The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence

Karl Agger; Paul A C Cloos; Lise Rudkjaer; Kristine Williams; Gitte Andersen; Jesper Christensen; Kristian Helin

doi:10.1101/gad.510809

The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence

Karl Agger, Paul A C Cloos, Lise Rudkjaer, Kristine Williams, Gitte Andersen, Jesper Christensen, Kristian Helin

317 Citations (Scopus)

Abstract

The tumor suppressor proteins p16INK4A and p14ARF, 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 p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.

Original language	English
Journal	Genes & Development
Volume	23
Issue number	10
Pages (from-to)	1171-6
Number of pages	5
ISSN	0890-9369
DOIs	https://doi.org/10.1101/gad.510809
Publication status	Published - 2009

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@article{76a71af05ff611dea8de000ea68e967b,

title = "The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence",

abstract = "The tumor suppressor proteins p16INK4A and p14ARF, 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 p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.",

author = "Karl Agger and Cloos, {Paul A C} and Lise Rudkjaer and Kristine Williams and Gitte Andersen and Jesper Christensen and Kristian Helin",

note = "Keywords: Animals; Cell Aging; Cell Line; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16; Fibroblasts; Gene Expression Regulation; Genes, p16; Humans; Mice; Neoplasms; Oncogenes; Oxidoreductases, N-Demethylating; Proto-Oncogene Proteins B-raf; Stress, Physiological; raf Kinases; ras Proteins",

year = "2009",

doi = "10.1101/gad.510809",

language = "English",

volume = "23",

pages = "1171--6",

journal = "Genes & Development",

issn = "0890-9369",

publisher = "Cold Spring Harbor Laboratory Press",

number = "10",

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TY - JOUR

T1 - The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence

AU - Agger, Karl

AU - Cloos, Paul A C

AU - Rudkjaer, Lise

AU - Williams, Kristine

AU - Andersen, Gitte

AU - Christensen, Jesper

AU - Helin, Kristian

N1 - Keywords: Animals; Cell Aging; Cell Line; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16; Fibroblasts; Gene Expression Regulation; Genes, p16; Humans; Mice; Neoplasms; Oncogenes; Oxidoreductases, N-Demethylating; Proto-Oncogene Proteins B-raf; Stress, Physiological; raf Kinases; ras Proteins

PY - 2009

Y1 - 2009

N2 - The tumor suppressor proteins p16INK4A and p14ARF, 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 p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.

AB - The tumor suppressor proteins p16INK4A and p14ARF, 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 p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.

U2 - 10.1101/gad.510809

DO - 10.1101/gad.510809

M3 - Journal article

C2 - 19451217

SN - 0890-9369

VL - 23

SP - 1171

EP - 1176

JO - Genes & Development

JF - Genes & Development

IS - 10

ER -

The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence

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