{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:43:11Z","timestamp":1783352591085,"version":"3.54.6"},"reference-count":48,"publisher":"Society for Neuroscience","issue":"17","license":[{"start":{"date-parts":[[2007,10,25]],"date-time":"2007-10-25T00:00:00Z","timestamp":1193270400000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2007,4,25]]},"abstract":"<jats:p>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<jats:sup>Waf1\/Cip1<\/jats:sup>. In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21<jats:sup>Waf1\/Cip1<\/jats:sup>at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21<jats:sup>Waf1\/Cip1<\/jats:sup>preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21<jats:sup>Waf1\/Cip1<\/jats:sup>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<jats:sup>Waf1\/Cip1<\/jats:sup>deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21<jats:sup>Waf1\/Cip1<\/jats:sup>suffices to protect neurons from apoptosis. We identify p21<jats:sup>Waf1\/Cip1<\/jats:sup>as a novel antiapoptotic factor for postmitotic neurons and implicate p21<jats:sup>Waf1\/Cip1<\/jats:sup>as the molecular target of neuroprotection by high-dose glucocorticoids.<\/jats:p>","DOI":"10.1523\/jneurosci.5110-06.2007","type":"journal-article","created":{"date-parts":[[2007,4,25]],"date-time":"2007-04-25T16:38:41Z","timestamp":1177519121000},"page":"4562-4571","source":"Crossref","is-referenced-by-count":53,"title":["Phosphatidylinositol 3-Akt-Kinase-Dependent Phosphorylation of p21<sup>Waf1\/Cip1<\/sup>as a Novel Mechanism of Neuroprotection by Glucocorticoids"],"prefix":"10.1523","volume":"27","author":[{"given":"Christoph","family":"Harms","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Harms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Seidel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludger","family":"Hauck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Baldinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"H\u00fcbner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Golo","family":"Kronenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Ruscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Meisel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Dirnagl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"von Harsdorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Endres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heide","family":"H\u00f6rtnagl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2007,4,25]]},"reference":[{"key":"2023041303250585000_27.17.4562.1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2826.2001.00705.x"},{"key":"2023041303250585000_27.17.4562.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(02)01147-4"},{"key":"2023041303250585000_27.17.4562.3","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.5.1223"},{"key":"2023041303250585000_27.17.4562.4","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400815"},{"key":"2023041303250585000_27.17.4562.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2003.12.005"},{"key":"2023041303250585000_27.17.4562.6","doi-asserted-by":"publisher","DOI":"10.1210\/en.138.1.101"},{"key":"2023041303250585000_27.17.4562.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.1997.tb01442.x"},{"key":"2023041303250585000_27.17.4562.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.4.1998"},{"key":"2023041303250585000_27.17.4562.9","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0962-8924(02)00043-0","article-title":"New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment?","volume":"3","author":"Coqueret","year":"2003","journal-title":"Trends Cell Biol"},{"key":"2023041303250585000_27.17.4562.10","doi-asserted-by":"publisher","DOI":"10.1210\/en.138.9.3677"},{"key":"2023041303250585000_27.17.4562.11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.4.2008"},{"key":"2023041303250585000_27.17.4562.12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200420926"},{"key":"2023041303250585000_27.17.4562.13","doi-asserted-by":"publisher","DOI":"10.1210\/en.141.5.1854"},{"key":"2023041303250585000_27.17.4562.14","first-page":"140","article-title":"Long-term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo","volume":"222","author":"Fisher","year":"1982","journal-title":"J Pharmacol Exp Ther"},{"key":"2023041303250585000_27.17.4562.15","first-page":"639","article-title":"The role of the cyclin-dependent kinase inhibitor p21 in apoptosis","volume":"1","author":"Gartel","year":"2002","journal-title":"Mol Cancer Ther"},{"key":"2023041303250585000_27.17.4562.16","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(99)00565-5"},{"key":"2023041303250585000_27.17.4562.17","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401341"},{"key":"2023041303250585000_27.17.4562.18","doi-asserted-by":"publisher","DOI":"10.1038\/nm0502-473"},{"key":"2023041303250585000_27.17.4562.19","doi-asserted-by":"publisher","DOI":"10.1096\/fj.99-0899com"},{"key":"2023041303250585000_27.17.4562.20","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1523\/JNEUROSCI.21-08-02600.2001","article-title":"Differential mechanisms of neuroprotection by 17 \u03b2-estradiol in apoptotic versus necrotic neurodegeneration","volume":"21","author":"Harms","year":"2001","journal-title":"J Neurosci"},{"key":"2023041303250585000_27.17.4562.