title: Specificity protein 1-zinc finger protein 179 pathway is involved in the attenuation of oxidative stress following brain injury.
abstract: After sudden traumatic brain injuries, secondary injuries may occur during the following days or weeks, which leads to the accumulation of reactive oxygen species (ROS). Since ROS exacerbate brain damage, it is important to protect neurons against their activity. Zinc finger protein 179 (Znf179) was shown to act as a neuroprotective factor, but the regulation of gene expression under oxidative stress remains unknown. In this study, we demonstrated an increase in Znf179 protein levels in both in vitro model of hydrogen peroxide (H2O2)-induced ROS accumulation and animal models of traumatic brain injury. Additionally, we examined the sub-cellular localization of Znf179, and demonstrated that oxidative stress increases Znf179 nuclear shuttling and its interaction with specificity protein 1 (Sp1). Subsequently, the positive autoregulation of Znf179 expression, which is Sp1-dependent, was further demonstrated using luciferase reporter assay and green fluorescent protein (GFP)-Znf179-expressing cells and transgenic mice. The upregulation of Sp1 transcriptional activity induced by the treatment with nerve growth factor (NGF) led to an increase in Znf179 levels, which further protected cells against H2O2-induced damage. However, Sp1 inhibitor, mithramycin A, was shown to inhibit NGF effects, leading to a decrease in Znf179 expression and lower cellular protection. In conclusion, the results obtained in this study show that Znf179 autoregulation through Sp1-dependent mechanism plays an important role in neuroprotection, and NGF-induced Sp1 signaling may help attenuate more extensive (ROS-induced) damage following brain injury.
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 110, Taiwan. Electronic address: chuangcy@tmu.edu.tw.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Chuang
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 110, Taiwan. Electronic address: geokao@tmu.edu.tw.
authors.forename: Tzu-Jen
authors.initials: TJ
authors.lastname: Kao
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Medical Science, Taipei Medical University, Taipei 110, Taiwan. Electronic address: linivy9@yahoo.com.tw.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Medical Science, Taipei Medical University, Taipei 110, Taiwan. Electronic address: anchinwu@gmail.com.
authors.forename: An-Chih
authors.initials: AC
authors.lastname: Wu
authors.affiliation: Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA. Electronic address: pin-tse.lee@nih.gov.
authors.forename: Pin-Tse
authors.initials: PT
authors.lastname: Lee
authors.affiliation: Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA. Electronic address: TSU@intra.nida.nih.gov.
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan. Electronic address: bau9763@nhri.org.tw.
authors.forename: Shiu-Hwa
authors.initials: SH
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 110, Taiwan. Electronic address: yc590626@gmail.com.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan. Electronic address: johnwu@tmu.edu.tw.
authors.forename: Chung-Che
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Medical Science, Taipei Medical University, Taipei 110, Taiwan. Electronic address: wcchang@tmu.edu.tw.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D000070642:Brain Injuries, Traumatic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics*; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; C113383:ZNF179 protein, mouse; D020932:Nerve Growth Factor; C066851:mithramycin A; D006861:Hydrogen Peroxide; D008926:Plicamycin
keywords: Nerve growth factor; Reactive oxygen species; Specificity protein 1; Traumatic brain injury; Zinc finger protein 179