PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival

Mol Cell. 2008 Apr 25;30(2):203-13. doi: 10.1016/j.molcel.2008.02.024.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / genetics
  • Cell Line
  • Cell Nucleus / enzymology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • DNA Breaks, Double-Stranded*
  • DNA-Activated Protein Kinase / analysis
  • DNA-Activated Protein Kinase / genetics
  • DNA-Activated Protein Kinase / metabolism*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gamma Rays
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / analysis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / analysis
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Radiation Tolerance / genetics
  • Serine / genetics
  • Serine / metabolism
  • Transcription, Genetic

Substances

  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Serine
  • DNA-Activated Protein Kinase
  • Prkdc protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt