IR@PKUHSC  > 北京大学基础医学院  > 病理学系
学科主题基础医学
JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation
Wang, Feng1; He, Lin1; Huangyang, Peiwei1; Liang, Jing1; Si, Wenzhe1,2; Yan, Ruorong1; Han, Xiao1; Liu, Shumeng1; Gui, Bin1; Li, Wanjin1; Miao, Di3; Jing, Chao4; Liu, Zhihua4; Pei, Fei5; Sun, Luyang1; Shang, Yongfeng1,2
刊名PLOS BIOLOGY
2014-03-01
DOI10.1371/journal.pbio.1001819
12期:3
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology ; Biology
研究领域[WOS]Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics
关键词[WOS]DAMAGE-INDUCED PHOSPHORYLATION ; UBIQUITIN-PROTEIN LIGASE ; DNA-DAMAGE ; PHOSPHATIDYLSERINE RECEPTOR ; BREAST-CANCER ; HISTONE MODIFICATION ; TUMOR-SUPPRESSOR ; APOPTOTIC CELLS ; MDM2 ; ACETYLATION
英文摘要

Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an -ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G(1) phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.

Author Summary JMJD6 belongs to the Jumonji C domain-containing family of proteins. The majority of this family are histone demethylases implicated in chromatin-associated events, but there have also been some reports of lysyl hydroxylase activity for JMJD6. Here we report a new posttranslational modification for the tumor suppressor protein p53 that is mediated by JMJD6. Via a physical associations with p53, JMJD6 catalyzes the hydroxylation of p53, thereby repressing its transcriptional activity. Depletion of JMJD6 promotes cell apoptosis, arrests cells in the G1 phase, sensitizes cells to DNA damaging agent-induced cell death, and represses p53-dependent colon cell proliferation and tumorigenesis. Significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.

语种英语
WOS记录号WOS:000333406800001
项目编号91219201 ; 81130048 ; 81071673 ; 81372223 ; 2011CB504204 ; 2014CB542004
资助机构National Natural Science Foundation of China ; Ministry of Science and Technology of China
引用统计
被引频次:27[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/59581
专题北京大学基础医学院_病理学系
北京大学基础医学院
北京大学第三临床医学院_检验科
北京大学第三临床医学院_眼科
北京大学临床肿瘤学院_核医学科
作者单位1.Peking Univ, Dept Biochem & Mol Biol, Key Lab Carcinogenesis & Translat Res, Minist Educ,Sci Ctr, Beijing 100871, Peoples R China
2.Tianjin Med Univ, Dept Biochem & Mol Biol, Collaborat Innovat Ctr Tianjin Med Epigenet 2011, Tianjin Key Lab Med Epigenet, Tianjin, Peoples R China
3.Tsinghua Univ, Prote Facil, Sch Life Sci, Beijing 100084, Peoples R China
4.Chinese Acad Med Sci, Inst Canc, Peking Union Med Coll, State Key Lab Mol Oncol, Beijing 100021, Peoples R China
5.Peking Univ, Dept Pathol, Hlth Sci Ctr, Beijing 100871, Peoples R China
推荐引用方式
GB/T 7714
Wang, Feng,He, Lin,Huangyang, Peiwei,et al. JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation[J]. PLOS BIOLOGY,2014,12(3).
APA Wang, Feng.,He, Lin.,Huangyang, Peiwei.,Liang, Jing.,Si, Wenzhe.,...&Shang, Yongfeng.(2014).JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation.PLOS BIOLOGY,12(3).
MLA Wang, Feng,et al."JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation".PLOS BIOLOGY 12.3(2014).
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