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The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death
Dysregulation of Akt signaling is a critical player in a broad range of diseases including cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. Here we show that global ischemia in intact rats triggers expression and activation of the Akt inhibitor CTMP (Ca...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724841/ https://www.ncbi.nlm.nih.gov/pubmed/19349976 http://dx.doi.org/10.1038/nn.2299 |
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author | Miyawaki, Takahiro Ofengeim, Dimitry Noh, Kyung-Min Latuszek-Barrantes, Adrianna Hemmings, Brian A. Follenzi, Antonia Zukin, R. Suzanne |
author_facet | Miyawaki, Takahiro Ofengeim, Dimitry Noh, Kyung-Min Latuszek-Barrantes, Adrianna Hemmings, Brian A. Follenzi, Antonia Zukin, R. Suzanne |
author_sort | Miyawaki, Takahiro |
collection | PubMed |
description | Dysregulation of Akt signaling is a critical player in a broad range of diseases including cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. Here we show that global ischemia in intact rats triggers expression and activation of the Akt inhibitor CTMP (Carboxyl-Terminal Modulator Protein) in vulnerable hippocampal neurons, that CTMP binds and extinguishes Akt activity and that CTMP is essential to ischemia-induced neuronal death. Whereas ischemia induces a dramatic phosphorylation and nuclear translocation of Akt, p-Akt in postischemic neurons is not active, as assessed by kinase assays and phosphorylation of downstream targets GSK-3β and FOXO3A. RNA-interference-mediated depletion of CTMP in a clinically relevant model of stroke restores Akt activity and rescues hippocampal neurons. These findings document a critical role for CTMP in the neurodegeneration associated with stroke and identify CTMP as a novel therapeutic target for amelioration of hippocampal injury and cognitive deficits. |
format | Text |
id | pubmed-2724841 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
record_format | MEDLINE/PubMed |
spelling | pubmed-27248412009-11-01 The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death Miyawaki, Takahiro Ofengeim, Dimitry Noh, Kyung-Min Latuszek-Barrantes, Adrianna Hemmings, Brian A. Follenzi, Antonia Zukin, R. Suzanne Nat Neurosci Article Dysregulation of Akt signaling is a critical player in a broad range of diseases including cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. Here we show that global ischemia in intact rats triggers expression and activation of the Akt inhibitor CTMP (Carboxyl-Terminal Modulator Protein) in vulnerable hippocampal neurons, that CTMP binds and extinguishes Akt activity and that CTMP is essential to ischemia-induced neuronal death. Whereas ischemia induces a dramatic phosphorylation and nuclear translocation of Akt, p-Akt in postischemic neurons is not active, as assessed by kinase assays and phosphorylation of downstream targets GSK-3β and FOXO3A. RNA-interference-mediated depletion of CTMP in a clinically relevant model of stroke restores Akt activity and rescues hippocampal neurons. These findings document a critical role for CTMP in the neurodegeneration associated with stroke and identify CTMP as a novel therapeutic target for amelioration of hippocampal injury and cognitive deficits. 2009-04-06 2009-05 /pmc/articles/PMC2724841/ /pubmed/19349976 http://dx.doi.org/10.1038/nn.2299 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Miyawaki, Takahiro Ofengeim, Dimitry Noh, Kyung-Min Latuszek-Barrantes, Adrianna Hemmings, Brian A. Follenzi, Antonia Zukin, R. Suzanne The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death |
title | The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death |
title_full | The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death |
title_fullStr | The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death |
title_full_unstemmed | The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death |
title_short | The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death |
title_sort | endogenous inhibitor of akt, ctmp, is critical to ischemia-induced neuronal death |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724841/ https://www.ncbi.nlm.nih.gov/pubmed/19349976 http://dx.doi.org/10.1038/nn.2299 |
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