title: SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence.
abstract: Recent evidence has revealed that senescence induction requires fine-tuned activation of p53, however, mechanisms underlying the regulation of p53 activity during senescence have not as yet been clearly established. We demonstrate here that SCF(Fbxo22)-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCF(Fbxo22) ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. Ectopic expression of a catalytic mutant of KDM4A stabilizes p53 and enhances p53 interaction with PHF20 in the presence of Fbxo22. SCF(Fbxo22)-KDM4A is required for the induction of p16 and senescence-associated secretory phenotypes during the late phase of senescence. Fbxo22(-/-) mice are almost half the size of Fbxo22(+/-) mice owing to the accumulation of p53. These results indicate that SCF(Fbxo22)-KDM4A is an E3 ubiquitin ligase that targets methylated p53 and regulates key senescent processes.
authors: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Yoshikazu
authors: Y
authors: Johmura
authors: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Jia
authors: J
authors: Sun
authors: Department of Molecular Biology, Hamamatsu University School of Medicine, Higashi-ku, 431-3192 Hamamatsu, Japan.
authors: Kyoko
authors: K
authors: Kitagawa
authors: Department of Perinatology, Aichi Human Service Center, Institute for Developmental Research, 713-8 Kamiya-cho, Kasugai, Aichi 489-0392, Japan.
authors: Keiko
authors: K
authors: Nakanishi
authors: Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Toshiya
authors: T
authors: Kuno
authors: Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Aya
authors: A
authors: Naiki-Ito
authors: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Yumi
authors: Y
authors: Sawada
authors: Department of Comparative and Experimental Medicine and Center for Animal Sciences, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Tomomi
authors: T
authors: Miyamoto
authors: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, 153-8904 Tokyo, Japan.
authors: Atsushi
authors: A
authors: Okabe
authors: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, 153-8904 Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Zhongshan Hospital of Dalian University, 6 Jiefang St, Zhongshan District, 116001 Dalian, China.
authors: ShengFan
authors: S
authors: Li
authors: Department of Comparative and Experimental Medicine and Center for Animal Sciences, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Ichiro
authors: I
authors: Miyoshi
authors: Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Satoru
authors: S
authors: Takahashi
authors: Department of Molecular Biology, Hamamatsu University School of Medicine, Higashi-ku, 431-3192 Hamamatsu, Japan.
authors: Masatoshi
authors: M
authors: Kitagawa
authors: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601 Nagoya, Japan.
authors: Makoto
authors: M
authors: Nakanishi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D047369:Chromatin Immunoprecipitation; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D005434:Flow Cytometry; D057809:HEK293 Cells; D006367:HeLa Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D061986:MCF-7 Cells; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C561886:FBXO22 protein, human; C000608615:Fbxo22 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D056466:Histone Demethylases; C560307:JMJD2A protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D044767:Ubiquitin-Protein Ligases