TY - JOUR T1 - Phosphatidylinositol 3-Akt-Kinase-Dependent Phosphorylation of p21<sup>Waf1/Cip1</sup> as a Novel Mechanism of Neuroprotection by Glucocorticoids JF - The Journal of Neuroscience JO - J. Neurosci. SP - 4562 LP - 4571 DO - 10.1523/JNEUROSCI.5110-06.2007 VL - 27 IS - 17 AU - Christoph Harms AU - Katharina Albrecht AU - Ulrike Harms AU - Kerstin Seidel AU - Ludger Hauck AU - Tina Baldinger AU - Denise Hübner AU - Golo Kronenberg AU - Junfeng An AU - Karsten Ruscher AU - Andreas Meisel AU - Ulrich Dirnagl AU - Rüdiger von Harsdorf AU - Matthias Endres AU - Heide Hörtnagl Y1 - 2007/04/25 UR - http://www.jneurosci.org/content/27/17/4562.abstract N2 - 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 p21Waf1/Cip1. In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21Waf1/Cip1 at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21Waf1/Cip1 preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21Waf1/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 p21Waf1/Cip1 deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21Waf1/Cip1 suffices to protect neurons from apoptosis. We identify p21Waf1/Cip1 as a novel antiapoptotic factor for postmitotic neurons and implicate p21Waf1/Cip1 as the molecular target of neuroprotection by high-dose glucocorticoids. ER -