Document Detail

4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors.
MedLine Citation:
PMID:  8643497     Owner:  NLM     Status:  MEDLINE    
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.
C C Achkar; F Derguini; B Blumberg; A Langston; A A Levin; J Speck; R M Evans; J Bolado; K Nakanishi; J Buck; L J Gudas
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  93     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1996 May 
Date Detail:
Created Date:  1996-07-18     Completed Date:  1996-07-18     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4879-84     Citation Subset:  IM    
Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA.
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MeSH Terms
Cell Differentiation / drug effects
Cell Line
Gene Expression / drug effects
Receptors, Retinoic Acid / drug effects,  genetics,  metabolism*
Retinoids / pharmacology
Signal Transduction
Trans-Activators / metabolism,  pharmacology
Tumor Cells, Cultured
Vitamin A / analogs & derivatives*,  chemistry,  metabolism,  pharmacology
Xenopus laevis / embryology,  metabolism
Grant Support
Reg. No./Substance:
0/Receptors, Retinoic Acid; 0/Retinoids; 0/Trans-Activators; 11103-57-4/Vitamin A; 62702-55-0/4-oxoretinol

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