Network analysis of oncogenic Ras activation in cancer.
To investigate the unregulated Ras activation associated with cancer, we developed and validated a mathematical model of Ras signaling. The model-based predictions and associated experiments help explain why only one of two classes of activating Ras point mutations with in vitro transformation potential is commonly found in cancers. Model-based analysis of these mutants uncovered a systems-level process that contributes to total Ras activation in cells. This predicted behavior was supported by experimental observations. We also used the model to identify a strategy in which a drug could cause stronger inhibition on the cancerous Ras network than on the wild-type network. This system-level analysis of the oncogenic Ras network provides new insights and potential therapeutic strategies.
Stites
Edward C
EC
Beirne B. Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
Trampont
Paul C
PC
Ma
Zhong
Z
Ravichandran
Kodi S
KS
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003198:Computer Simulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011905:Genes, ras; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008433:Mathematics; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D015398:Signal Transduction; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D020690:GTPase-Activating Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; D018631:ras Proteins