title: Keap1: one stone kills three birds Nrf2, IKKβ and Bcl-2/Bcl-xL.
abstract: 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. IKKβ as positive regulator of NF-κB is also destabilized by Keap1, which resulted in inhibiting NF-κB-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, IKKβ and Bcl-2/Bcl-xL, with emphasis on the recent findings indicating the cancer guarder function of Keap1.
authors: Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu, PR China.
authors: Hui
authors: H
authors: Tian
authors: Baofu
authors: B
authors: Zhang
authors: JieHui
authors: J
authors: Di
authors: Guan
authors: G
authors: Jiang
authors: FeiFei
authors: F
authors: Chen
authors: HuiZhong
authors: H
authors: Li
authors: LianTao
authors: L
authors: Li
authors: DongSheng
authors: D
authors: Pei
authors: JunNian
authors: J
authors: Zheng
mesh_terms: D000818:Animals; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D051550:I-kappa B Kinase