gms | German Medical Science

Question: Tumors are exposed to an unfavorable environment leading to several different stress responses. Brain and other tumors with mutations (R132H) in the isocitrate dehydrogenase 1 (IDH1) gene are exposed to a stress inducing metabolite, namely 2-hydroxygluterate (2-HG). Upon synthesis 2-HG hinders proper collagen maturation in the ER leading to an ER stress response known as unfolded protein response (UPR). Therefore we want to characterize the UPR in neural stem and progenitor cells (NSC) and investigate the influence of tumor relevant mutations.

Methods: Murine NSCs cultured in medium containing fibroblast growth factor (FGF) and epidermal growth factor (EGF) were treated with UPR inducing drugs tunicamycin and thapsigargin in vitro. We used classic western blot and quantitative PCR techniques to gain insides into the UPR. These NSCs carried inducible mutations in IDH1 (R132H) or p53 deletions. Further we assessed the cell cycle upon UPR induction by BrdU/7AAD staining and flow cytometric analysis.

Results: With these we gained evidence of different UPR response kinetics and outcomes dependent on cell type and drug. We further investigated the influence of p53 knock out (KO) or the IDH1-R132H mutation on the cell cycle of NSCs under ER stress.

Conclusion: From these observations we concluded, that the UPR is cell type specific and that different tumor relevant mutations, like alterations in p53, modify the signaling outcome.