title: 4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors.
abstract: All-trans-retinoic acid (at-RA) induces cell differentiation in a wide variety of cell types, including F9 embryonic teratocarcinoma cells, and can influence axial pattern formation during embryonic development. We now identify a novel retinoid synthetic pathway in differentiating F9 cells that results in the intracellular production of 4-oxoretinol (4-oxo-ROL) from retinol (vitamin A). Approximately 10-15% of the total retinol in the culture is metabolized to 4-hydroxyretinol and 4-oxo-ROL by the at-RA-treated, differentiating F9 cells over an 18-hr period, but no detectable metabolism of all-trans-retinol to at-RA or 9-cis-retinoic acid is observed in these cells. Remarkably, we show that 4-oxo-ROL can bind and activate transcription of the retinoic acid receptors whereas all-trans-retinol shows neither activity. Low doses of 4-oxo-ROL (e.g., 10(-9) or 10(-10 M) can activate the retinoic acid receptors even though, unlike at-RA, 4-oxo-ROL does not contain an acid moiety at the carbon 15 position. 4-oxo-ROL does not bind or transcriptionally activate the retinoid X receptors. Treatment of F9 cells with 4-oxo-ROL induces differentiation without conversion to the acid and 4-oxo-ROL is active in causing axial truncation when administered to Xenopus embryos at the blastula stage. Thus, 4-oxo-ROL is a natural, biologically active retinoid that is present in differentiated F9 cells. Our data suggest that 4-oxo-ROL may be a novel signaling molecule and regulator of cell differentiation.
authors.affiliation: Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Achkar
authors.forename: F
authors.initials: F
authors.lastname: Derguini
authors.forename: B
authors.initials: B
authors.lastname: Blumberg
authors.forename: A
authors.initials: A
authors.lastname: Langston
authors.forename: A A
authors.initials: AA
authors.lastname: Levin
authors.forename: J
authors.initials: J
authors.lastname: Speck
authors.forename: R M
authors.initials: RM
authors.lastname: Evans
authors.forename: J
authors.initials: J
authors.lastname: Bolado
authors.forename: K
authors.initials: K
authors.lastname: Nakanishi
authors.forename: J
authors.initials: J
authors.lastname: Buck
authors.forename: L J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction; D013237:Stereoisomerism; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014982:Xenopus laevis / Q000196:embryology / Q000378:metabolism
chemical_list: D018168:Receptors, Retinoic Acid; D012176:Retinoids; D015534:Trans-Activators; D014801:Vitamin A; C041819:4-oxoretinol