Structural and functional evidence for activation of a chick retinoid X receptor by eicosanoids.
The retinoid X receptors (RXR-alpha, RXR-beta and RXR-gamma) are members of the steroid-thyroid hormone receptor superfamily of ligand-dependent transcription factors. They appear to function as auxiliary proteins that regulate high-affinity DNA binding and enhance transcriptional activity through heterodimer formation with other members of the superfamily. The RXR-alpha, RXR-beta and RXR-gamma proteins bind and are activated by the naturally occurring retinoid, 9-cis-retinoic acid. Structural similarities are apparent between retinoic acid and various eicosanoids, raising the possibility that eicosanoids may also activate retinoid receptors in vivo. We present evidence that lipoxygenase metabolites of arachidonic acid at submicromolar concentrations are capable of activating RXR-gamma activity in transient transfection assays. In addition, molecular modelling predicts conformational similarities between some lipoxygenase products and retinoic acid. Consistent with this, hydroxyeicosatetraenoic acids are known to mimic some actions of retinoids in cell-based assays. These observations raise the possibility that eicosanoids, already known to act both as local hormones and as intracellular second messengers, may also have a direct role in transcriptional activation via nuclear receptors.
Department of Biochemistry and Molecular Biology, University College and Middlesex School of Medicine, London, U.K.
N S
NS
Eager
P M
PM
Brickell
C
C
Snell
J N
JN
Wood
D000818:Animals; D001665:Binding Sites; D002645:Chickens; D015777:Eicosanoids / Q000494:pharmacology*; D008968:Molecular Conformation; D009687:Nuclear Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D015777:Eicosanoids; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors