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:Mutations in oncogenes such as KRAS, NRAS and BRAF promote cancer cell survival and proliferation, while excessive RAS/RAF/MEK/ERK signaling instead exerts an inhibitory effect on tumor growth. The precise regulatory mechanism of moderate RAS/RAF/MEK/ERK pathway activation during tumorigenesis remains elusive. Here, we discovered that a circular RNA, circRAPGEF5, was significantly upregulated in KRAS mutant colorectal cancer (CRC) cells. CircRAPGEF5 suppressed mutant and constitutively activated KRAS and the expression of the death receptor TNFRSF10A. Silencing of circRAPGEF5 induced RAS/RAF/MEK/ERK signaling hyperactivation and apoptosis in CRC cells. Moreover, the circularization of circRAPGEF5 was promoted by EIF4A3, whose expression was also elevated in tumor tissues. Taken together, our findings reveal a mechanism of accurate regulation of RAS/RAF/MEK/ERK signaling during CRC progression and provide potential targets for cancer therapy.
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.
Project description:Asthma is a chronic inflammatory airway disease characterized by airway inflammation and remodeling. The role of 15-oxo-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-oxoETE), a 15-HETE metabolite catalyzed by 15-prostaglandin dehydrogenase (15-PGDH), has been relatively unexplored in asthma. In this study, we used RNA-seq to explore the effect of 15-KETE on the transcriptome of airway epithelial cells, aiming to identify its potential downstream targets and mechanisms of action.
Project description:The role of FGF-MEK-ERK signalling pathway during embryonic heart development has not been fully elucidated. Here, we inhibited the pathway for 1 day using PD0325901, a MEK inhibitor, at the lateral plate mesoderm stage during cardiac differentiation of human embryonic stem cells. Cells were collected on day 2 (before PD0325901 administration), day 3 and day 8 to determine the effect of a transient FGF-MEK-ERK pathway modulation on the cardiac cell fate choice.
