Akt phosphorylates and suppresses the transactivation of retinoic acid receptor α
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The transactivation of nuclear receptors is regulated by both ligand binding and phosphorylation. We previously showed that RARα (retinoic acid receptor α) phosphorylation by c-Jun N-terminal kinase contributes to retinoid resistance in a subset of NSCLC cells (non-small cell lung cancer cells), but the aetiology of this resistance in the remainder has not been fully elucidated [Srinivas, Juroske, Kalyankrishna, Cody, Price, Xu, Narayanan, Weigel and Kurie (2005) Mol. Cell. Biol. 25, 1054–1069]. In the present study, we report that Akt, which is constitutively activated in NSCLC cells, phosphorylates RARα and inhibits its transactivation. Biochemical and functional analyses showed that Akt interacts with RARα and phosphorylates the Ser96 residue of its DNA-binding domain. Mutation of Ser96 to alanine abrogated the suppressive effect of Akt. Overexpression of a dominant-negative form of Akt in an NSCLC cell line decreased RAR phosphorylation, increased RAR transactivation and enhanced the growth-inhibitory effects of an RAR ligand. The findings presented here show that Akt inhibits RAR transactivation and contributes to retinoid resistance in a subset of NSCLC cells.
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In these cancers and others, the RA-induced activation of the MAPK pathway is abrogated, and RARα and RXRα are aberrantly phosphorylated.
“Most interestingly, in these cancers and others, the RA-induced activation of the MAPK pathway is abrogated ( 115 ), and RAR ␣ and RXR ␣ are aberrantly phosphorylated ( 166-168 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [167]
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Hybrid analysis of gene dynamics predicts context-specific expression and offers regulatory insights
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Swanson, G. M., Nassan, F. L., Ford, J. B., Hauser, R. B., Pilsner, J. R., & Krawetz, S. A. (2024) · Figshare · doi:10.6084/m9.figshare.26563770
Swanson, G. M., Nassan, F. L., Ford, J. B., Hauser, R. B., Pilsner, J. R., & Krawetz, S. A. (2024) · Figshare · doi:10.6084/m9.figshare.26563758
Swanson, G. M., Nassan, F. L., Ford, J. B., Hauser, R. B., Pilsner, J. R., & Krawetz, S. A. (2024) · Figshare · doi:10.6084/m9.figshare.26563773
Swanson, G. M., Nassan, F. L., Ford, J. B., Hauser, R. B., Pilsner, J. R., & Krawetz, S. A. (2024) · Figshare · doi:10.6084/m9.figshare.26563761
Swanson, G. M., Nassan, F. L., Ford, J. B., Hauser, R. B., Pilsner, J. R., & Krawetz, S. A. (2024) · Figshare · doi:10.6084/m9.figshare.26563779
Swanson, G. M., Nassan, F. L., Ford, J. B., Hauser, R. B., Pilsner, J. R., & Krawetz, S. A. (2024) · Figshare · doi:10.6084/m9.figshare.26563767
Swanson, G. M., Nassan, F. L., Ford, J. B., Hauser, R. B., Pilsner, J. R., & Krawetz, S. A. (2024) · Figshare · doi:10.6084/m9.figshare.26563764
Swanson, G. M., Nassan, F. L., Ford, J. B., Hauser, R. B., Pilsner, J. R., & Krawetz, S. A. (2024) · Figshare · doi:10.6084/m9.figshare.26563782
- Authors
- Srinivas, H., Xia, D., Moore, N. L., Uray, I. P., Kim, H., Ma, L., Weigel, N. L., Brown, P. H., & Kurie, J. M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
- Corresponding author
- Srinivas, Harish
- Xia, Dianren
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2006-04-11
- Volume
- 395
- Issue
- 3
- Pages
- 653-662
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2001536896
- Cited by
- 49
- References
- 53
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2021: 3 · 2020: 2 · 2019: 5 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 2
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- green
- biochemj.org
- Licence
- other-oa
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
- Funders
- National Cancer Institute (R01CA080686)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Akt, retinoic acid receptor alpha, protein phosphorylation, retinoid resistance, non-small cell lung cancer, DNA-binding domain, nuclear receptor regulation, dominant-negative Akt
- MeSH terms
- Retinoic Acid Receptor alpha, Animals, Cell Line, Chlorocebus aethiops, DNA, DNA-Binding Proteins, Humans, Ligands, Mutation, Phosphorylation, Phosphoserine, Protein Binding, Retinoids, Substrate Specificity, Transcriptional Activation, Down-Regulation, Receptors, Retinoic Acid, Proto-Oncogene Proteins c-akt
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