerization with RXRs for efficient DNA binding and gene regulation, while the RXRs can bind to DNA and function as homodimers in the presence of 9-cis-retinoic acid. In addition, RXRs can form heterodimers with thyroid hormone receptors and the vitamin D3 receptor and other receptors. Thus the RXRs have a very central role in serving as a partner for several hormone and vitamin receptors and thus may allow cross talk between different hormone signals. Retinoid responses can be restricted by the COUP-TF orphan receptors which bind to overlapping DNA sequences. Besides the classical way of action via DNA binding, the retinoid receptors can also interfere with other signaling pathways by interacting with the transcription factor AP-1. The advances made in understanding the mechanism of action of retinoids promise to contribute to the understanding and control of physiological responses and diseases.