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PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival.| Authors: | Lana Bozulic, Banu Surucu, Debby Hynx, Brian A Hemmings | | Language: | Eng. | | Date: | 28-04-2008 | | Journal: |
(1097-4164)
| | Release: | Mol Cell. 2008 Apr;30(2):203-13 | |
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Abstract:
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Protein kinase B (PKB/Akt) is a well-established regulator of several essential cellular processes. Here, we report a route by which activated PKB promotes survival in response to DNA insults in vivo. PKB activation following DNA damage requires 3-phosphoinositide-dependent kinase 1 (PDK1) and DNA-dependent protein kinase (DNA-PK). Active PKB localizes in the nucleus of gamma-irradiated cells adjacent to DNA double-strand breaks, where it colocalizes and interacts with DNA-PK. Levels of active PKB inversely correlate with DNA damage-induced apoptosis. A significant portion of p53- and DNA damage-regulated genes are misregulated in cells lacking PKBalpha. PKBalpha knockout mice show impaired DNA damage-dependent induction of p21 and increased tissue apoptosis after single-dose whole-body irradiation. Our findings place PKB downstream of DNA-PK in the DNA damage response signaling cascade, where it provides a prosurvival signal, in particular by affecting transcriptional p21 regulation. Furthermore, this function is apparently restricted to the PKBalpha isoform.
| | Copyright: |
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. | | Full text: |  EBSCO - HTML (needs subscription) | | Terms: | Animals, Apoptosis, Cell Line, Cell Nucleus, Cyclin-Dependent Kinase Inhibitor p21, DNA Breaks, Double-Stranded, DNA-Activated Protein Kinase, DNA-Binding Proteins, Gamma Rays, Gene Expression Regulation, Humans, Mice, Mice, Knockout, Nuclear Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Radiation Tolerance, Serine, Transcription, Genetic | | |
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