德克萨斯大学M. D. Anderson癌症研究中心在本周的Molecular Cell发表了他们的研究报告，他们发现一种肿瘤抑制蛋白KEAP1能够“抓住”致癌酶IKKβ(IkB kinase β)，对其进行分子标记并进行破坏。
KEAP1(Kelch-like ECH-associated protein 1)是最近发现的一种肿瘤抑制因子，但其作用机制尚不清楚；为一种重要肿瘤蛋白，能通过两种不同的方式引发癌症，其调节机制也还未知，据报告作者Mien-Chie Hung称，这篇研究报告将能同时回答上述两个问题。
研究表明，KEAP1能结合到IKKβ上并与泛素连接。此外，研究人员还发现，KEAP1表达量低与乳腺癌患者的高死亡率有关，在一些乳腺癌，肝癌，肺癌以及结肠癌患者中，KEAP1发生了突变和失活。
阻断IKKβ的过量表达非常关键，研究表明IKKβ能一直至少两种以上重要的肿瘤抑制因子，而且，IKK?能激活NF-κB(nuclear factor-κb)信号通路，NF-κB信号通路能调节包括免疫应答，细胞增殖，血管生成，肿瘤侵润生长及转移等多种基因表达。
Hung及其同事通过一系列实验首次证实KEAP1能抑制NF-κB信号通路。他们发现KEAP1的减少能引起IKKβ积累，然后肿瘤抑制因子能结合到IKKβ的特殊位点，并呈递给蛋白酶复合体进行分解。
KEAP1是一种泛素连接酶，与另一种连接泛素的蛋白CUL3组成复合体与靶蛋白相连。研究人员对119名乳腺癌患者的KEAP1和 CUL3同时进行分析，发现KEAP1表达量低与乳腺癌患者的高死亡率有关，而KEAP1和CUL3二者同时高表达水平能提高80%的生存率。
研究人员对26个癌细胞株及119种原发性肿瘤的KEAP1基因进行测序，发现有两个基因发生了功能性突变，并引起调节IKKβ的蛋白关闭。这两个突变还影响KEAP1蛋白结合到IKKβ的能力。（生物谷Bioon.com）
生物谷推荐原始出处：
Molecular Cell,9 October 2009 doi:10.1016/j.molcel.2009.07.025
KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ
Dung-Fang Lee1, 2, Hsu-Ping Kuo1, 2, 8, Mo Liu1, 2, 8, Chao-Kai Chou1, 2, 8, Weiya Xia1, Yi Du1, 2, Jia Shen1, 2, Chun-Te Chen1, 2, Longfei Huo1, Ming-Chuan Hsu1, Chia-Wei Li1, Qingqing Ding1, Tsai-Lien Liao3, Chien-Chen Lai4, 5, Ann-Chi Lin3, Ya-Hui Chang3, Shih-Feng Tsai3, Long-Yuan Li6, 7 and Mien-Chie Hung1, 2, 6, 7, ,
1 Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
2 Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
3 Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan
4 Graduate Institute of Chinese Medical Science, China Medical University, Taichung 404, Taiwan
5 Institute of Molecular Biology, National Chung Hsing University, Taichung 402, Taiwan
6 Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung 404, Taiwan
7 Asia University, Taichung 413, Taiwan
IκB kinase β (IKKβ) is involved in tumor development and progression through activation of the nuclear factor (NF)-κB pathway. However, the molecular mechanism that regulates IKKβ degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKβ ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKβ and to upregulation of NF-κB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKβ degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKβ ubiquitination may contribute to tumorigenesis.
