Ryu Hoon, Lee Junghee, Zaman Khalequz, Kubilis James, Ferrante Robert J, Ross Brian D, Neve Rachael, Ratan Rajiv R
Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2003 May 1;23(9):3597-606. doi: 10.1523/JNEUROSCI.23-09-03597.2003.
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.
神经元对氧化应激产生的细胞死亡可能反映了内源性适应性机制的失效。然而，在神经元中由氧化应激诱导并触发适应性基因反应的转录激活因子尚未完全阐明。我们报告，在体外培养的皮质神经元中，锌指转录因子Sp1和Sp3的基础DNA结合出乎意料地低，并且在这些细胞中由谷胱甘肽耗竭诱导或过氧化氢诱导的氧化应激会显著诱导其结合。Sp1/Sp3 DNA结合的增加部分反映了皮质神经元细胞核中Sp1和Sp3蛋白水平的升高。在亨廷顿舞蹈病的化学或遗传模型的体内神经元中也观察到Sp1和Sp3蛋白的类似诱导，这两种啮齿动物模型中神经元的丢失被归因于氧化应激。全长Sp1或全长Sp3而非单独的Sp1锌指DNA结合域的持续高水平表达可防止因氧化应激、DNA损伤或两者引起的细胞死亡。综上所述，这些结果确立了Sp1和Sp3作为皮质神经元中氧化应激诱导的转录因子，它们对神经元存活具有正向调节作用。
