Phosphatidylinositol 3-Akt-Kinase-Dependent Phosphorylation of p21(Waf1/Cip1) as a Novel Mechanism of Neuroprotection by Glucocorticoids
| Autor: | Tina Baldinger, Golo Kronenberg, Matthias Endres, Junfeng An, Kerstin Seidel, Denise Hübner, Andreas Meisel, Heide Hörtnagl, Ludger Hauck, Karsten Ruscher, Rüdiger von Harsdorf, Katharina Albrecht, Ulrich Dirnagl, Ulrike Harms, Christoph Harms |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
medicine.medical_specialty Cytoplasm Transcription Genetic Apoptosis Mice Inbred Strains Biology Neuroprotection Gene Expression Regulation Enzymologic chemistry.chemical_compound Mice Phosphatidylinositol 3-Kinases Mineralocorticoid receptor Downregulation and upregulation Corticosterone Internal medicine medicine Neurotoxin Animals Phosphorylation Rats Wistar neoplasms Glucocorticoids Cells Cultured Mice Knockout Neurons Kinase General Neuroscience Articles Rats Endocrinology Neuroprotective Agents chemistry Cardiovascular and Metabolic Diseases biological phenomena cell phenomena and immunity Proto-Oncogene Proteins c-akt Glucocorticoid medicine.drug Signal Transduction |
| Popis: | 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/Cip1at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21Waf1/Cip1preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21Waf1/Cip1and 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/Cip1deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21Waf1/Cip1suffices to protect neurons from apoptosis. We identify p21Waf1/Cip1as a novel antiapoptotic factor for postmitotic neurons and implicate p21Waf1/Cip1as the molecular target of neuroprotection by high-dose glucocorticoids. |
| Databáze: | OpenAIRE |
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