title: JMJD5 interacts with p53 and negatively regulates p53 function in control of cell cycle and proliferation.
abstract: JMJD5 is a Jumonji C domain-containing demethylase/hydroxylase shown to be essential in embryological development, osteoclastic maturation, circadian rhythm regulation and cancer metabolism. However, its role and underlying mechanisms in oncogenesis remain unclear. Here, we demonstrate that JMJD5 forms complex with the tumor suppressor p53 by interacting with p53 DNA-binding domain (DBD), and negatively regulates its activity. Downregulation of JMJD5 resulted in increased expression of multiple p53 downstream genes, such as the cell cycle inhibitor CDKN1A and DNA repair effector P53R2, only in p53-proficient lung cancer cells. Upon DNA damage, the JMJD5-p53 association decreased, and thereby, promoted p53 recruitment to the target genes and stimulated its transcriptional activity. Furthermore, JMJD5 facilitated the cell cycle progression in a p53-dependent manner under both normal and DNA damage conditions. Depletion of JMJD5 inhibited cell proliferation and enhanced adriamycin-induced cell growth suppression in the presence of p53. Collectively, our results reveal that JMJD5 is a novel binding partner of p53 and it functions as a positive modulator of cell cycle and cell proliferation mainly through the repression of p53 pathway. Our study extends the mechanistic understanding of JMJD5 function in cancer development and implicates JMJD5 as a potential therapeutic target for cancer.
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Shuilian
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Pulmonology, Sir Run Run Shaw Hospital, Hangzhou 310016, China.
authors.forename: Zhengyang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA, USA.
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: shaojimin@zju.edu.cn.
authors.forename: Jimin
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: shenjingwzy@zju.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D056466:Histone Demethylases; C550342:KDM8 protein, human; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases
keywords: Cancer development; Cell cycle; Gene transcription; JMJD5; p53 tumor suppressor