Phosphatidylinositol 3-Akt-Kinase-Dependent Phosphorylation of p21Waf1/Cip1 as a Novel Mechanism of Neuroprotection by Glucocorticoids

C. Harms, K. Albrecht, U. Harms, K. Seidel, L. Hauck, T. Baldinger, D. Hubner, G. Kronenberg, J. An, K. Ruscher, A. Meisel, U. Dirnagl (+3 others)
2007 Journal of Neuroscience  
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
more » ... 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.
doi:10.1523/jneurosci.5110-06.2007 pmid:17460069 fatcat:nfce4w7xdnfp5bf7ab5drzoeaq