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

Brumby, A. M., Goulding, K. R., Schlosser, T., Loi, S., Galea, R., Khoo, P., Bolden, J. E., Aigaki, T., Humbert, P. O., Richardson, H. E. (May 2011) Identification of novel Ras-cooperating oncogenes in Drosophila melanogaster: A RhoGEF/Rho-family/JNK pathway is a central driver of tumorigenesis. Genetics, 188 (1). pp. 105-125. ISSN 00166731 (ISSN)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/21368274
DOI: 10.1534/genetics.111.127910

Abstract

We have shown previously that mutations in the apico-basal cell polarity regulators cooperate with oncogenic Ras (RasACT) to promote tumorigenesis in Drosophila melanogaster and mammalian cells. To identify novel genes that cooperate with RasACT in tumorigenesis, we carried out a genome-wide screen for genes that when overexpressed throughout the developing Drosophila eye enhance RasACT-driven hyperplasia. RasACT-cooperating genes identified were Rac1 Rho1, RhoGEF2, pbl, rib, and east, which encode cell morphology regulators. In a clonal setting, which reveals genes conferring a competitive advantage over wild-type cells, only Rac1, an activated allele of Rho1 (Rho1ACT), RhoGEF2, and pbl cooperated with RasACT, resulting in reduced differentiation and large invasive tumors. Expression of RhoGEF2 or Rac1 with RasACT upregulated Jun kinase (JNK) activity, and JNK upregulation was essential for cooperation. However, in the whole-tissue system, upregulation of JNK alone was not sufficient for cooperation with RasACT, while in the clonal setting, JNK upregulation was sufficient for RasACT-mediated tumorigenesis. JNK upregulation was also sufficient to confer invasive growth of RasV12-expressing mammalian MCF10A breast epithelial cells. Consistent with this, HER21 human breast cancers (where human epidermal growth factor 2 is overex-pressed and Ras signaling upregulated) show a significant correlation with a signature representing JNK pathway activation. Moreover, our genetic analysis in Drosophila revealed that Rho1 and Rac are important for the cooperation of RhoGEF2 or Pbl overexpression and of mutants in polarity regulators, Dlg and aPKC, with RasACT in the whole-tissue context. Collectively our analysis reveals the importance of the RhoGEF/ Rho-family/JNK pathway in cooperative tumorigenesis with RasACT. © 2011 by the Genetics Society of America.

Item Type: Paper
Subjects: diseases & disorders > cancer
organism description > animal > insect > Drosophila
organism description > animal > mammal
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: CSHL Librarian
Date: May 2011
Date Deposited: 20 Oct 2011 14:58
Last Modified: 26 Feb 2018 17:18
PMCID: PMC3120157
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15610

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