PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival.
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.
Bozulic
Lana
L
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Surucu
Banu
B
Hynx
Debby
D
Hemmings
Brian A
BA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D051747:DNA-Activated Protein Kinase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005720:Gamma Rays; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011836:Radiation Tolerance / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012694:Serine; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt