Direct Channeling of Retinoic Acid between Cellular Retinoic Acid-Binding Protein II and Retinoic Acid Receptor Sensitizes Mammary Carcinoma Cells to Retinoic Acid-Induced Growth Arrest
Open accessAbstract
Cellular retinoic acid-binding protein II (CRABP-II) is an intracellular lipid-binding protein that associates with retinoic acid with a subnanomolar affinity. We previously showed that CRABP-II enhances the transcriptional activity of the nuclear receptor with which it shares a common ligand, namely, the retinoic acid receptor (RAR), and we suggested that it may act by delivering retinoic acid to this receptor. Here, the mechanisms underlying the effects of CRABP-II on the transcriptional activity of RAR and the functional consequences of these effects were studied. We show that CRABP-II, a predominantly cytosolic protein, massively undergoes nuclear localization upon binding of retinoic acid; that it interacts with RAR in a ligand-dependent fashion; and that, in the presence of retinoic acid, the CRABP-II-RAR complex is a short-lived intermediate. The data establish that potentiation of the transcriptional activity of RAR stems directly from the ability of CRABP-II to channel retinoic acid to the receptor. We demonstrate further that overexpression of CRABP-II in MCF-7 mammary carcinoma cells dramatically enhances their sensitivity to retinoic acid-induced growth inhibition. Conversely, diminished expression of CRABP-II renders these cells retinoic acid resistant. Taken together, the data unequivocally establish the function of CRABP-II in modulating the RAR-mediated biological activities of retinoic acid.
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In the cytosol, RA binds CRABPII, which belongs to the intracellular lipid binding protein (iLBP) family.
“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 [17]
The resulting complex channels RA from the binding protein to the RAR and markedly facilitates the formation of the liganded receptor.
“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 [17]
CRABPII specifically associates with RA with subnanomolar affinities.
“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 [17]
CRABPII significantly enhances the transcriptional activity of RARs and sensitizes the cells to RA biological activities.
“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 [17]
Upon binding of RA, CRABPII mobilizes to the nucleus, where it associates with RARs through direct protein-protein interactions.
“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 [17]
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BackgroundMultiplicity generates diversity in the retinoic acid signalling pathways
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- Authors
- Budhu, A. S., & Noy, N.
- Affiliations
- Cornell University (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2002-04-01
- Volume
- 22
- Issue
- 8
- Pages
- 2632-2641
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC133717
- OpenAlex
- W2122256734
- Cited by
- 296
- References
- 4
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 7 · 2023: 5 · 2022: 5 · 2021: 10 · 2020: 6 · 2019: 7 · 2018: 12 · 2017: 9 · 2016: 16 · 2015: 14 · 2014: 19 · 2013: 11 · 2012: 20
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- 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
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- CRABP2, retinoic acid receptor, retinoic acid, nuclear localization, transcriptional activity, breast cancer, MCF-7 cells, growth arrest, retinoic acid resistance, nuclear receptor ligand binding
- MeSH terms
- Animals, Biological Transport, Active, Breast Neoplasms, Cell Division, Female, Humans, Ligands, Models, Biological, Recombinant Fusion Proteins, Transcription, Genetic, Tretinoin, Receptors, Retinoic Acid, COS Cells, Mice, In Vitro Techniques
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