APE/Ref-1 responses to ischemia in rat brain

Edwards, Michael J.; Kent, Thomas A.; Rea, Harriett C.; Wei, Jingna; Quast, Mike; Izumi, Tohru; Mitra, Sankar; Perez‐Polo, J. Regino

doi:10.1097/00001756-199812210-00005

Cited by 37 publications

(26 citation statements)

References 7 publications

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“…It appears that the cell uses p53 to downregulate APE1 expression in response to DNA damage, and promotes apoptosis. Consistent with this idea, several earlier studies showed reduction of APE1 expression during apoptosis in neurons after transient global cerebral ischemia in rats (34,50,90,143). Additional studies are needed to unravel the physiological significance of such downregulation.…”

Section: Regulation Of Ape1 Expressionmentioning

confidence: 52%

“…Isobaric hyperoxia (100% oxygen) stimulated APE1 expression in the hippocampus and basal forebrain of young rats, while aged rats showed no significant changes in APE1 protein levels in all brain areas after hyperoxia (35,118). In contrast, several studies showed that global cerebral ischemia or traumatic brain injury or cold injury-induced brain trauma (100) induced oxidative stress decreases APE1 expression in the hippocampus and is associated with neuronal apoptosis in rats (34,50,143). This specific inhibition of APE1 expression may affect the extent of apoptosis after ischemia.…”

Section: Ape1 In Neurodegenerative and Cardiovascular Diseasesmentioning

confidence: 99%

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Transcriptional Regulatory Functions of Mammalian AP-Endonuclease (APE1/Ref-1), an Essential Multifunctional Protein

Bhakat

Mantha

Mitra

2009

Antioxidants & Redox Signaling

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226

256

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The mammalian AP-endonuclease (APE1/Ref-1) plays a central role in the repair of oxidized and alkylated bases in mammalian genomes via the base excision repair (BER) pathway. However, APE1, unlike its E. coli prototype Xth, has two unique and apparently distinct transcriptional regulatory activities. APE1 functions as a redox effector factor (Ref-1) for several transcription factors including AP-1, HIF1-␣, and p53. APE1 was also identified as a direct trans-acting factor for repressing human parathyroid hormone (PTH) and renin genes by binding to the negative calcium-response element (nCaRE) in their promoters. We have characterized APE1's post-translational modification, namely, acetylation which modulates its transcriptional regulatory function. Furthermore, stable interaction of APE1 with several other trans-acting factors including HIF-1␣, STAT3, YB-1, HDAC1, and CBP/p300 and formation of distinct trans-acting complexes support APE1's direct regulatory function for diverse genes. Multiple functions of mammalian APE1, both in DNA repair and gene regulation, warrant extensive analysis of its own regulation and dissection of the mechanisms. In this review, we have discussed APE1's own regulation and its role as a transcriptional coactivator or corepressor by both redox-dependent and redox-independent (acetylation-mediated) mechanisms, and explore the potential utility of targeting these functions for enhancing drug sensitivity of cancer cells. Antioxid. Redox Signal. 11,[621][622][623][624][625][626][627][628][629][630][631][632][633][634][635][636][637]

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Section: Regulation Of Ape1 Expressionmentioning

confidence: 52%

Section: Ape1 In Neurodegenerative and Cardiovascular Diseasesmentioning

confidence: 99%

Transcriptional Regulatory Functions of Mammalian AP-Endonuclease (APE1/Ref-1), an Essential Multifunctional Protein

Bhakat

Mantha

Mitra

2009

Antioxidants & Redox Signaling

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226

256

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“…The early rapid reduction of APE is also seen in vulnerable hippocampal CA 1 neurons in rodents after transient global cerebral ischemia (Edwards et al, 1998;Kawase et al, 1999a). The rapid reduction of APE appears to be sensitive to oxidative stress because overexpression of CuZnSOD in SOD1 mice prevents the early reduction of APE in the ischemic brain (Fujimura et al, 1999c).…”

