德克薩斯大學(xué)M. D. Anderson癌癥研究中心在本周的Molecular Cell發(fā)表了他們的研究報告，他們發(fā)現(xiàn)一種腫瘤抑制蛋白KEAP1能夠“抓住”致癌酶IKKβ(IkB kinase β),，對其進(jìn)行分子標(biāo)記并進(jìn)行破壞,。
KEAP1(Kelch-like ECH-associated protein 1)是最近發(fā)現(xiàn)的一種腫瘤抑制因子，但其作用機(jī)制尚不清楚,；為一種重要腫瘤蛋白,，能通過兩種不同的方式引發(fā)癌癥，其調(diào)節(jié)機(jī)制也還未知,，據(jù)報告作者M(jìn)ien-Chie Hung稱,，這篇研究報告將能同時回答上述兩個問題。
研究表明，KEAP1能結(jié)合到IKKβ上并與泛素連接,。此外,，研究人員還發(fā)現(xiàn)，KEAP1表達(dá)量低與乳腺癌患者的高死亡率有關(guān),，在一些乳腺癌,，肝癌，肺癌以及結(jié)腸癌患者中,，KEAP1發(fā)生了突變和失活,。
阻斷IKKβ的過量表達(dá)非常關(guān)鍵，研究表明IKKβ能一直至少兩種以上重要的腫瘤抑制因子,，而且,，IKK?能激活NF-κB(nuclear factor-κb)信號通路，NF-κB信號通路能調(diào)節(jié)包括免疫應(yīng)答,，細(xì)胞增殖,，血管生成，腫瘤侵潤生長及轉(zhuǎn)移等多種基因表達(dá),。
Hung及其同事通過一系列實(shí)驗(yàn)首次證實(shí)KEAP1能抑制NF-κB信號通路,。他們發(fā)現(xiàn)KEAP1的減少能引起IKKβ積累，然后腫瘤抑制因子能結(jié)合到IKKβ的特殊位點(diǎn),，并呈遞給蛋白酶復(fù)合體進(jìn)行分解,。
KEAP1是一種泛素連接酶，與另一種連接泛素的蛋白CUL3組成復(fù)合體與靶蛋白相連,。研究人員對119名乳腺癌患者的KEAP1和 CUL3同時進(jìn)行分析,，發(fā)現(xiàn)KEAP1表達(dá)量低與乳腺癌患者的高死亡率有關(guān)，而KEAP1和CUL3二者同時高表達(dá)水平能提高80%的生存率,。
研究人員對26個癌細(xì)胞株及119種原發(fā)性腫瘤的KEAP1基因進(jìn)行測序,，發(fā)現(xiàn)有兩個基因發(fā)生了功能性突變，并引起調(diào)節(jié)IKKβ的蛋白關(guān)閉,。這兩個突變還影響KEAP1蛋白結(jié)合到IKKβ的能力,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
