Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence.
Open accessAbstract
Oncogene-induced senescence (OIS) is a potent tumor-suppressive mechanism that is thought to come at the cost of aging. The Forkhead box O (FOXO) transcription factors are regulators of life span and tumor suppression. However, whether and how FOXOs function in OIS have been unclear. Here, we show a role for FOXO4 in mediating senescence by the human BRAF(V600E) oncogene, which arises commonly in melanoma. BRAF(V600E) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-Jun NH(2) terminal kinase-mediated activation of FOXO4 via its phosphorylation on Thr(223), Ser(226), Thr(447), and Thr(451). BRAF(V600E)-induced FOXO4 phosphorylation resulted in p21(cip1)-mediated cell senescence independent of p16(ink4a) or p27(kip1). Importantly, melanocyte-specific activation of BRAF(V600E) in vivo resulted in the formation of skin nevi expressing Thr(223)/Ser(226)-phosphorylated FOXO4 and elevated p21(cip1). Together, these findings support a model in which FOXOs mediate a trade-off between cancer and aging.
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Increased expression of p21 has been implicated in induction of cellular senescence independent of p16.
“increased expression of p21 has been implicated in induction of cellular senescence independent of p16.44,45”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [44]
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References 52 · Cited by 94
- Authors
- de Keizer, P. L. J., Packer, L. M., Szypowska, A. A., Riedl-Polderman, P. E., van den Broek, N. J. F., de Bruin, A., Dansen, T. B., Marais, R., Brenkman, A. B., & Burgering, B. M. T.
- Affiliations
- Authors' Affiliations: 1Department of Physiological Chemistry and Center for Biomedical Genetics, University Medical Center Utrecht; 2Department Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; and 3Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, Institute of Cancer Research, London, United Kingdom
- Institute of Cancer Research (GB)
- Corresponding author
- Burgering, Boudewijn M.T.
- Venue
- Cancer Research
- Published
- 2010-10-31
- Volume
- 70
- Issue
- 21
- Pages
- 8526-8536
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2989643
- OpenAlex
- W2168451979
- Cited by
- 94
- References
- 52
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 10 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 8 · 2017: 5 · 2016: 8 · 2015: 6 · 2014: 4 · 2013: 9 · 2012: 3
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Cancer Research UK (Ref C107/A10433, A10433)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- FOXO4, FOXO transcription factors, oncogene-induced senescence, BRAF V600E mutation, p21, melanoma, ERK signaling, c-Jun N-terminal kinase, reactive oxygen species, skin nevi, tumor suppression
- MeSH terms
- Animals, Colony-Forming Units Assay, Humans, Melanocytes, Melanoma, Phosphorylation, RNA, Messenger, Skin Neoplasms, Transcription Factors, Blotting, Western, Signal Transduction, Cellular Senescence, Apoptosis, Reactive Oxygen Species, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p16, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Xenograft Model Antitumor Assays, RNA, Small Interfering, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins B-raf, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Mice, Forkhead Transcription Factors
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