Cells have evolved highly intertwined kinase networks to finely tune cellular homeostasis to the environment. The network converging on the mechanistic target of rapamycin (MTOR) kinase constitutes a central hub that integrates metabolic signals and adapts cellular metabolism and functions to nutritional changes and stress. Feedforward and feedback loops, crosstalks and a plethora of modulators finely balance MTOR-driven anabolic and catabolic processes. This complexity renders it difficult — if not impossible — to intuitively decipher signaling dynamics and network topology. Over the last two decades, systems approaches have emerged as powerful tools to simulate signaling network dynamics and responses. In this review, we discuss the contribution of systems studies to the discovery of novel edges and modulators in the MTOR network in healthy cells and in disease.
Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and is up‐regulated by variety of tumours. An endogenous family of anti‐angiogenic isoforms termed VEGFxxxb has been identified in many normal, non‐angiogenic tissues, and, in contrast with the angiogenic VEGFxxx isoforms, is down‐regulated in epithelial tumours including colorectal and prostate carcinoma. This is the first study of the anti‐angiogenic variant VEGF165b in neuroblastic tumours of childhood, which range from highly malignant neuroblastoma to benign ganglioneuroma.Twenty neuroblastic tumour samples were assessed for VEGFxxx and VEGFxxxb mRNA and protein expression by RT‐PCR and ELISA, respectively. VEGFxxx but not VEGFxxxb was up‐regulated in neuroblastoma (N=12) when compared with ganglioneuroma (N=6) at mRNA level. At the protein level, the ratio between VEGFxxxb and total VEGF was significantly lower in neuroblastomas (0.53±0.08; N=15) than in ganglioneuromas (0.96±0.23; N=4). Immunohistochemistry identified VEGF165b in ganglioneuroma but not neuroblastoma, which showed higher expression of total VEGF. These results suggest that alternative splicing of VEGF in neuroblastoma may contribute to its malignant characteristics. Research funded by the CLIC Sargent
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