Section: P H Chanmentioning

confidence: 99%

Reactive Oxygen Radicals in Signaling and Damage in the Ischemic Brain

Chan

2001

J Cereb Blood Flow Metab

1,438

959

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Summary:Reactive oxygen species have been implicated in brain injury after ischemic stroke. These oxidants can react and damage the cellular macromolecules by virtue of the reactivity that leads to cell injury and necrosis. Oxidants are also mediators in signaling involving mitochondria, DNA repair enzymes, and transcription factors that may lead to apoptosis after cerebral ischemia. Transgenic or knockout mice with cell-or sitespecific prooxidant and antioxidant enzymes provide useful tools in dissecting the events involving oxidative stress in signaling and damage in ischemic brain injury. Key Words: Reactive oxygen species-Free radicals-Apoptosis-Cerebral ischemia-Transgenic and knockout mice-Oxidative stress signaling.Reactive oxygen radicals have been implicated in the pathophysiology of many neurologic disorders and brain dysfunctions (Kontos, 1985;Siesjö et al., 1989;Chan, 1994). Evidence has accumulated during the past two decades showing that reactive oxygen radicals are involved in brain injuries such as cerebral ischemia and reperfusion. In focal or global cerebral ischemia, cerebral blood flow (CBF) is reduced in brain regions that are supplied with oxygen by the occluded vessels. Reoxygenation during spontaneous or thrombolytic reperfusion provides oxygen as a substrate for numerous enzymatic oxidation reactions in the cytosolic compartments or subcellular organelles and mitochondria. It has been demonstrated that approximately 2% to 5% of the electron flow in isolated brain mitochondria produces superoxide anion radicals (O 2 ·− ) and hydrogen peroxide (H 2 O 2 ) (Boveris and Chance, 1973). These constantly produced reactive oxygen species (ROS) are scavenged by superoxide dismutase (SOD), glutathione peroxidase (GSHPx), and catalase. Other small molecular antioxidants, including glutathione (GSH), ascorbic acid, and ␣-tocopherol, are also involved in the detoxification of free radicals. During reperfusion, these endogenous antioxidative defenses are likely to be perturbed as a result of overproduction of oxygen radicals by cytosolic prooxidant enzymes and mitochondria, inactivation of detoxification systems, consumption of antioxidants, and failure to adequately replenish antioxidants in ischemic brain tissue. It has been demonstrated in numerous studies that ROS are directly involved in oxidative damage with cellular macromolecules such as lipids, proteins, and nucleic acids in ischemic tissues, which lead to cell death. Recent studies have provided evidence that indirect signaling pathways by ROS can also cause cellular damage and death in cerebral ischemia and reperfusion. Despite many existing methodologies that allow investigators to quantify various oxygen radicals such as hydroxyl radical (Oliver et al., 1990) and nitric oxide radical

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“…For example, studies have shown that APE1 expression is lowered by ischemia before cell death (14,21,24,29,34). APE1 levels decrease after both transient cerebral ischemia (24,29) and traumatic brain injury (35), generally preceding DNA fragmentation.…”

Section: Ape1 Preserves Neuronal Structure and Functionmentioning

confidence: 99%

Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

Leak

Li²,

Zhang³

et al. 2015

Antioxidants & Redox Signaling

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Aims: Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that participates in base-excision repair of oxidative DNA damage and in the redox activation of transcription factors. We tested the hypothesis that APE1 upregulation protects neuronal structure and function against transient global cerebral ischemia (tGCI). Results: Upregulation of APE1 by low-dose proton irradiation (PI) or by transgene overexpression protected hippocampal CA1 neurons against tGCI-induced cell loss and reduced apurinic/apyrimidinic sites and DNA fragmentation. Conversely, APE1 knockdown attenuated the protection afforded by PI and ischemic preconditioning. APE1 overexpression inhibited the DNA damage response, as evidenced by lower phospho-histone H2A and p53-upregulated modulator of apoptosis levels. APE1 overexpression also partially rescued dendritic spines and attenuated the decrease in field excitatory postsynaptic potentials in hippocampal CA1. Presynaptic and postsynaptic markers were reduced after tGCI, and this effect was blunted in APE1 transgenics. The Morris water maze test revealed that APE1 protected against learning and memory deficits for at least 27 days post-injury. Animals expressing DNA repair-disabled mutant APE1 (D210A) exhibited more DNA damage than wild-type controls and were not protected against tGCI-induced cell loss. Innovation: This is the first study that thoroughly characterizes structural and functional protection against ischemia after APE1 upregulation by measuring synaptic markers, electrophysiological function, and long-term neurological deficits in vivo. Furthermore, disabling the DNA repair activity of APE1 was found to abrogate its protective impact. Conclusion: APE1 upregulation, either endogenously or through transgene overexpression, protects DNA, neuronal structures, synaptic function, and behavioral output from ischemic injury. Antioxid. Redox Signal. 22,[135][136][137][138][139][140][141][142][143][144][145][146][147][148]

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APE/Ref-1 responses to ischemia in rat brain

Cited by 37 publications

References 7 publications

Transcriptional Regulatory Functions of Mammalian AP-Endonuclease (APE1/Ref-1), an Essential Multifunctional Protein

Transcriptional Regulatory Functions of Mammalian AP-Endonuclease (APE1/Ref-1), an Essential Multifunctional Protein

Reactive Oxygen Radicals in Signaling and Damage in the Ischemic Brain

Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

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