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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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