Abstract
Hypoxic preconditioning is thought to rely on gene products regulated by hypoxia-inducible factor (HIF)-1. Here, we show that the HIF-1 target gene cyclin-dependent kinase inhibitor 1, p21(WAF1/CIP1), is essential for neuroprotection by hypoxic/aglycemic or erythropoietin preconditioning using wild-type and p21(WAF1/CIP1)-deficient neurons. Furthermore, overexpression of wild-type p21(WAF1/CIP1) or phospho-mutants significantly increased cell death after hypoxia/aglycemia. Moreover, deferoxamine-induced endogenous tolerance did not involve p21(WAF1/CIP1) expression in cortical neurons. Our data suggest that balanced expression and potentially posttranslational regulation of p21(WAF1/CIP1) is required for hypoxic preconditioning.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Death / drug effects
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Cell Death / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Deferoxamine / pharmacology
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Erythropoietin / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Hypoxia, Brain / genetics
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Hypoxia, Brain / metabolism*
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Hypoxia, Brain / pathology
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Hypoxia-Inducible Factor 1 / genetics
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Hypoxia-Inducible Factor 1 / metabolism
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Ischemic Preconditioning*
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Mice
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Mice, Knockout
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Mutation
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Nerve Tissue Proteins / biosynthesis*
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Nerve Tissue Proteins / genetics
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Siderophores / pharmacology
Substances
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Hypoxia-Inducible Factor 1
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Nerve Tissue Proteins
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Siderophores
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Erythropoietin
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Deferoxamine