GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2.
GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2.
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发表时间：
2007
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通讯作者：
Abhinav K. Jain;A. Jaiswal
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作者：
Abhinav K. Jain;A. Jaiswal
NF-E2相关因子2（Nrf 2）调节一系列化学保护基因的表达和协调诱导，以响应氧化和亲电应激。这导致对氧化应激和肿瘤疾病的保护。Nrf 2的核输入和输出在控制Nrf 2的核水平以及Nrf 2下游基因的表达方面发挥着重要作用。酪氨酸激酶Fyn磷酸化Nrf 2的酪氨酸568，导致Nrf 2的核输出。在这项研究中，我们研究了上游因子在调控Fyn和Fyn介导的Nrf 2核输出。这些研究揭示了Nrf 2调节氧化应激的新机制。我们证明GSK-3 β作用于Fyn激酶的上游，控制Nrf 2的核输出。GSK-3 β的化学和短干扰RNA介导的抑制导致Nrf 2的核积累和Nrf 2下游基因nqo 1的转录激活。GSK-3 β和Fyn单独和组合的化学和短干扰RNA抑制显示，这两种激酶遵循相同的途径来调节Nrf 2的核输出。我们进一步证明过氧化氢磷酸化GSK-3 β的酪氨酸216。这导致GSK-3 β的激活。活化的GSK-3 β在苏氨酸残基处磷酸化Fyn。磷酸化的Fyn在细胞核中积累，并在酪氨酸568处磷酸化Nrf 2。这导致核输出、泛素化和Nrf 2的降解。
NF-E2-related factor 2 (Nrf2) regulates expression and coordinated induction of a battery of chemoprotective genes in response to oxidative and electrophilic stress. This leads to protection against oxidative stress and neoplastic diseases. Nuclear import and export of Nrf2 play a significant role in control of nuclear levels of Nrf2 and thus the expression of Nrf2 down-stream genes. Tyrosine kinase Fyn phosphorylates tyrosine 568 of Nrf2 that leads to the nuclear export of Nrf2. In this study, we investigated the upstream factor(s) in regulation of Fyn and Fyn-mediated nuclear export of Nrf2. The investigations shed light on a novel mechanism of Nrf2 regulation in response to oxidative stress. We demonstrate that GSK-3beta acts upstream of Fyn kinase in control of nuclear export of Nrf2. Chemical and short interfering RNA-mediated inhibition of GSK-3beta led to nuclear accumulation of Nrf2 and transcriptional activation of the Nrf2 downstream gene nqo1. Chemical and short interfering RNA inhibition of GSK-3beta and Fyn individually and in combination revealed that both kinases follow the same pathway to regulate nuclear export of Nrf2. We further demonstrate that hydrogen peroxide phosphorylates tyrosine 216 of GSK-3beta. This leads to activation of GSK-3beta. The activated GSK-3beta phosphorylates Fyn at threonine residue(s). Phosphorylated Fyn accumulates in the nucleus and phosphorylates Nrf2 at tyrosine 568. This leads to nuclear export, ubiquitination, and degradation of Nrf2.