GRK 1739 - Research Projects
Project 6Role of the protein kinase B/AKT pathway for the cellular radiation response
Prof. Dr. rer. nat. Verena Jendrossek
Dept. of Molecular Cell Biology
University Hospital Essen
The project focuses on the functions of protein kinase B/AKT, a survival kinase with clinical relevance to radiation resistance thought to derive from contributions to the DNA damage response (DDR). Various reports implicate AKT in DNA double strand break (DSB) repair and apoptosis, but prevailing models and suggested mechanisms remain poorly defined and are often contradictory. Our previous work showed that activation-associated AKT mutants with prominent nuclear localization accelerate DSB repair and improve cell survival upon IR whereas the constitutively active membrane-bound myrAKT had opposite effects. We use genetic, biochemical and pharmacological approaches to elucidate AKT`s role in specific DSB repair pathways and place particular emphasis on identifying proteins that integrate AKT into DDR, including cell fate decisions. We will validated our findings in murine tumor models and patient-derived cells and explore the potential of new AKT inhibitors for radiosensitization.
Klein D, Steens J, Wiesemann A, Schulz FC, Kaschani F, Röck K, Yamaguchi M, Wirsdörfer F, Kaiser M, Fischer J, Stuschke M, Jendrossek V. Mesenchymal stem cell therapy protects lungs from radiation-induced endothelial cell loss by restoring superoxide dismutase 1 expression Antioxid Redox Signal Aug 29 2016 [Epub ahead of print] PMID 27572073.
Wirsdörfer F*, de Leve S*, Cappuccini F*, Eldh T, Meyer AV, Gau E, Thompson LF, Chen NY, Karmouty-Quintana H, Fischer U, Kasper M, Klein D, Ritchey J, Blackburn MR, Westendorf A, Stuschke M, Jendrossek V. Extracellular adenosine production by ecto-5´-nucleotidase (CD73) enhances radiation-induced lung fibrosis. Cancer Res May 15;76(10):3045-56 (2016). doi: 10.1158/0008-5472.CAN-15-2310. Epub 2016 Feb 26. * shared first.
Matschke J, Riffkin H, Klein D, Handrick R, Lüdemann L, Metzen E, Shlomi T, Stuschke M, Jendrossek V. Targeted inhibition of glutamine-dependent glutathione metabolism overcomes death resistance induced by chronic cycling hypoxia Antioxid Redox Signal 2016 Mary 9 [Epub ahead of print]
Handrick R, Ontikatze T, Bauer KD, Freier F, Rübel A, Dürig J, Belka C, Jendrossek V. Dihydroartemisinin induces apoptosis by a Bak-dependent intrinsic pathway. Mol Cancer Ther 9(9):2497-510 (2010).
Jendrossek V, Henkel M, Hennenlotter J, Vogel U, Ganswindt U, Müller I, Handrick R, Kuczyk M, Stenzl A, Belka C. Analysis of complex PKB/Akt signaling pathways in human prostate cancer samples Brit J Urol 102, 371-382 (2008).