title: CK2 is a novel negative regulator of NADPH oxidase and a neuroprotectant in mice after cerebral ischemia.
abstract: NADPH oxidase is a major complex that produces reactive oxygen species (ROSs) during the ischemic period and aggravates brain damage and cell death after ischemic injury. Although many approaches have been tested for preventing production of ROSs by NADPH oxidase in ischemic brain injury, the regulatory mechanisms of NADPH oxidase activity after cerebral ischemia are still unclear. In this study, we identified casein kinase 2 (CK2) as a critical modulator of NADPH oxidase and elucidated the role of CK2 as a neuroprotectant after oxidative insults to the brain. We found that the protein levels of the catalytic subunits CK2alpha and CK2alpha', as well as the total activity of CK2, are significantly reduced after transient focal cerebral ischemia (tFCI). We also found this deactivation of CK2 caused by ischemia/reperfusion increases expression of Nox2 and translocation of p67(phox) and Rac1 to the membrane after tFCI. Interestingly, we found that the inactive status of Rac1 was captured by the catalytic subunit CK2alpha under normal conditions. However, binding between CK2alpha and Rac1 was immediately diminished after tFCI, and Rac1 activity was markedly increased after CK2 inhibition. Moreover, we found that deactivation of CK2 in the mouse brain enhances production of ROSs and neuronal cell death via increased NADPH oxidase activity. The increased brain infarct volume caused by CK2 inhibition was restored by apocynin, a NADPH oxidase inhibitor. This study suggests that CK2 can be a direct molecular target for modulation of NADPH oxidase activity after ischemic brain injury.
authors: Department of Neurosurgery, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Gab Seok
authors: GS
authors: Kim
authors: Joo Eun
authors: JE
authors: Jung
authors: Kuniyasu
authors: K
authors: Niizuma
authors: Pak H
authors: PH
authors: Chan
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000009:adverse effects; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; C079789:neutrophil cytosol factor 67K; C056165:acetovanillone; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D047390:Casein Kinase II; D020830:rac1 GTP-Binding Protein