RRC ID 34863
著者 Doggett K, Turkel N, Willoughby LF, Ellul J, Murray MJ, Richardson HE, Brumby AM.
タイトル BTB-Zinc Finger Oncogenes Are Required for Ras and Notch-Driven Tumorigenesis in Drosophila.
ジャーナル PLoS One
Abstract During tumorigenesis, pathways that promote the epithelial-to-mesenchymal transition (EMT) can both facilitate metastasis and endow tumor cells with cancer stem cell properties. To gain a greater understanding of how these properties are interlinked in cancers we used Drosophila epithelial tumor models, which are driven by orthologues of human oncogenes (activated alleles of Ras and Notch) in cooperation with the loss of the cell polarity regulator, scribbled (scrib). Within these tumors, both invasive, mesenchymal-like cell morphology and continual tumor overgrowth, are dependent upon Jun N-terminal kinase (JNK) activity. To identify JNK-dependent changes within the tumors we used a comparative microarray analysis to define a JNK gene signature common to both Ras and Notch-driven tumors. Amongst the JNK-dependent changes was a significant enrichment for BTB-Zinc Finger (ZF) domain genes, including chronologically inappropriate morphogenesis (chinmo). chinmo was upregulated by JNK within the tumors, and overexpression of chinmo with either RasV12 or Nintra was sufficient to promote JNK-independent epithelial tumor formation in the eye/antennal disc, and, in cooperation with RasV12, promote tumor formation in the adult midgut epithelium. Chinmo primes cells for oncogene-mediated transformation through blocking differentiation in the eye disc, and promoting an escargot-expressing stem or enteroblast cell state in the adult midgut. BTB-ZF genes are also required for Ras and Notch-driven overgrowth of scrib mutant tissue, since, although loss of chinmo alone did not significantly impede tumor development, when loss of chinmo was combined with loss of a functionally related BTB-ZF gene, abrupt, tumor overgrowth was significantly reduced. abrupt is not a JNK-induced gene, however, Abrupt is present in JNK-positive tumor cells, consistent with a JNK-associated oncogenic role. As some mammalian BTB-ZF proteins are also highly oncogenic, our work suggests that EMT-promoting signals in human cancers could similarly utilize networks of these proteins to promote cancer stem cell states.
巻・号 10(7)
ページ e0132987
公開日 2015-7-24
DOI 10.1371/journal.pone.0132987
PII PONE-D-15-19958
PMID 26207831
PMC PMC4514741
MeSH Animals Animals, Genetically Modified Carcinogenesis / genetics* Drosophila Proteins / genetics Drosophila Proteins / physiology* Drosophila melanogaster Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, ras / physiology* Microarray Analysis Nuclear Proteins / chemistry Nuclear Proteins / genetics Oncogenes / physiology* Protein Interaction Domains and Motifs / genetics Receptors, Notch / physiology* Zinc Fingers / genetics*
IF 2.74
引用数 14
WOS 分野 CELL BIOLOGY
リソース情報
ショウジョウバエ 4807R-2 17156R-1 17156R-2