Keap1: One stone kills three birds Nrf2, IKK¦Â and Bcl-2/Bcl-xL

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• 作者：Hui Tian ; BaoFu Zhang ; JieHui Di ; Guan Jiang ; FeiFei Chen ; HuiZhong Li ; LianTao Li ; DongSheng Pei ; JunNian Zheng
• 关键词：Keap1 ; Nrf2 ; IKK¦Â ; Bcl-2/Bcl-xL
• 刊名：Cancer Letters
• 出版年：2012
• 出版时间：1 December, 2012
• 年：2012
• 卷：325
• 期：1
• 页码：26-34
• 全文大小：702 K

文摘

Oxidative stress, implicated in the etiology of cancer, results from an imbalance in the production of Reactive Oxygen Species (ROS) and cell¡¯s own antioxidant defenses. As a oxidative stress sensor, Keap1 functions as both an adaptor for Cul3?Rbx1 E3 ligase complex mediated degradation of the transcription factor Nrf2, and a master regulator of cytoprotective gene expression. Although Nrf2 is a well known substrate for Keap1, the DGR domain of Keap1 has been reported also to bind other proteins directly or indirectly. IKK¦Â as positive regulator of NF-¦ÊB is also destabilized by Keap1, which resulted in inhibiting NF-¦ÊB-derived tumor promotion. In addition, anti-apoptotic Bcl-2/Bcl-xL protein was identified as another substrate for the Keap1-Cul3-E3 ligase complex. Keap1 led to the repression and destabilization of Bcl-2, decreased Bcl-2:Bax heterodimers and facilitated cancer cells apoptosis. Given that Keap1 might function as a tumor suppressor protein to mitigate tumor progression, the different kinds of Keap1 somatic mutations were detected in numerous cancer cells. Therefore, it is important to understand the Keap1-involved signaling cascades. This review primarily focuses on the prevention of tumorigenesis role of Keap1 through negative regulation of three substrates Nrf2, IKK¦Â and Bcl-2/Bcl-xL, with emphasis on the recent findings indicating the cancer guarder function of Keap1.