Activation of mammalian retinoid X receptors by the insect growth regulator methoprene

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 13; pp. 6157 - 6160
• Main Authors: Harmon, M A, Boehm, M F, Heyman, R A, Mangelsdorf, D J
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 20-06-1995; National Academy of Sciences
• Subjects: Animals; beta-Galactosidase - biosynthesis; Binding, Competitive; Biochemistry; Cell Line; Cercopithecus aethiops; DNA-Binding Proteins; Drosophila; Drosophila melanogaster; Fungal Proteins - biosynthesis; Fungal Proteins - metabolism; Gene Expression - drug effects; Genes; Insects; Kidney; Kinetics; Luciferases - biosynthesis; Luciferases - metabolism; Methoprene - pharmacology; Receptors, Retinoic Acid - biosynthesis; Receptors, Retinoic Acid - drug effects; Receptors, Retinoic Acid - metabolism; Recombinant Proteins - biosynthesis; Recombinant Proteins - drug effects; Recombinant Proteins - metabolism; Retinoid X Receptors; Retinoids - metabolism; Saccharomyces cerevisiae Proteins; Transcription Factors - biosynthesis; Transcription Factors - drug effects; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transfection; Vertebrates
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.13.6157

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.