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The Journal of Neuroscience, May 1, 2003, 23(9):3597

Sp1 and Sp3 Are Oxidative Stress-Inducible, Antideath Transcription Factors in Cortical Neurons

Hoon Ryu1, 4, Junghee Lee1, 4, Khalequz Zaman1, 4, James Kubilis6, 7, Robert J. Ferrante6, 7, Brian D. Ross8, Rachael Neve2, 3, 5, and Rajiv R. Ratan1, 3, 4

Departments of 1 Neurology and 2 Psychiatry and the 3 Program in Neuroscience, Harvard Medical School and 4 Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 02115, 5 McLean Hospital, Belmont, Massachusetts 02478, 6 Geriatric Research and Education and Clinical Center, Bedford Veterans Affairs Medical Center, and 7 Neurology, Pathology, and Psychiatry Departments, Boston University School of Medicine, Boston, Massachusetts 02118, and 8 Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109

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.

Key words: Sp1; oxidative stress; neurons; antioxidants; Huntington's disease; DNA damage

Copyright © 2003 Society for Neuroscience  0270-6474/03/2393597-10$05.00/0

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