Nuclear oncoprotein prothymosin α is a partner of Keap1:: Implications for expression of oxidative stress-protecting genes
Nuclear oncoprotein prothymosin α is a partner of Keap1:: Implications for expression of oxidative stress-protecting genes
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DOI：
10.1128/mcb.25.3.1089-1099.2005
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发表时间：
2005-02-01
影响因子：
5.3
通讯作者：
Vartapetian, AB
中科院分区：
文献类型：
--
作者：
Karapetian, RN;Evstafieva, AG;Vartapetian, AB
动物细胞通过转录因子Nrf 2介导的一组解毒和抗氧化酶基因的协调表达来抵抗氧化应激和嗜电攻击。在未应激的细胞中，Nrf 2似乎通过与抑制蛋白Keap 1结合而被隔离在细胞质中。给你...通过使用酵母双杂交筛选，人Keap 1已被鉴定为核蛋白原胸腺素α的配偶体。体内和体外数据表明，前胸腺素ci-Keap 1相互作用是直接的，高度特异性的，功能相关的。此外，我们表明Keap 1是一种核质穿梭蛋白，具有核输出信号，这对其抑制作用很重要。胸腺素原cc能够通过与Nrf 2竞争结合Keapt的相同结构域，在体外从Nrf 2-Keap 1抑制复合物中释放Nrf 2。在体内，Nrf 2依赖的转录水平与细胞内水平的胸腺素原α通过使用胸腺素原α过度生产和mRNA干扰的方法。我们的数据归因于前胸腺素α的作用的核内解离的NRF 2-Keap 1复合物。从而揭示了胸腺素原ET的新功能，并为氧化应激保护基因表达的分子机制增加了新的维度。
Animal cells counteract oxidative stress and clectrophilic attack through coordinated expression of a set of detoxifying and antioxidant enzyme genes mediated by transcription factor Nrf2. In unstressed cells, Nrf2 appears to be sequestered in the cytoplasm via association with an inhibitor protein, Keap1. Here.. by using the yeast two-hybrid screen, human Keap1 has been identified as a partner of the nuclear protein prothymosin alpha. The in vivo and in vitro data indicated that the prothymosin ci-Keap1 interaction is direct, highly specific, and functionally relevant. Furthermore, we showed that Keap1 is a nuclear-cytoplasmic shuttling protein equipped with a nuclear export signal that is important for its inhibitory action. Prothymosin cc was able to liberate Nrf2 from the Nrf2-Keap1 inhibitory complex in vitro through competition with Nrf2 for binding to the same domain of Keapt. In vivo, the level of Nrf2-dependent transcription was correlated with the intracellular level of prothymosin a by using prothymosin alpha overproduction and mRNA interference approaches. Our data attribute to prothymosin alpha the role of intranuclear dissociator of the Nrf2-Keap1 complex. thus revealing a novel function for prothymosin et and adding a new dimension to the molecular mechanisms underlying expression of oxidative stress-protecting genes.