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General Information
Name
colorectal cancer, multigenic
FlyBase ID
FBhh0000658
Disease Ontology Term
Parent Disease
OMIM
Overview

This report encompasses a series of multigenic models of colorectal cancer, using combinations of Drosophila genes related to 5 human genes implicated in this disease: human NRAS (using an activated form of Dmel\Ras85D), human TP53 (using RNAi-knockdown targeted to Dmel\p53), human APC (using RNAi-knockdown targeted to Dmel\Apc), human PIK3CA (using RNAi-knockdown targeted to Dmel\Pten, a negative regulator of the PIK3 signaling pathway), and human SMAD4 (using RNAi-knockdown targeted to Dmel\Med). Multigenic combinations were created in the adult hindgut epithelium using GAL4 driven by the hindgut-specific byn promoter. 32 different combinations that correspond those found in colorectal human tumors have been characterized; mechanisms of drug resistance have been investigated.

See also human disease model reports for 'colorectal cancer' (FBhh0000178), 'cancer, multiple, RAS-related' (FBhh0000474), 'cancer, multiple, TP53-related' (FBhh0000340), 'cancer, multiple, PIK3C-related' (FBhh0000400), 'familial adenomatous polyposis 1' (FBhh0000135).

[updated Nov. 2017 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: colorectal cancer, multigenic
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics

Genes recurrently mutated in colon tumors lead to misregulation of five distinct signalling pathways: Wnt, receptor tyrosine kinase/Ras, p53, transforming growth factor-b and PI3K (FBrf0234055).

Cellular phenotype and pathology
Molecular information
External links
Disease synonyms
colon cancer
CRC
Ortholog Information
Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (5)
      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
      p53 (p53) encodes a transcriptional factor required for adaptive responses to genotoxic stress, including cell death, compensatory proliferation and DNA repair. [Date last reviewed: 2019-03-14]
      Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human genes TP53, TP63 and TP73 (1 Drosophila to many human). Dmel\p53 shares 20-24% identity and 36-41% similarity with the human genes.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      APC-like (Apc) encodes one of two Drosophila APC family proteins. It is a key negative regulator of Wingless signaling, as a critical component of the destruction complex that phosphorylates beta-catenin and thus targets it for ubiquitination and proteasomal destruction. It is the primary family member during CNS and eye development, and functions redundantly with the product of Apc2 in adult development. [Date last reviewed: 2019-03-07]
      Gene Groups / Pathways
      Comments on ortholog(s)

