候选院士北大尚永丰最新PNAS文章

　　

生物通报道，09候选院士北京大学基础医学院生化与分子生物学系尚永丰带领的实验室在最新一期的PNAS上发表研究成果，JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation。

 

尚永丰教授2002年全从美国哈佛职回国，回国后曾在Nature上发表雌激素和三苯氧胺对子宫内膜癌发病的机制。主要从事分子肿瘤学，基因专利调控和新基因的克隆鉴定和功能分析方面的研究。

 

本次在PNAS上发表的研究文章主要解析一种泛素化酶对抑癌基因p53的调控作用。P53是人体中的一种抑癌基因，在多种细胞压力条件下p53的变化对基因组的稳定性和完整性具有重要的调控意义，并且对细胞的增殖也具有重要的作用。

 

目前，有几种泛素化连接酶被认为是调控p53的重要组分。在本研究中，尚永丰等人报道了人类Kelch domain-containing F-box Protein（JFK）对p53基因的调节机制。JFK通过与Skp1-Cull1-F-box形成复合物对p53发挥降解的作用。

 

JFK抑制p53依赖的细胞转录，促进细胞凋亡，阻止细胞进入G1期，提高细胞对电离辐射的敏感性诱导细胞死亡。

 

这些数据表明，JFK是p53的负调节因子，同时是维持无压力细胞p53水平的因子。

（生物通 小茜）

生物通推荐原文检索：

JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation

 

Luyang Sun,1, Lei Shi,1, Wenqian Li, Wenhua Yu, Jing Liang, Hua Zhang, Xiaohan Yang, Yan Wang, Ruifang Li, Xingrong Yao, Xia Yi and Yongfeng Shang,2

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China

↵1L. Sun and L. Shi contributed equally to this work.

【Abstract】

The p53 tumor suppressor plays a central role in integrating cellular responses to various stresses. Tight regulation of p53 is thus essential for the maintenance of genome integrity and normal cell proliferation. Currently, several ubiquitin ligases, including the single-subunit RING-finger types—MDM2, Pirh2, and COP1—and the HECT-domain type—ARF-BP1—have been reported to target p53 for degradation. Here, we report the identification of a human Kelch domain-containing F-box protein, JFK. We showed that JFK promotes ubiquitination and degradation of p53. But unlike MDM2, Pirh2, COP1, and ARF-BP1, all of which possess an intrinsic ubiquitin ligase activity, JFK destabilizes p53 through the assembly of a Skp1-Cul1-F-box complex. Significantly, JFK inhibits p53-dependent transcription, and depletion of JFK stabilizes p53, promotes cell apoptosis, arrests cells in the G1 phase, and sensitizes cells to ionizing radiation-induced cell death. These data indicate that JFK is a critical negative regulator of p53 and represents a pathway for the maintenance of p53 levels in unstressed cells. Our experiments link the Skp1-Cul1-F-box system to p53 regulation.