Sp1 and Sp3 Are Oxidative Stress-Inducible, Antideath Transcription Factors in Cortical Neurons-猫眼课题宝

DOI：

10.1523/jneurosci.23-09-03597.2003

发表时间：

2003-05

期刊：

The Journal of Neuroscience

影响因子：

--

通讯作者：

中科院分区：

其他

文献类型：

--

作者：

H. Ryu;Junghee Lee;K. Zaman;James Kubilis;R. Ferrante;B. Ross;R. Neve;R. Ratan

氧化应激引起的神经细胞死亡可能反映了内源性适应机制的失败。然而，氧化应激在神经元中诱导的转录激活物触发适应性遗传反应还没有完全阐明。我们报道，锌指转录因子Sp1和Sp3的基础DNA结合量在体外的皮质神经元中出人意料地低，并且显著地被谷胱甘肽耗竭诱导或过氧化氢诱导的氧化应激诱导。Sp1/Sp3 DNA结合量的增加部分反映了皮质神经元细胞核中Sp1和Sp3蛋白水平的增加。在亨廷顿病的化学或遗传模型中，体内神经元中也观察到类似的Sp1和SP3蛋白的诱导，在这两种啮齿动物模型中，神经元的丢失被归因于氧化应激。持续的全长Sp1或全长Sp3的高水平表达，而不是Sp1锌指DNA结合域的持续高水平表达，可以防止因氧化应激、DNA损伤或两者兼而有之而导致的死亡。综上所述，这些结果证实了Sp1和Sp3是皮层神经元中氧化应激诱导的转录因子，对神经元的存活起积极的调节作用。

Neuronal cell death in response to oxidative stress may reflect the failure of endogenous adaptive mechanisms. However, the transcriptional activators induced by oxidative stress in neurons that trigger adaptive genetic responses have yet to be fully elucidated. We report that basal DNA binding of the zinc finger transcription factors Sp1 and Sp3 is unexpectedly low in cortical neurons in vitro and is significantly induced by glutathione depletion-induced or hydrogen peroxide-induced oxidative stress in these cells. The increases in Sp1/Sp3 DNA binding reflect, in part, increased levels of Sp1 and Sp3 protein in the nuclei of cortical neurons. Similar induction of Sp1 and Sp3 protein is also observed in neurons in vivo in a chemical or a genetic model of Huntington's disease, two rodent models in which neuronal loss has been attributed to oxidative stress. Sustained high-level expression of full-length Sp1 or full-length Sp3, but not the Sp1 zinc finger DNA-binding domain alone, prevents death in response to oxidative stress, DNA damage, or both. Taken together, these results establish Sp1 and Sp3 as oxidative stress-induced transcription factors in cortical neurons that positively regulate neuronal survival.