Giudice Aldo, Montella Maurizio
G. Pascale Foundation National Cancer Institute, Unit of Epidemiology and Prevention, Naples, Italy.
Bioessays. 2006 Feb;28(2):169-81. doi: 10.1002/bies.20359.
A major protective mechanism against oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis is the induction of phase II detoxification and antioxidant enzymes by chemopreventive agents. A key finding in the field of chemoprevention has been the discovery that the induction of these enzymes is mediated by the cytoplasmic oxidative stress system (Nrf2-Keap1). Under basal (reducing) conditions, Keap1 anchors the Nrf2 transcription factor within the cytoplasm, targeting it for ubiquitination and proteasome degradation, thus repressing its ability to induce phase II genes. When cells are exposed to chemopreventive agents and oxidative stress, however, a signal involving phosphorylation and/or redox modification is transmitted to the Nrf2-Keap1 complex, leading to its dissociation and the nuclear translocation of Nrf2, which, after hetero-dimerically partnering with other transcription factors, binds to the AREs/EpREs present within phase II gene promoters, increasing their transcription. These data should assist in developing new phase II detoxification enzyme inducers as cancer chemopreventive agents within the clinical environment.
一种针对能够破坏DNA完整性并引发致癌作用的氧化物质的主要保护机制，是化学预防剂诱导II期解毒和抗氧化酶。化学预防领域的一项关键发现是，这些酶的诱导是由细胞质氧化应激系统（Nrf2-Keap1）介导的。在基础（还原）条件下，Keap1将Nrf2转录因子锚定在细胞质中，使其成为泛素化和蛋白酶体降解的靶点，从而抑制其诱导II期基因的能力。然而，当细胞暴露于化学预防剂和氧化应激时，一个涉及磷酸化和/或氧化还原修饰的信号会传递到Nrf2-Keap1复合物，导致其解离以及Nrf2的核转位，Nrf2在与其他转录因子形成异源二聚体后，会与II期基因启动子中的AREs/EpREs结合，增加它们的转录。这些数据应有助于在临床环境中开发新的II期解毒酶诱导剂作为癌症化学预防剂。