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2003.09.012"},{"key":"2023041303250585000_27.17.4562.22","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000041030.98642.41"},{"key":"2023041303250585000_27.17.4562.23","doi-asserted-by":"crossref","first-page":"5045","DOI":"10.1523\/JNEUROSCI.21-14-05045.2001","article-title":"Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death","volume":"21","author":"Katchanov","year":"2001","journal-title":"J Neurosci"},{"key":"2023041303250585000_27.17.4562.24","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(87)90041-0"},{"key":"2023041303250585000_27.17.4562.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(99)00599-0"},{"key":"2023041303250585000_27.17.4562.26","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-5618.2002.01144.x"},{"key":"2023041303250585000_27.17.4562.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501371200"},{"key":"2023041303250585000_27.17.4562.28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200215481"},{"key":"2023041303250585000_27.17.4562.29","doi-asserted-by":"crossref","unstructured":"Maddika S Ande SR Panigrahi S Paranjothy T Weglarczyk K Zuse A Eshraghi M Manda KD Wiechec E Los M (2007) Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat, in press.","DOI":"10.1016\/j.drup.2007.01.003"},{"key":"2023041303250585000_27.17.4562.30","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00477-8"},{"key":"2023041303250585000_27.17.4562.31","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1097\/00001756-200012180-00013","article-title":"Corticosteroids protect oligodendrocytes from cytokine-induced cell death","volume":"11","author":"Melcangi","year":"2000","journal-title":"NeuroReport"},{"key":"2023041303250585000_27.17.4562.32","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(99)01624-4"},{"key":"2023041303250585000_27.17.4562.33","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000080381.76409.B2"},{"key":"2023041303250585000_27.17.4562.34","doi-asserted-by":"publisher","DOI":"10.1210\/me.11.5.577"},{"key":"2023041303250585000_27.17.4562.35","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106157200"},{"key":"2023041303250585000_27.17.4562.36","doi-asserted-by":"crossref","first-page":"10291","DOI":"10.1523\/JNEUROSCI.22-23-10291.2002","article-title":"Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model","volume":"22","author":"Ruscher","year":"2002","journal-title":"J Neurosci"},{"key":"2023041303250585000_27.17.4562.37","doi-asserted-by":"publisher","DOI":"10.1210\/en.142.2.802"},{"key":"2023041303250585000_27.17.4562.38","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)00431-X"},{"key":"2023041303250585000_27.17.4562.39","doi-asserted-by":"publisher","DOI":"10.1038\/35035131"},{"key":"2023041303250585000_27.17.4562.40","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202021"},{"key":"2023041303250585000_27.17.4562.41","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202409"},{"key":"2023041303250585000_27.17.4562.42","doi-asserted-by":"crossref","first-page":"3842","DOI":"10.1128\/MCB.19.5.3842","article-title":"Mitochondrial regulation of cell death: mitochondria are essential for procaspase 3-p21 complex formation to resist Fas-mediated cell death","volume":"19","author":"Suzuki","year":"1999","journal-title":"Mol Cell Biol"},{"key":"2023041303250585000_27.17.4562.43","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400706"},{"key":"2023041303250585000_27.17.4562.44","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2001.0590051706.x"},{"key":"2023041303250585000_27.17.4562.45","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-7634(96)00007-3"},{"key":"2023041303250585000_27.17.4562.46","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.85.2.128"},{"key":"2023041303250585000_27.17.4562.47","first-page":"1653","article-title":"Prevention of photoreceptor apoptosis by activation of the glucocorticoid receptor","volume":"42","author":"Wenzel","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2023041303250585000_27.17.4562.48","doi-asserted-by":"publisher","DOI":"10.1038\/35060032"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.5110-06.2007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T17:58:46Z","timestamp":1681408726000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.5110-06.2007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,4,25]]},"references-count":48,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2007,4,25]]},"published-print":{"date-parts":[[2007,4,25]]}},"alternative-id":["10.1523\/JNEUROSCI.5110-06.2007"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.5110-06.2007","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,4,25]]}}}