title: Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth.
abstract: Oncogenic mutations in Ras deregulate cell death and proliferation to cause cancer in a significant number of patients. Although normal Ras signaling during development has been well elucidated in multiple organisms, it is less clear how oncogenic Ras exerts its effects. Furthermore, cancers with oncogenic Ras mutations are aggressive and generally resistant to targeted therapies or chemotherapy. We identified the exocytosis component Sec15 as a synthetic suppressor of oncogenic Ras in an in vivo Drosophila mosaic screen. We found that oncogenic Ras elevates exocytosis and promotes the export of the pro-apoptotic ligand Eiger (Drosophila TNF). This blocks tumor cell death and stimulates overgrowth by activating the JNK-JAK-STAT non-autonomous proliferation signal from the neighboring wild-type cells. Inhibition of Eiger/TNF exocytosis or interfering with the JNK-JAK-STAT non-autonomous proliferation signaling at various steps suppresses oncogenic Ras-mediated overgrowth. Our findings highlight important cell-intrinsic and cell-extrinsic roles of exocytosis during oncogenic growth and provide a new class of synthetic suppressors for targeted therapy approaches.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
authors.forename: Chiswili
authors.initials: C
authors.lastname: Chabu
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA tian.xu@yale.edu.
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004330:Drosophila / Q000254:growth & development* / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology*; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D029721:Drosophila Proteins; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C464573:egr protein, Drosophila; C417283:Ras85D protein, Drosophila; D018631:ras Proteins
keywords: Eiger; Exocytosis; Oncogenic Ras; TNF; Tumors