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Sp1 and Sp3 are oxidative stress-inducible, antideath transcription factors in cortical neurons
Hoon Ryu1, Junghee Lee, Khalequz Zaman
1Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
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.
Insights
Oxidative stress can kill neurons, but Sp1 and Sp3 transcription factors help protect them. These factors are activated by oxidative stress, increasing their levels and promoting neuronal survival.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Neuronal cell death from oxidative stress suggests failed adaptive mechanisms.
- Transcriptional activators that mediate neuronal adaptive responses to oxidative stress are not fully understood.
Purpose of the Study:
- To investigate the role of Sp1 and Sp3 transcription factors in neuronal response to oxidative stress.
- To determine if Sp1 and Sp3 can protect neurons from oxidative damage and promote survival.
Main Methods:
- Assessed DNA binding of Sp1 and Sp3 in cortical neurons under oxidative stress (glutathione depletion, hydrogen peroxide).
- Measured Sp1 and Sp3 protein levels in neuronal nuclei in vitro and in vivo (Huntington's disease models).
- Examined the effect of Sp1 and Sp3 expression on neuronal survival under oxidative stress and DNA damage.
Main Results:
- Basal DNA binding of Sp1 and Sp3 was low in cortical neurons but significantly increased with oxidative stress.
- Increased Sp1/Sp3 DNA binding correlated with higher nuclear Sp1 and Sp3 protein levels.
- Sp1 and Sp3 protein induction was observed in neurons in Huntington's disease models.
- Expression of full-length Sp1 or Sp3, but not a DNA-binding domain alone, protected neurons from death due to oxidative stress and DNA damage.
Conclusions:
- Sp1 and Sp3 are transcription factors induced by oxidative stress in cortical neurons.
- Sp1 and Sp3 play a positive role in regulating neuronal survival against oxidative damage.
- These findings identify Sp1 and Sp3 as key players in neuronal adaptive responses to oxidative stress.
