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PMID: 18757368 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

In vivo analysis of protein kinase B (PKB)/Akt regulation in DNA-PKcs-null mice reveals a role for PKB/Akt in DNA damage response and tumorigenesis.

The Journal of biological chemistry ·Vol. 283 ·No. 44 ·2008-10-31 ·Pages 30025-33

Surucu B, Bozulic L, Hynx D, Parcellier A, Hemmings BA

Abstract

Full activation of protein kinase B (PKB/Akt) requires phosphorylation on Thr-308 and Ser-473. It is well established that Thr-308 is phosphorylated by 3-phosphoinositide-dependent kinase-1 (PDK1). Ser-473 phosphorylation is mediated by both mammalian target of rapamycin-rictor complex (mTORC2) and DNA-dependent protein kinase (DNA-PK) depending on type of stimulus. However, the physiological role of DNA-PK in the regulation of PKB phosphorylation remains to be established. To address this, we analyzed basal, insulin-induced, and DNA damage-induced PKB Ser-473 phosphorylation in DNA-PK catalytic subunit-null DNA-PKcs(-/-) mice. Our results revealed that DNA-PK is required for DNA damage-induced phosphorylation but dispensable for insulin- and growth factor-induced PKB Ser-473 phosphorylation. Moreover, DNA-PKcs(-/-) mice showed a tissue-specific increase in basal PKB phosphorylation. In particular, persistent PKB hyperactivity in the thymus apparently contributed to spontaneous lymphomagenesis in DNA-PKcs(-/-) mice. Significantly, these tumors could be prevented by deletion of PKBalpha. These findings reveal stimulus-specific regulation of PKB activation by specific upstream kinases and provide genetic evidence of PKB deregulation in DNA-PKcs(-/-) mice.

MeSH Terms
Animals DNA Damage DNA-Activated Protein Kinase/metabolism Fibroblasts/metabolism Flow Cytometry/methods Gene Expression Profiling Gene Expression Regulation, Neoplastic Glucose Tolerance Test Insulin/metabolism Mice Mice, Transgenic Models, Genetic Phosphorylation Proto-Oncogene Proteins c-akt/metabolism Time Factors
Chemicals
Insulin DNA-Activated Protein Kinase Proto-Oncogene Proteins c-akt
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Surucu Banu
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH 4058, Switzerland.
Bozulic Lana
Hynx Debby
Parcellier Arnaud
Hemmings Brian A
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M803053200
Published
2008-10-31
Epub
2008-00-29
Pages
30025-33
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2662067
Subset
IM
External Links
PubMed source DOI: 10.1074/jbc.M803053200 PMC Full Text View journal details
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