Cyclin H binding to the RARα activation function (AF)-2 domain directs phosphorylation of the AF-1 domain by cyclin-dependent kinase 7
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The transcriptional activity of nuclear retinoic acid receptors (RARs), which act as RAR/retinoid X receptor (RXR) heterodimers, depends on two activation functions, AF-1 and AF-2, which are targets for phosphorylations and synergize for the activation of retinoic acid target genes. The N-terminal AF-1 domain of RARα is phosphorylated at S77 by the cyclin-dependent kinase (cdk)-activating kinase (CAK) subcomplex (cdk7/cyclin H/MAT1) of the general transcription factor TFIIH. Here, we show that phosphorylation of S77 governing the transcriptional activity of RARα depends on cyclin H binding at a RARα region that encompasses loop 8–9 and the N-terminal tip of helix 9 of the AF-2 domain. We propose a model in which the structural constraints of this region control the architecture of the RAR/RXR/TFIIH complex and therefore the efficiency of RARα phosphorylation by cdk7. To our knowledge, this study provides the first example of a cooperation between the AF-2 and AF-1 domains of RARs through a kinase complex.
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The correct positioning of cdk7 and the efficiency of NTD phosphorylation by cdk7 rely on the docking of cyclin H at a specific site of the LBD located in loop L8-9 and the N-terminal part of H9.
“The correct positioning of the cdk7 kinase and thereby the effi ciency of the NTD phosphorylation by cdk7 rely on the docking of cyclin H at a specifi c site of the LBD located in loop L8-9 and the N-terminal part of H9 ( 36 ) ( Fig. 2B ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [36]
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Rochette-Egly, C., Adam, S., Rossignol, M., Egly, J.-M., & Chambon, P. (1997) · Cell · doi:10.1016/s0092-8674(00)80317-7 · Cited by 308 · see citing works
Self-citationKeriel, A., Stary, A., Sarasin, A., Rochette-Egly, C., & Egly, J.-M. (2002) · Cell · doi:10.1016/s0092-8674(02)00692-x · Cited by 192 · see citing works
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Retinoic acid receptors: From molecular mechanisms to cancer therapy
di Masi, A., Leboffe, L., De Marinis, E., Pagano, F., Cicconi, L., Rochette-Egly, C., Lo-Coco, F., Ascenzi, P., & Nervi, C. (2015) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2014.12.003 · Cited by 403 · see citing works
Self-citationVitamin A and retinoid signaling: genomic and nongenomic effects
Al Tanoury, Z., Piskunov, A., & Rochette-Egly, C. (2013) · Journal of Lipid Research · doi:10.1194/jlr.r030833 · Cited by 408 · see citing works
Self-citationA coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARα to target promoters
Bruck, N., Vitoux, D., Ferry, C., Duong, V., Bauer, A., de Thé, H., & Rochette‐Egly, C. (2009) · The EMBO Journal · doi:10.1038/emboj.2008.256 · Cited by 108 · see citing works
Self-citationAllosteric Regulation in the Ligand Binding Domain of Retinoic Acid Receptorγ
Chebaro, Y., Sirigu, S., Amal, I., Lutzing, R., Stote, R. H., Rochette-Egly, C., Rochel, N., & Dejaegere, A. (2017) · PLOS ONE · doi:10.1371/journal.pone.0171043 · Cited by 8 · see citing works
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- Authors
- Bour, G., Gaillard, E., Bruck, N., Lalevée, S., Plassat, J.-L., Busso, D., Samama, J.-P., & Rochette-Egly, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Département de Biologie Cellulaire et de Transduction du Signal and Département de Biologie et Génomique Structurales, 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, UMR 7104, BP 10142, 67404 Illkirch Cedex, France
- ORCID
- Busso, Didier
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-11-07
- Volume
- 102
- Issue
- 46
- Pages
- 16608-16613
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1283805
- OpenAlex
- W2105412223
- Cited by
- 45
- References
- 2
- Citations by year
- 2026: 2 · 2023: 1 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2015: 5 · 2014: 5 · 2013: 2 · 2012: 3
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- 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 › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- retinoic acid receptor alpha, AF-2, activation functions, cyclin H, cyclin-dependent kinase 7, CDK7, protein phosphorylation, TFIIH, protein-protein interaction, transcriptional activation
- MeSH terms
- Retinoic Acid Receptor alpha, Cyclin-Dependent Kinase-Activating Kinase, Animals, Base Sequence, Cell Line, Models, Molecular, Phosphorylation, Protein Binding, Transcription, Genetic, Cyclins, DNA Primers, Receptors, Retinoic Acid, Spodoptera, Cyclin-Dependent Kinases, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Cyclin H
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