ABSTRACT
The Notch1-mediated signaling pathway has a central role in the maintenance of neural stem cells and contributes to growth and progression of glioblastomas, the most frequent malignant brain tumors in adults. Here, we demonstrate that the Notch1 receptor promotes survival of glioblastoma cells by regulation of the anti-apoptotic Mcl-1 protein. Notch1-dependent regulation of Mcl-1 occurs cell type dependent at a transcriptional or post-translational level and is mediated by the induction of epidermal growth factor receptor (EGFR). Inhibition of the Notch1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation, the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or the Bcl-2/Bcl-XL inhibitor ABT-737. In conclusion, targeting Notch1 might represent a promising novel strategy in the treatment of glioblastomas.
Subject(s)
ErbB Receptors/metabolism , Glioblastoma/genetics , Glioblastoma/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Receptor, Notch1/metabolism , Signal Transduction , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation , Cell Survival/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Gene Silencing , Humans , Myeloid Cell Leukemia Sequence 1 Protein , Proto-Oncogene Proteins c-raf/metabolism , RNA Processing, Post-Transcriptional , Receptor, Notch1/genetics , Transcription, GeneticABSTRACT
The Djungarian hamster is an animal that is prominent for distinct seasonal adaptations. Cued by shortening day length in autumn they spontaneously exhibit reductions in food intake, body mass (BM), fat mass and also in lean mass (LM). The mechanisms behind the seasonal regulation of body composition are only partly resolved. Although most studies focused on the participation of body fat in seasonal body weight regulation, we addressed the influence of LM, moreover of muscle mass (MM) on seasonal BM changes. Therefore, we analyzed body composition, MM and the expression of myostatin, a hormone negatively regulating muscle growth and differentiation, in Djungarian hamsters in response to naturally changing photoperiod in winter compared to long photoperiod (LP). Winter-acclimated hamsters upregulated myostatin mRNA when compared with hamsters adapted to natural and artificial LP, whereas MM remained unchanged when compared with natural LP. Moreover, in natural short photoperiod, individual myostatin expression levels were negatively correlated with MM. These results suggest that myostatin is under seasonal control in order to regulate MM and hence contributes to the overall LM and therefore BM changes in seasonal mammals.
