Project description:We report the results NGS based of miRNA profiling in human bronchial epithelial cells (16HBE) up on ER stress induction with Tunicamycin (2.5ug/ml) and ALLN (100uM)
Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.
Project description:The most common oncogenic mutations in multiple myeloma (MM) affect N- and K-RAS leading to constitutive activation of RAS-dependent signaling. Signal transduction via RAS, Raf and MAPK has been well described as a canonical pathway. In accordance with this assumption, we showed that the activity of the MEK/ERK module is strictly dependent on pan-Raf activity. However, inhibition of MEK/ERK has no or only minor effects on MM cell survival, whereas oncogenic Ras and pan-Raf critically contribute to survival of multiple myeloma cells. Therefore, we aimed to learn more about Raf-dependent but MEK-independent signaling effectors. We analyzed gene expression profiles in INA-6 cells after either pan-Raf inhibition with SB-590885 or MEK inhibition with PD-325901.
