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PMID: 7823950 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Targeted disruption of retinoic acid receptor alpha (RAR alpha) and RAR gamma results in receptor-specific alterations in retinoic acid-mediated differentiation and retinoic acid metabolism.

Molecular and cellular biology ·Vol. 15 ·No. 2 ·1995-02-00 ·Pages 843-51

Boylan JF, Lufkin T, Achkar CC, Taneja R, Chambon P, Gudas LJ

Abstract

F9 embryonic teratocarcinoma stem cells differentiate into an epithelial cell type called extraembryonic endoderm when treated with retinoic acid (RA), a derivative of retinol (vitamin A). This differentiation is presumably mediated through the actions of retinoid receptors, the RARs and RXRs. To delineate the functions of each of the different retinoid receptors in this model system, we have generated F9 cell lines in which both copies of either the RAR alpha gene or the RAR gamma gene are disrupted by homologous recombination. The absence of RAR alpha is associated with a reduction in the RA-induced expression of both the CRABP-II and Hoxb-1 (formerly 2.9) genes. The absence of RAR gamma is associated with a loss of the RA-inducible expression of the Hoxa-1 (formerly Hox-1.6), Hoxa-3 (formerly Hox-1.5), laminin B1, collagen IV (alpha 1), GATA-4, and BMP-2 genes. Furthermore, the loss of RAR gamma is associated with a reduction in the metabolism of all-trans-RA to more polar derivatives, while the loss of RAR alpha is associated with an increase in metabolism of RA relative to wild-type F9 cells. Thus, each of these RARs exhibits some specificity with respect to the regulation of differentiation-specific gene expression. These results provide an explanation for the expression of multiple RAR types within one cell type and suggest that each RAR has specific functions.

MeSH Terms
Animals Base Sequence Cell Differentiation/drug effects Cell Division Cell Line Chromatography, High Pressure Liquid DNA Primers Gene Expression/drug effects Kinetics Mice Molecular Sequence Data Mutagenesis Polymerase Chain Reaction Receptors, Retinoic Acid/biosynthesis,metabolism Recombinant Proteins/biosynthesis,metabolism Recombination, Genetic Retinoic Acid Receptor alpha Retinoids/isolation & purification,metabolism,pharmacology Teratocarcinoma Transfection Tretinoin/metabolism,pharmacology Tumor Cells, Cultured
Chemicals
DNA Primers Rara protein, mouse Receptors, Retinoic Acid Recombinant Proteins Retinoic Acid Receptor alpha Retinoids retinoic acid receptor gamma Tretinoin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Boylan J F
Department of Pharmacology, Cornell University Medical College, New York, New York 10021.
Lufkin T
Achkar C C
Taneja R
Chambon P
Gudas L J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.15.2.843
Published
1995-02-00
Pages
843-51
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231962
Subset
IM
Grants
NCI NIH HHS · 1F32 CA09251-01 · United States
NCI NIH HHS · R01CA43796 · United States
NICHD NIH HHS · R01HD24319 · United States
External Links
PubMed source DOI: 10.1128/MCB.15.2.843 PMC Full Text View journal details
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