Activation of mammalian retinoid X receptors by the insect growth regulator methoprene.
We report that methoprene and its derivatives can stimulate gene transcription in vertebrates by acting through the retinoic acid-responsive transcription factors, the retinoid X receptors (RXRs). Methoprene is an insect growth regulator in domestic and agricultural use as a pesticide. At least one metabolite of methoprene, methoprene acid, directly binds to RXR and is a transcriptional activator in both insect and mammalian cells. Unlike the endogenous RXR ligand, 9-cis-retinoic acid, this activity is RXR-specific; the methoprene derivatives do not activate the retinoic acid receptor pathway. Methoprene is a juvenile hormone analog that acts to retain juvenile characteristics during insect growth, preventing metamorphosis into an adult, and it has been shown to have ovicidal properties in some insects. Thus, a pesticide that mimics the action of juvenile hormone in insects can also activate a mammalian retinoid-responsive pathway. This finding provides a basis through which the potential bioactivity of substances exposed to the environment may be reexamined and points the way for discovery of new receptor ligands in both insects and vertebrates.
Harmon
M A
MA
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75235-9050, USA.
Boehm
M F
MF
Heyman
R A
RA
Mangelsdorf
D J
DJ
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D004331:Drosophila melanogaster; D005656:Fungal Proteins / Q000096:biosynthesis / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D007668:Kidney; D007700:Kinetics; D008156:Luciferases / Q000096:biosynthesis / Q000378:metabolism; D008726:Methoprene / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D001616:beta-Galactosidase / Q000096:biosynthesis
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D008726:Methoprene; D008156:Luciferases; D001616:beta-Galactosidase