Identification of novel Ras-cooperating oncogenes in Drosophila melanogaster: a RhoGEF/Rho-family/JNK pathway is a central driver of tumorigenesis.

摘要: We have shown previously that mutations in the apico-basal cell polarity regulators cooperate with oncogenic Ras (RasACT) to promote tumorigenesis Drosophila melanogaster and mammalian cells. To identify novel genes RasACT tumorigenesis, we carried out a genome-wide screen for when overexpressed throughout developing eye enhance RasACT-driven hyperplasia. RasACT-cooperating identified were Rac1 Rho1, RhoGEF2, pbl, rib, east, which encode morphology regulators. In clonal setting, reveals conferring competitive advantage over wild-type cells, only Rac1, an activated allele of Rho1 (Rho1ACT), pbl cooperated RasACT, resulting reduced differentiation large invasive tumors. Expression RhoGEF2 or upregulated Jun kinase (JNK) activity, JNK upregulation was essential cooperation. However, whole-tissue system, alone not sufficient cooperation while RasACT-mediated tumorigenesis. also confer growth RasV12-expressing MCF10A breast epithelial Consistent this, HER2+ human cancers (where epidermal factor 2 is signaling upregulated) show significant correlation signature representing pathway activation. Moreover, our genetic analysis revealed Rac are important Pbl overexpression mutants regulators, Dlg aPKC, context. Collectively importance RhoGEF/Rho-family/JNK cooperative RasACT.