This report describes a Drosophila model of cancer that combines an activated mutation in the Drosophila RAS protein Ras85D with mutations in different genes of the mitochondrial respiratory system, including ND-PDSW, mRpL4 and COX5A. Mutations in these genes were recovered in a genetic screen using Ras85DV12 clones in the adult eye. Such clones exhibit overgrowth and develop into benign tumors; additional mutations within the clone that induce non-autonomous growth of the surrounding tissue were identified. Within the clones, upregulation of the secreted ligands encoded by Dmel\wg and Dmel\upd1 is observed.
In the original screen, the surrounding tissue was wild-type for Ras85D; when similar clones are surrounded by Ras85DV12-expressing tissue, the phenotype is more extreme, with over-proliferating cells also exhibiting invasive behavior. This system is comparable to human cancers in which somatic mutations in mitochondrial DNA or nuclear mitochondrial genes have been observed to occur in a clone of cells within a developing tumor.
The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers and are crucial players in many signaling networks affecting cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence. Originally defined as oncogenes, the RAS GTPase family includes KRAS (MIM:190070), HRAS (MIM:190020), and NRAS (MIM:164790); mutations in these three genes are among the most common events in human cancers. For KRAS, HRAS and NRAS, there is a single high-scoring ortholog in Drosophila, Ras85D, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. There are multiple other paralogous and orthologous genes in both species. Of the three human RAS GTPase genes, a tagged UAS construct of Hsap\HRAS has been introduced into flies, but has not been characterized.
The constitutively active Ras85D mutation, Ras85DV12, is analogous to oncogenic mutations found in human RAS proteins. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G12V in the fly Ras85D gene (corresponds to G12V in the human KRAS and HRAS genes). See also the human disease model reports 'cancer, multiple, RAS-related'.
Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. Most work relevant to cancer has been done with an activated form of the gene, Ras85DV12. This allele is usually lethal during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85DV12 exhibit an overgrowth phenotype in multiple different tissues tested. Many physical and genetic interactions for Dmel\Ras85D have been described; see below and in the gene report for Ras85D.
See also the human disease model reports 'cancer, multiple, RAS-related' (FBhh0000474) and 'cancer, non-autonomous proliferation, RAB5-related' (FBhh0000775).
[updated Nov. 2018 by FlyBase; FBrf0222196]
The RAS proteins are members of a large superfamily of low-molecular-weight GTP-binding proteins. The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. Three members of the RAS family, HRAS, KRAS and NRAS, are found to be activated by mutation in human tumors. These three members are very closely related, having 85% amino acid sequence identity (Downward, 2003; pubmed:12509763).
High-scoring ortholog of human NDUFB10 (1 Drosophila to 1 human); Dmel\ND-PDSW shares 32% identity and 55% similarity with the human gene.
High-scoring ortholog of human MRPL4 (1 Drosophila to 1 human); Dmel\mRpL4 shares 46% identity and 63% similarity with the human gene.
High-scoring ortholog of human COX5A (1 Drosophila to 1 human); Dmel\COX5A shares 46% identity and 62% similarity with the human gene.
