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Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21(Waf1/Cip1) as a novel mechanism of neuroprotection by glucocorticoids

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Item Type:Article
Title:Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21(Waf1/Cip1) as a novel mechanism of neuroprotection by glucocorticoids
Creators Name:Harms, C. and Albrecht, K. and Harms, U. and Seidel, K. and Hauck, L. and Baldinger, T. and Huebner, D. and Kronenberg, G. and An, J. and Ruscher, K. and Meisel, A. and Dirnagl, U. and von Harsdorf, R. and Endres, M. and Hoertnagl, H.
Abstract:The role of glucocorticoids in the regulation of apoptosis remains incongruous. Here, we demonstrate that corticosterone protects neurons from apoptosis by a mechanism involving the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21(Waf1/Cip1) at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21(Waf1/Cip1) preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21(Waf1/Cip1) and neuroprotection are completely abolished by glucocorticoid and mineralocorticoid receptor antagonists as well as inhibitors of PI3- and Akt-kinase. Both germline and somatically induced p21(Waf1/Cip1) deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21(Waf1/Cip1) suffices to protect neurons from apoptosis. We identify p21(Waf1/Cip1) as a novel antiapoptotic factor for postmitotic neurons and implicate p21(Waf1/Cip1) as the molecular target of neuroprotection by high-dose glucocorticoids.
Keywords:Apoptosis, Neuroprotection, Cortical neurons, p21Waf1/Cip1, Glucocorticoid, Akt-kinase
Source:Journal of Neuroscience
Publisher:Society for Neuroscience
Page Range:4562-4571
Date:25 April 2007
Additional Information:Copyright (c) 2007 by The Society for Neuroscience
Official Publication:https://doi.org/10.1523/JNEUROSCI.5110-06.2007
PubMed:View item in PubMed

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