JDP2 (Jun Dimerization Protein 2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence.
JDP2 (Jun dimerization protein 2, an AP-1 transcription factor) is involved in the regulation of the differentiation and proliferation of cells. We report here that JDP2-deficient mouse embryonic fibroblasts (Jdp2(-/-) MEF) are resistant to replicative senescence. In the absence of JDP2, the level of expression of p16(Ink4a), which is known to rise as normal fibroblasts age, fell significantly when cells were cultured for more than 2 months. Conversely, the overexpression of JDP2 induced the expression of genes for p16(Ink4a) and p19(Arf). Moreover, at the promoter of the gene for p16(Ink4a) in Jdp2(-/-) MEF, the extent of methylation of lysine 27 of histone H3 (H3K27), which is important for gene silencing, increased. Polycomb-repressive complexes (PRC-1 and PRC-2), which are responsible for histone methylation, bound efficiently to the promoter to repress the expression of the gene for p16(Ink4a). As a result, JDP2-deficient MEF became resistant to replicative senescence. Our results indicate that JDP2 is involved in the signaling pathway for senescence via epigenetic regulation of the expression of the gene for p16(Ink4a).
Nakade
Koji
K
Gene Engineering Division, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan. nakade@rtc.riken.jp
Pan
Jianzhi
J
Yamasaki
Takahito
T
Murata
Takehide
T
Wasylyk
Bohdan
B
Yokoyama
Kazunari K
KK
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
C417743:Cdkn2a protein, mouse; D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; C491386:Jundp2 protein, mouse; D034741:RNA, Small Interfering; D012097:Repressor Proteins