Sürücü, Banu. Regulation of protein kinase B (PKB/Akt) by DNA-dependent protein kinase (DNA-PK) under physiological conditions. 2010, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_9131
The present study made use of genetically modified mouse models to investigate PKB regulation by DNA-PK, as phosphorylation of Ser473 may be stimulus-, signalling pathway- and/or cell type-specific. In this study, we investigated the role of DNA-PK in basal, insulin-induced, and DNA damage-induced phosphorylation of PKB Ser473 under physiological conditions. We report that DNA-PK phosphorylated PKB on Ser473 upon DNA damage induced by γ-irradiation in vivo. In contrast, DNA-PK was dispensable for insulin and growth factor-induced PKB activation. Interestingly, analysis of basal PKB Ser473 phosphorylation in DNA-PKcs−/− mice showed tissue-specific deregulation of the PKB/FoxO pathway. In particular, we provide evidence that persistent PKB hyperactivity in the thymus apparently contributes to spontaneous tumourigenesis in DNA-PKcs−/− mice. Lymphomagenesis could be prevented by the deletion of PKBa and implies deregulation of PKB in DNA-PKcs−/− thymi.
Deregulation of PKB is implicated in various types of cancer and PI3K/PKB pathway is one of the most deregulated pathways in human malignancies. Therefore PI3K/PKB pathway is a major focus of current efforts for the treatment of cancer. In the second part of the study we made use of differential activation of PKB by upstream kinases in response to specific stimuli as a tool to dissect the mode of action of a small molecule inhibitor BBD130.
|Advisors:||Hemmings, Brian A.|
|Committee Members:||Affolter, Markus and Matthias, Patrick D.|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum|
|Bibsysno:||Link to catalogue|
|Number of Pages:||112 S.|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||01 Oct 2010 07:45|
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