      Ortholog of human genes APC and APC2 (2 Drosophila to 2 human). Dmel\Apc shares 25-26% identity and 37% similarity with both human genes; it lacks a microtubule-binding domain found at the C terminus of the human APC gene.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      Phosphatase and tensin homolog (Pten) encodes a dual lipid and protein phosphatase that primarily counters the effects of the insulin-regulated lipid kinase, encoded by Pi3K92E. It inhibits cell growth, cell proliferation and cellular events controlling cytoskeletal and junctional rearrangements. [Date last reviewed: 2018-10-18]
      Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human PTEN (1 Drosophila to 1 human); Dmel\Pten shares 39% 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
      Medea (Med) encodes a protein that belongs to the highly conserved Smad family. It can bind its siblings encoded by Mad or Smox to facilitate signal transduction for the product of dpp or Activin ligands in the TGF-beta family. Med-complexes function as transcriptional regulators. Many developmental roles include dorsal-ventral patterning, patterning and proliferation of the wing disc and gene expression in the mushroom body of the larval brain. [Date last reviewed: 2019-03-14]
      Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human SMAD4 (1 Drosophila to 1 human); Dmel\Med shares 50% identity and 56% 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 (237 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, anti tag coimmunoprecipitation, anti tag western blot, pull down
      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
      coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation, western blot, pull down, autoradiography
      pull down, autoradiography
      bimolecular fluorescence complementation, fluorescence microscopy
      anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot
      pull down, autoradiography
      pull down, autoradiography
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      anti tag coimmunoprecipitation, western blot
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based, two hybrid array
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      anti tag coimmunoprecipitation, anti tag western blot, pull down, autoradiography, western blot
      pull down, autoradiography
      pull down, autoradiography
      anti tag coimmunoprecipitation, western blot, two hybrid
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography, two hybrid
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      anti bait coimmunoprecipitation, western blot, pull down
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      anti bait coimmunoprecipitation, western blot
      pull down, autoradiography
      pull down, autoradiography
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based, anti bait coimmunoprecipitation, western blot
      anti bait coimmunoprecipitation, western blot
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      two hybrid, pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot, pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      two hybrid array, bimolecular fluorescence complementation, fluorescence microscopy
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      enzymatic study, western blot
      anti tag coimmunoprecipitation, western blot
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      two hybrid, pull down, autoradiography
      pull down, autoradiography
      two hybrid, pull down, autoradiography
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      pull down, autoradiography
      anti bait coimmunoprecipitation, western blot
      pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      two hybrid array, pull down, autoradiography
      pull down, autoradiography
      pull down, autoradiography
      two hybrid, pull down, autoradiography
      anti tag coimmunoprecipitation, western blot, pull down, coimmunoprecipitation, anti tag western blot
      bimolecular fluorescence complementation, fluorescence microscopy
      pull down, autoradiography
      enzymatic study, western blot
      anti bait coimmunoprecipitation, western blot
      pull down, autoradiography
      anti tag coimmunoprecipitation, anti tag western blot
      RNA-RNA
      Interacting group
      Assay
      References
      fluorescence technology, luminiscence technology
      luminiscence technology
      luminiscence technology, fluorescence technology
      fluorescence technology, necessary binding region, luminiscence technology
      luminiscence technology
      protein-protein
      Interacting group
      Assay
      References
      colocalization, fluorescence microscopy, inferred by author, two hybrid
      pull down, autoradiography
      pull down, anti tag western blot
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, anti tag western blot, two hybrid
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      RNA-RNA
      Interacting group
      Assay
      References
      luminiscence technology
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      two hybrid, anti tag coimmunoprecipitation, anti tag western blot
      two hybrid, pull down, autoradiography
      anti tag coimmunoprecipitation, autoradiography, pull down, tag visualisation, anti tag western blot
      anti bait coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation, western blot, fluorescent resonance energy transfer, fluorescence microscopy
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (38 alleles)
      Models Based on Experimental Evidence ( 4 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 11 )
      Allele
      Disease
      Interaction
      References
      model of  cancer
      is ameliorated by Sec6GD11616
      is ameliorated by Sec8KK101531
      is ameliorated by Sec151
      is ameliorated by Sec15GD12109
      is ameliorated by Src64BGD12263
      is exacerbated by Nek2UAS.GFP
      is ameliorated by TimpUAS.cPa
      is ameliorated by JraNIG.2275R
      is ameliorated by bskDN.UAS
      is ameliorated by bskHMS00777
      is exacerbated by hepAct.UAS
      is exacerbated by imdUAS.cGa
      ameliorates  cancer
      model of  prostate cancer
      model of  kidney cancer
      is ameliorated by Pka-C1B3
      is ameliorated by TorΔP
      model of  carcinoma
      Models Based on Experimental Evidence ( 7 )
      Modifiers Based on Experimental Evidence ( 11 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 2 )
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      is ameliorated by ewgP1
      Models Based on Experimental Evidence ( 1 )
      Modifiers Based on Experimental Evidence ( 2 )
      Models Based on Experimental Evidence ( 1 )
      Modifiers Based on Experimental Evidence ( 3 )
      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
      amorphic allele - genetic evidence
      amorphic allele - molecular evidence
      Delta2-3 transposase
      amorphic allele - molecular evidence
      Delta2-3 transposase
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      ethyl methanesulfonate
      loss of function allele
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      References (8)