Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression
Open accessAbstract
We previously reported an intricate mechanism underlying the homeostasis of Oct4 expression in normally proliferating stem cell culture of P19, mediated by SUMOylation of orphan nuclear receptor TR2. In the present study, we identify a signaling pathway initiated from the nongenomic activity of all-trans retinoic acid (atRA) to stimulate complex formation of extracellular signal-regulated kinase 2 (ERK2) with its upstream kinase, mitogen-activated protein kinase kinase (MEK). The activated ERK2 phosphorylates threonine-210 (Thr-210) of TR2, stimulating its subsequent SUMOylation. Dephosphorylated TR2 recruits coactivator PCAF and functions as an activator for its target gene Oct4 . Upon phosphorylation at Thr-210, TR2 increasingly associates with promyelocytic leukemia (PML) nuclear bodies, becomes SUMOylated, and recruits corepressor RIP140 to act as a repressor for its target, Oct4 . To normally proliferating P19 stem cell culture, exposure to a physiological concentration of atRA triggers a rapid nongenomic signaling cascade to suppress Oct4 gene and regulate cell proliferation.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In neuronal cells, Sertoli cells, and embryonic stem cells, RA instead activates p42/p44 Erk or classical MAPKs.
“However, in neuronal cells, Sertoli cells, and embryonic stem cells, RA instead activates the p42/p44 extracellular signal-regulated kinases (Erk) or classical MAPKs ( 116-122 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [116]
In RA-treated P19 cells, activated Erks phosphorylate TR2, which then becomes a repressor of the Oct4 gene, thus facilitating the differentiation program expected in response to RA.
“As an example, in RA-treated P19 cells, the activated Erks phosphorylate testicular nuclear receptor 2 (TR2) that then becomes a repressor of the octamer-binding transcription factor 4 ( Oct4 ) gene, thus facilitating the differentiation program that is expected to take place in response to RA ( 116 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [116]
Cites
Rapid effects of retinoic acid on CREB and ERK phosphorylation in neuronal cells
Cañón, E., Cosgaya, J. M., Scsucova, S., & Aranda, A. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-05-0439 · Cited by 184 · see citing works
Chen, N., & Napoli, J. L. (2008) · The FASEB Journal · doi:10.1096/fj.07-8739com · Cited by 166 · see citing works
Ross, A. C. (2003) · The Journal of Nutrition · doi:10.1093/jn/133.1.291s · Cited by 161 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Vitamin 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
Nuclear receptor coactivators: structural and functional biochemistry
Bulynko, Y. A., & O’Malley, B. W. (2011) · Biochemistry · doi:10.1021/bi101762x · Cited by 113 · see citing works
Chebaro, Y., Amal, I., Rochel, N., Rochette-Egly, C., Stote, R. H., & Dejaegere, A. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003012 · Cited by 25 · see citing works
- Authors
- Gupta, P., Ho, P.-C., Huq, M. M., Ha, S. G., Park, S. W., Khan, A. A., Tsai, N.-P., & Wei, L.-N.
- Affiliations
- University of Minnesota (US)
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-08-12
- Volume
- 105
- Issue
- 32
- Pages
- 11424-11429
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2516243
- OpenAlex
- W2085649942
- Cited by
- 74
- References
- 3
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2020: 4 · 2019: 3 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 10 · 2012: 3
- FWCI
- 3.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Philip Morris International
- National Institutes of Health (DK54733, DK60521)
- National Institute on Drug Abuse (DA11190, K02 DA 13926, R01DA011190, K02DA013926)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060521, [DK54733, DK-60521, R01DK054733)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- retinoic acid, SUMOylation, ERK2 phosphorylation, MEK signaling, non-genomic signaling, PML nuclear bodies, stem cell proliferation, P19 cells, transcriptional repression
- MeSH terms
- Promyelocytic Leukemia Protein, Nuclear Receptor Interacting Protein 1, p300-CBP-Associated Factor, Animals, Antineoplastic Agents, Cell Line, Gene Expression Regulation, Homeostasis, Nuclear Proteins, Phosphorylation, Receptors, Thyroid Hormone, Repressor Proteins, Transcription Factors, Tretinoin, Mitogen-Activated Protein Kinase 1, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Tumor Suppressor Proteins, SUMO-1 Protein, Adaptor Proteins, Signal Transducing, Octamer Transcription Factor-3, p300-CBP Transcription Factors, Mice, Embryonic Stem Cells, Nuclear Receptor Subfamily 2, Group C, Member 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
