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Role of cyclooxygenase-2 induction by transcription factor Sp1 and Sp3 in neuronal oxidative and DNA damage response

Junghee Lee^*,, Bela Kosaras, Hossein Aleyasin^||, Jeong A. Han^¶, David S. Park^||, Rajiv R. Ratan, Neil W. Kowall^*,,, Robert J. Ferrante^*,,, Sam W. Lee^¶ and Hoon Ryu^*,,1

^* Geriatric Research Education and Clinical Center, Bedford Veteran’s Affairs Medical Center, and

Neurology,

Pathology, and Psychiatry Departments, Boston University School of Medicine, Boston, Massachusetts, USA;

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;

^|| Neuroscience Research Program of Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada;

^¶ Harvard Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA; and

Department of Neurology, Weill Medical College of Cornell University and Burke-Cornell Medical Research Institute, White Plains, New York, USA

¹Correspondence: The GRECC Unit 182B, VA Medical Center, 200 Springs Rd., Bedford, MA 01730, USA. E-mail: hoonryu{at}bu.edu

ABSTRACT

Cyclooxygenase-2 (COX-2) has been implicated in neuronal survival and death. However, the precise regulatory mechanisms involved in COX-2 function are unclear. In the present study we found that COX-2 is induced in response to glutathione depletion-induced oxidative stress in primary cortical neurons. Two proximal specific Sp1 and Sp3 binding sites are responsible for the COX-2 promoter activity under normal as well as oxidative stress conditions through enhanced Sp1 and Sp3 DNA binding activity. Site-directed mutagenesis confirmed that –268/–267 positions serve as specific Sp1 and Sp3 recognition sites under oxidative stress. Enforced expression of Sp1 and Sp3 using HSV vectors increased the promoter activity, transcription, and protein level of COX-2 in cortical neurons. The dominant negative form of Sp1 abrogated the oxidative stress-induced promoter activity and expression of COX-2. We also demonstrated that adenovirus-mediated COX-2 gene delivery protected neurons from DNA damage induced by oxidative, genotoxic, and excitotoxic stresses and by ischemic injury. Moreover, COX-2^–/– cortical neurons were more susceptible to DNA damage-induced cell death. These results indicate that in primary neurons Sp1 and Sp3 play an essential role in the modulation of COX-2 transcription, which mediates neuronal homeostasis and survival by preventing DNA damage in response to neuronal stress.—Lee, J., Kosaras, B., Aleyasin, H., Han, J. A., Park, D. S., Ratan, R. R., Kowall, N. W., Ferrante, R. J., Lee, S. W., Ryu, H. Role of cyclooxygenase-2 induction by transcription factor Sp1 and Sp3 in neuronal oxidative and DNA damage response.