Involvement of Akt in preconditioning-induced tolerance to ischemia in PC12 cells
The serine-threonine protein kinase Akt has been identified as an important mediator of cell survival able to counteract apoptotic stimuli. However, hibernation, a model of natural tolerance to cerebral ischemia, is associated with downregulation of Akt. We previously established a model of ischemic...
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Published in | Journal of cerebral blood flow and metabolism Vol. 26; no. 10; pp. 1323 - 1331 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
London, England
SAGE Publications
01.10.2006
Lippincott Williams & Wilkins Sage Publications Ltd |
Subjects | |
Online Access | Get full text |
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Summary: | The serine-threonine protein kinase Akt has been identified as an important mediator of cell survival able to counteract apoptotic stimuli. However, hibernation, a model of natural tolerance to cerebral ischemia, is associated with downregulation of Akt. We previously established a model of ischemic tolerance in a PC12 cell line and using this model we now addressed the question whether ischemic tolerance also downregulates Akt in PC12 cells. Kinetic studies showed decreased Akt phosphorylation in tolerized cells. Similarly, phosphorylated levels of three major targets of Akt and well-known proapoptotic factors, the glycogen synthase kinase 3 (GSK-3), a Forkhead family member, FoxO4, and the protein murine double minute 2 (MDM2), all inactivated upon phosphorylation by Akt, were decreased in preconditioned cells. In addition, pharmacological blockade of the phosphoinositide 3-kinase (PI3K)/Akt pathway reduced cell death induced by oxygen and glucose deprivation (OGD) and increased the protective effect of preconditioning (PC). Furthermore, decreasing availability of P-Akt by transfecting PC12 cells with constructs of inactive Akt also resulted in protection against OGD and potentiation of the protective effect of PC. Depending on the environment, GSK-3, FOXO-4, and MDM2 can trigger apoptotic responses or cell cycle arrest, and thus, in a situation of reduced energy, driving the cells into a state of quiescence might be neuroprotective. This work suggests that in the context of tolerance downregulation of Akt is beneficial. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Current address: The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 1015, Baltimore, Maryland 21205-2109, USA. E-mail: jhilliol@jhmi.edu |
ISSN: | 0271-678X 1559-7016 |
DOI: | 10.1038/sj.jcbfm.9600286 |