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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Cell Nucleus / metabolism
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / metabolism*
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DNA / metabolism
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DNA Damage
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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DNA-Binding Proteins / pharmacology
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Disease Models, Animal
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Glutathione / metabolism
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Homocysteine / analogs & derivatives*
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Homocysteine / pharmacology
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Huntington Disease / chemically induced
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Huntington Disease / genetics
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Huntington Disease / metabolism*
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Male
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Mice
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Mice, Transgenic
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Neurons / cytology
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Neurons / metabolism*
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Nitro Compounds
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Oxidants / pharmacology
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Oxidative Stress / physiology
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Propionates
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Rats
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Rats, Sprague-Dawley
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Response Elements / physiology
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Sp1 Transcription Factor / genetics
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Sp1 Transcription Factor / metabolism*
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Sp1 Transcription Factor / pharmacology
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Sp3 Transcription Factor
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription Factors / pharmacology
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Transfection
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Zinc Fingers / genetics
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Zinc Fingers / physiology
Substances
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DNA-Binding Proteins
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Nitro Compounds
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Oxidants
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Propionates
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Sp1 Transcription Factor
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Sp3 protein, mouse
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Sp3 protein, rat
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Transcription Factors
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Homocysteine
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homocysteic acid
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Sp3 Transcription Factor
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DNA
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Glutathione
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3-nitropropionic acid