FB2025_01 , released February 20, 2025
Human Disease Model Report: cancer, intestinal stem cell, RAS-related
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General Information
Name
cancer, intestinal stem cell, RAS-related
FlyBase ID
FBhh0001032
Disease Ontology Term
Parent Disease
OMIM
Overview

The Drosophila posterior midgut is closely analogous to the mammalian small intestine; the midgut epithelium is maintained by frequent division of self-renewing intestinal stem cells (ISCs). A model of intestinal cancer has been developed using an activated form of the Drosophila RAS gene Ras85D. The constitutively active Ras85D mutation, Ras85DV12, is analogous to oncogenic mutations found in human RAS proteins.

Expression of Ras85DV12 targeted to ISCs in the adult fly results in stem cell hyperproliferation and intestinal dysplasia. Tumor growth correlates with an expansion of tracheal cell branching, similar to increased angiogenesis observed for human cancers. Ras85DV12 expression in renal and nephric stem cells (RNSCs) and hindgut intestinal stem cells (HISCs) has also been characterized.

Several studies using these systems address the role of specific lipids within the plasma membrane and the impact of diet and interacting genes on lipid usage within transformed stem cells. Using animals with Ras85DV12 expression targeted to ISCs, supplementing the diet with long-chain n-3 fatty acids (n-3 PUFA) has been found to reduce the hyperproliferation phenotype; the distribution of RAS-signaling nanoclusters in the plasma membrane has been characterized in the Ras85DV12 animals without and without n-3 PUFA dietary supplementation.

Knockdown of genes encoding components of the coat protein complex I is thought to attenuate the lipolysis pathway; in animals carrying these mutations plus Ras85DV12, normal and transformed intestinal stem cells are killed, but differentiated cells are not.

See the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474) for additional information concerning the Ras85DV12 cancer model.

[updated Jul. 2021 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, intestinal stem cell, RAS-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
External links
Disease synonyms
Search term: hyperplastic phenotype(s)
Ortholog Information
Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      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
      Other Genes Used: Viral, Bacterial, Synthetic (0)
        Summary of Physical Interactions (28 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
        two hybrid, anti tag coimmunoprecipitation, autoradiography
        anti tag coimmunoprecipitation, peptide massfingerprinting
        anti tag coimmunoprecipitation, peptide massfingerprinting
        anti tag coimmunoprecipitation, peptide massfingerprinting
        anti tag coimmunoprecipitation, anti tag western blot
        anti tag coimmunoprecipitation, peptide massfingerprinting
        anti tag coimmunoprecipitation, peptide massfingerprinting
        gtpase assay, autoradiography
        anti tag coimmunoprecipitation, peptide massfingerprinting
        pull down, western blot, two hybrid
        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
        anti tag coimmunoprecipitation, Identification by mass spectrometry, pull down, covalent binding, western blot
        Alleles Reported to Model Human Disease (Disease Ontology) (25 alleles)
        Models Based on Experimental Evidence ( 16 )
        Allele
        Disease
        Evidence
        References
        model of  cancer
        Modifiers Based on Experimental Evidence ( 18 )
        Allele
        Disease
        Interaction
        References
        model of  cancer
        is exacerbated by ITPUAS.F
        model of  cancer
        is ameliorated by InRGL00139
        is ameliorated by InRJF01183
        is ameliorated by InRJF01482
        is ameliorated by NetBΔ
        is ameliorated by NetBKK103672
        is ameliorated by unc-5MI04273
        is ameliorated by bskDN.UAS
        is ameliorated by bskHMS00777
        is exacerbated by hepAct.UAS
        is exacerbated by imdUAS.cGa
        is ameliorated by JraNIG.2275R
        is ameliorated by TimpUAS.cPa
        ameliorates  cancer
        model of  kidney cancer
        is ameliorated by Pka-C1B3
        is ameliorated by mTorΔP
        model of  cancer
        is exacerbated by exe1
        is exacerbated by Ptp61FΔ
        is exacerbated by M6W186stop
        is ameliorated by Ptip3804
        is exacerbated by p53UAS.cUa
        is ameliorated by Ilp8MI00727
        Alleles Representing Disease-Implicated Variants
        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
        Related mammalian, viral, bacterial, or synthetic 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 (19)