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The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence
Open accessAbstract
The tumor suppressor proteins p16 INK4A and p14 ARF, encoded by the INK4A–ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS–RAF signaling pathway. JMJD3 is recruited to the INK4A–ARF locus and contributes to the transcriptional activation of p16 INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16 Ink4a and p19 Arf expression and in their immortalization.
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“For example, oncogene activation induces the expression of the histone 3 Lys27 (H3K27) demethylase, Jumonji domain-containing D3 (JMJD3), which removes the repressive H3K27 tri-methylation marks and thereby promotes p16 expression [19].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [19]
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“During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2 [83], and recruitment of JMJD3 [84,85], a histone lysine demethylase that catalyzes H3K27 demethylation, lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [84]
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Metadata
- Authors
- Agger, K., Cloos, P. A. C., Rudkjær, L., Williams, K., Andersen, G., Christensen, J., & Helin, K.
- Affiliations
- University of Copenhagen (DK)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2009-05-15
- Volume
- 23
- Issue
- 10
- Pages
- 1171-1176
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2685535
- OpenAlex
- W1970592702
- Cited by
- 427
- References
- 26
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 13 · 2023: 13 · 2022: 10 · 2021: 24 · 2020: 23 · 2019: 22 · 2018: 23 · 2017: 21 · 2016: 33 · 2015: 23 · 2014: 36 · 2013: 36 · 2012: 48
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Kræftens Bekæmpelse
- Sundhed og Sygdom, Det Frie Forskningsråd
- National Research Foundation
- Danmarks Grundforskningsfond
- Lundbeckfonden
- Novo Nordisk
- Harboefonden
- Novo Nordisk Fonden
- H. Lundbeck A/S
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- JMJD3, H3K27 demethylase, H3K27me3, INK4a/ARF locus, p16INK4a, p14ARF, cellular senescence, oncogene-induced senescence, stress-induced senescence, Ras/Raf signaling, histone demethylation, epigenetic silencing, transcriptional activation, cell immortalization, histone demethylase
- MeSH terms
- Animals, Cell Line, Fibroblasts, Gene Expression Regulation, Humans, Neoplasms, Oncogenes, Oxidoreductases, N-Demethylating, Stress, Physiological, Cellular Senescence, ras Proteins, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, raf Kinases, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice, Jumonji Domain-Containing Histone Demethylases
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