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General Information
Name
cancer, intercellular interactions, RAS-mito
FlyBase ID
FBhh0000774
Disease Ontology Term
Parent Disease
OMIM
Overview

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 (OMIM:190070), HRAS (OMIM:190020), and NRAS (OMIM: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]

Disease Summary Information
Disease Summary: cancer, intercellular interactions, RAS-mito
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
NDUFB10 (human ortholog of Dmel\ND-PDSW) encodes an accessory subunit of mitochondrial complex I; COX5A encodes a component of mitochondrial complex IV; MRPL4 (human ortholog of Dmel\mRpL4) encodes a mitochondrial ribosomal protein. [Gene Cards, NDUFB10, COX5A, MRPL4; 2018.03.22]
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).
External links
Disease synonyms
Search term: mitochondrial dysfunction
Search term: non-autonomous proliferation
Ortholog Information
Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (4)
      Gene Snapshot
      Ras oncogene at 85D (Ras85D) encodes a protein that acts downstream of several cell signals, most notably from Receptor Tyrosine Kinases, to regulate tissue growth and development. When abnormally activated it can direct developmental defects and tissue hyperplasia, mimicking aspects of human disease including Rasopathies and cancer, respectively. [Date last reviewed: 2019-03-14]
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human genes KRAS, HRAS, and NRAS (many to many; multiple paralogs and orthologs in both species). Dmel\Ras85D shares 78-86% identity and 86-92% similarity with KRAS, HRAS, and NRAS; for these three human genes, Ras85D is the highest-scoring ortholog in Drosophila.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      In progress.Contributions welcome.
      Molecular function (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human NDUFB10 (1 Drosophila to 1 human); Dmel\ND-PDSW shares 32% identity and 55% similarity with the human gene.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      In progress.Contributions welcome.
      Molecular function (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human MRPL4 (1 Drosophila to 1 human); Dmel\mRpL4 shares 46% identity and 63% similarity with the human gene.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      In progress.Contributions welcome.
      Molecular function (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human COX5A (1 Drosophila to 1 human); Dmel\COX5A shares 46% identity and 62% similarity with the human gene.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (56 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, autoradiography, two hybrid
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      gtpase assay, autoradiography
      anti tag coimmunoprecipitation, peptide massfingerprinting
      two hybrid, pull down, western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      two hybrid, pull down, anti tag coimmunoprecipitation, anti tag western blot
      pull down, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      protein-protein
      Interacting group
      Assay
      References
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      protein-protein
      Interacting group
      Assay
      References
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      blue native page, peptide massfingerprinting
      blue native page, peptide massfingerprinting
      blue native page, peptide massfingerprinting
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      blue native page, peptide massfingerprinting
      blue native page, peptide massfingerprinting
      blue native page, peptide massfingerprinting
      experimental knowledge based
      Alleles Reported to Model Human Disease (Disease Ontology) (14 alleles)
      Models Based on Experimental Evidence ( 4 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 9 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      loss of function allele
      loss of function allele
      P-element activity
      amorphic allele - genetic evidence
      References (13)