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

Harms, C.; Albrecht, K.; Harms, U.; Seidel, K.; Hauck, L.; Baldinger, T.; Huebner, D.; Kronenberg, G.; An, J.; Ruscher, K.; Meisel, A.; Dirnagl, U.; von Harsdorf, R.; Endres, M.; Hoertnagl, H.

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., Albrecht, K., Harms, U., Seidel, K., Hauck, L., Baldinger, T., Huebner, D., Kronenberg, G., An, J., Ruscher, K., Meisel, A., Dirnagl, U., von Harsdorf, R., 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
ISSN:	0270-6474
Publisher:	Society for Neuroscience
Volume:	27
Number:	17
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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