Phosphatidylinositol 3-Akt-kinase-dependent Phosphorylation of P21(Waf1/Cip1) As a Novel Mechanism of Neuroprotection by Glucocorticoids

Overview

Journal J Neurosci

Specialty Neurology

Date 2007 Apr 27

PMID 17460069

Citations 35

Authors

Christoph Harms

Katharina Albrecht

Ulrike Harms

Kerstin Seidel

Ludger Hauck

Tina Baldinger

Denise Hubner

Golo Kronenberg

Junfeng An

Karsten Ruscher

Andreas Meisel

Ulrich Dirnagl

Rudiger von Harsdorf

Matthias Endres

Heide Hortnagl

Affiliations

Soon will be listed here.

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.

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