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Distinct Roles for Cellular Retinoic Acid-binding Proteins I and II in Regulating Signaling by Retinoic Acid
Open accessAbstract
The pleiotropic effects of retinoic acid (RA) in mammalian cells are mediated by two classes of proteins: the retinoic acid receptors (RAR) and cellular retinoic acid-binding proteins (CRABP-I and CRABP-II). Here we show that expression of CRABP-II, but not CRABP-I, markedly enhanced RAR-mediated transcriptional activation of a reporter gene in COS-7 cells. The equilibrium dissociation constants of complexes of CRABP-I or CRABP-II with RA were found to differ by 2-fold. It is thus unlikely that the distinct effects of the two proteins on transactivation stem from differential ligand-binding affinities. The mechanisms by which RA transfers from the CRABPs to RAR were thus investigated directly. The rate constant for movement of RA from CRABP-II, but not from CRABP-I, to RAR strongly depended on the concentration of the acceptor. The data suggest that transfer of RA from CRABP-I to RAR involves dissociation of the ligand from the binding protein, followed by association with the receptor. In contrast, movement of RA from CRABP-II to the receptor is facilitated by a mechanism that involves direct interactions between CRABP-II and RAR. These findings reveal a striking functional difference between CRABP-I and CRABP-II, and point at a novel mechanism by which the transcriptional activity of RA can be regulated by CRABP-II.
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In the citing paper
“It is a small cytosolic protein, which specifi cally associates with RA with subnanomolar affi nities.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [19]
In the citing paper
“The resulting complex channels RA from the binding protein to the RAR and markedly facilitates the formation of the liganded receptor.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [19]
In the citing paper
“Upon binding of RA, CRABPII mobilizes to the nucleus, where it associates with RARs through direct protein-protein interactions (17)(18)(19).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [19]
In the citing paper
“In the cytosol, RA is well known to bind the cellular retinoic acid-binding protein CRABPII, which belongs to the intracellular lipid binding proteins iLBP family.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [19]
In the citing paper
“It was demonstrated that by directly delivering RA to RARs, CRABPII significantly enhances the transcriptional activity of RARs and sensitizes the cells to RA biological activities.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [19]
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Metadata
- Authors
- Dong, D., Ruuska, S. E., Levinthal, D. J., & Noy, N.
- Affiliations
- Cornell University (US)
- Corresponding author
- Noy, Noa
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-08
- Volume
- 274
- Issue
- 34
- Pages
- 23695-23698
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2001068122
- Cited by
- 362
- References
- 29
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 10 · 2023: 11 · 2022: 9 · 2021: 12 · 2020: 14 · 2019: 16 · 2018: 4 · 2017: 15 · 2016: 19 · 2015: 18 · 2014: 20 · 2013: 17 · 2012: 15
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 68150, R01CA068150)
- National Institute of Diabetes and Digestive and Kidney Diseases (5-T32-DK07158, T32DK007158)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- retinoic acid, cellular retinoic acid-binding protein I, CRABP2, retinoic acid receptor, ligand transfer, transcriptional activation, ligand dissociation, protein-protein interaction, ligand binding affinity
- MeSH terms
- Animals, Tretinoin, Transcriptional Activation, Receptors, Retinoic Acid, COS Cells
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