JMJD5 interacts with p53 and negatively regulates p53 function in control of cell cycle and proliferation
JMJD5 interacts with p53 and negatively regulates p53 function in control of cell cycle and proliferation
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JMJD5 与 p53 相互作用并负向调节 p53 控制细胞周期和增殖的功能。
DOI：
10.1016/j.bbamcr.2015.05.026
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发表时间：
2015-10-01
影响因子：
5.1
通讯作者：
Shen, Jing
中科院分区：
文献类型：
--
作者：
Huang, Xiaobin;Zhang, Shuilian;Shen, Jing
JMJD 5是一种含有Jumonji C结构域的脱甲基酶/羟化酶，在胚胎发育、骨细胞成熟、昼夜节律调节和癌症代谢中至关重要。然而，其在肿瘤发生中的作用和潜在机制仍不清楚。在这里，我们证明了JMJD 5通过与p53 DNA结合结构域（DBD）相互作用与肿瘤抑制因子p53形成复合物，并负调控其活性。JMJD 5的下调导致多个p53下游基因（例如细胞周期抑制剂CDKN 1A和DNA修复效应子P53 R2）的表达增加，仅在p53活性肺癌细胞中。在DNA损伤后，JMJD 5-p53结合减少，从而促进p53募集到靶基因并刺激其转录活性。此外，在正常和DNA损伤条件下，JMJD 5以p53依赖的方式促进细胞周期进展。在p53存在下，JMJD 5的耗尽抑制细胞增殖并增强阿霉素诱导的细胞生长抑制。总之，我们的研究结果表明，JMJD 5是一种新的p53结合伴侣，它作为一个积极的调节细胞周期和细胞增殖主要通过抑制p53途径。我们的研究扩展了对JMJD 5在癌症发展中功能的机制理解，并暗示JMJD 5是癌症的潜在治疗靶点。(C)2015 Elsevier B. V.版权所有。
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. (C) 2015 Elsevier B.V. All rights reserved.