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PMID: 9348290 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Specific and redundant functions of retinoid X Receptor/Retinoic acid receptor heterodimers in differentiation, proliferation, and apoptosis of F9 embryonal carcinoma cells.

The Journal of cell biology ·Vol. 139 ·No. 3 ·1997-11-03 ·Pages 735-47

Chiba H, Clifford J, Metzger D, Chambon P

Abstract

We have generated F9 murine embryonal carcinoma cells in which either the retinoid X receptor (RXR)alpha and retinoic acid receptor (RAR)alpha genes or the RXRalpha and RARgamma genes are knocked out, and compared their phenotypes with those of wild-type (WT), RXRalpha-/-, RARalpha-/-, and RARgamma-/- cells. RXRalpha-/-/ RARalpha-/- cells were resistant to retinoic acid treatment for the induction of primitive and parietal endodermal differentiation, as well as for antiproliferative and apoptotic responses, whereas they could differentiate into visceral endodermlike cells, as previously observed for RXRalpha-/- cells. In contrast, RXRalpha-/-/RARgamma-/- cells were defective for all three types of differentiation, as well as antiproliferative and apoptotic responses, indicating that RXRalpha and RARgamma represent an essential receptor pair for these responses. Taken together with results obtained by treatment of WT and mutant F9 cells with RAR isotype- and panRXR-selective retinoids, our observations support the conclusion that RXR/ RAR heterodimers are the functional units mediating the retinoid signal in vivo. Our results also indicate that the various heterodimers can exert both specific and redundant functions in differentiation, proliferation, and apoptosis. We also show that the functional redundancy exhibited between RXR isotypes and between RAR isotypes in cellular processes can be artifactually generated by gene knockouts. The present approach for multiple gene targeting should allow inactivation of any set of genes in a given cell.

MeSH Terms
Animals Apoptosis/drug effects,genetics,physiology Cell Differentiation/drug effects,genetics Cell Division/drug effects,genetics Dimerization Embryonal Carcinoma Stem Cells Endoderm/physiology Mice Mutagenesis, Site-Directed Neoplastic Stem Cells/drug effects,metabolism,pathology Nuclear Proteins/drug effects,genetics,physiology Receptors, Retinoic Acid/drug effects,genetics,physiology Retinoid X Receptors Retinoids/pharmacology Transcription Factors/drug effects,genetics,physiology Tumor Cells, Cultured
Chemicals
Nuclear Proteins Receptors, Retinoic Acid Retinoid X Receptors Retinoids Transcription Factors
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Chiba H
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, Collège de France, 67404 Illkirch-Cedex, France.
Clifford J
Metzger D
Chambon P
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.139.3.735
Published
1997-11-03
Pages
735-47
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2141719
Subset
IM
Grants
NIGMS NIH HHS · IF32GM15857 · United States
External Links
PubMed source DOI: 10.1083/jcb.139.3.735 PMC Full Text View journal details
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