The Potential Role of the Transcription Factor RZR/ROR as a Mediator of Nuclear Melatonin Signaling

The pineal gland hormone melatonin is well known as a regulator of circadian rhythmicity, but has also other functions in the central nervous system as well as in the periphery including the maturation of neurons and the regulation of cellular growth and differentiation. Three mechanisms of the hormone's action are currently discussed: a membrane signaling pathway, a nuclear signaling pathway and a receptor-independent radical scavenging function. Melatonin membrane receptors are seven transmembrane receptors and mediate their functions through a G-protein-coupled second messenger pathway. Nuclear melatonin signaling seems to be mediated via the transcription factor RZR/ROR, which is an orphan member of the nuclear receptor superfamily. The widespread distribution of the a-subtype of RZR/ROR suggests that this receptor may be an important mediator of those effects of melatonin that can not be explained by membrane receptors or radical scavenging. Interestingly, natural RZR/RORa "knock-out" mice (staggerer) show severe defects in the development of cerebellar Purkinje cells, a reduced body weight and immunological defects. RZR/ROR binds as a monomer to DNA, but also forms homodimers on appropriate binding sites. Natural RZR/ROR binding sites have been identified in the regulatory regions of many genes. 5-lipoxygenase, p21WAF1/CIP1, apolipoprotein A-1, N-myc and Purkinje cell protein 2 may be functionally important target genes. On some of these binding sites RZR/ROR competes with other members of the nuclear receptor superfamily (e.g., COUP-TF, RAR and Rev-ErbA) indicating a cross-talk between these transcription factors RZR/ROR often shows in transient transfection assays a high constitutive, i.e. ligand-independent activity. However, under conditions of low constitutive activity a significant and specific stimulation of RZR/ROR by low nanomolar concentrations of melatonin and structurally novel class of thiazolidinediones (lead structure: CGP52608) has been observed. Taken together, the effects of melatonin on transcriptional regulation clearly depend on the expression fo RZR/ROR and support the concept that the receptor is a mediator of nuclear melatonin signaling.