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General Information
Name
cancer, epithelial, compromised apoptosis
FlyBase ID
FBhh0001040
Disease Ontology Term
Parent Disease
OMIM
Overview

A principal feature of many cancer cells is that they can evade apoptosis. Work in flies investigates whether this characteristic can be an initiating step in the development of cancer: it has been shown that apoptosis-deficient calls are susceptible to becoming tumorigenic after stress events that are inconsequential in tissues in which apoptotic pathways are not compromised.

Initiation of apoptosis was prevented in imaginal discs using mutations in the caspase Dmel\Dronc or other pro-apoptotic genes; the JNK responses after various stress-inducing events [X-rays, a pulse of p53, or a pulse of JNK (bsk) itself] were assessed. Persistent JNK activity after a transient initiation event is observed, resulting in tissue overgrowth.

The constitutively active Ras85D mutation, Ras85DV12, is analogous to oncogenic mutations found in human RAS proteins. Typically, the Ras85DV12 activated mutation produces mild overproliferation phenotypes. In apoptosis-deficient cells in which this activated RAS mutation is expressed, a stress event results in much more dramatic overgrowth. See also the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474).

In related experiments, apoptosis was compromised in imaginal discs by mutation in the caspase Dmel\Drice gene or by expressing the caspase inhibitor BacA\p35. After X-irradiation, a number of tumorigenic phenotypes are observed: overgrowth and atypical migration of apoptosis-deficient cells; delamination of the epithelium; ectopic expression of wg (a measure of JNK signaling).

Assayed in wing discs, co-expression of BacA\p35 and Dmel\hid (normally an activator of apoptosis) results in sub-apoptotic caspase activation. This results in several phenotypes indicative of tumorigenic changes: cell invasion outside the restricted region of expression and elevated matrix metalloproteinase (Mmp1) expression (invading tumor cells typically express MMPs to degrade the extracellular matrix and basement membrane); caspase activation of JNK signaling plays a role in this process. These results support the hypothesis that effector caspase activity below levels sufficient to cause cell death play an important role in tumorigenesis.

[updated Jun. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, compromised apoptosis
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
External links
    Disease synonyms
    cancer, epithelial, compromised apoptosis
    cancer susceptibility, apoptosis-deficient cells
    Search term: hyperplastic phenotypes
    Ortholog Information
    Human gene(s) in FlyBase
      Other mammalian ortholog(s) used
        D. melanogaster Gene Information (4)
        Gene Groups / Pathways
        Comments on ortholog(s)

        No ortholog of Dmel\hid has been identified in human.

        Orthologs and Alignments from DRSC
        DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
        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
        Death regulator Nedd2-like caspase (Dronc) encodes an initiator caspase that is essential for caspase-dependent cell death. It is also implicated in the DNA damage response, sperm differentiation and cell specification. [Date last reviewed: 2018-10-18]
        Gene Groups / Pathways
        Comments on ortholog(s)

        Low- to moderate-scoring ortholog of multiple caspases in human (multiple in both species); most closely related human genes include CASP2, CASP1, CASP4 and CASP5. Dmel\Dronc shares 20-25% identity and 37-40% similarity with these genes.

        Orthologs and Alignments from DRSC
        DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
        Gene Snapshot
        Death related ICE-like caspase (Drice) encodes a major effector apoptotic caspase. It is essential for both developmental and damaged induced cell death, as well as several non-apoptotic vital cellular processes. It is activated by the product of Dark and the initiator caspase encoded by Dronc and is inhibited by the inhibitor of apoptosis encoded by Diap1. [Date last reviewed: 2019-03-07]
        Cellular component (GO)
        Gene Groups / Pathways
        Comments on ortholog(s)

        Moderate- to high-scoring ortholog of human CASP7, CASP3, and CASP6 (multiple in both species); low-scoring ortholog of multiple other caspases in human. Dmel\Dronc shares 37-43% identity and 54-61% similarity with CASP7, CASP3, and CASP6.

        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 (1)
        Summary of Physical Interactions (78 groups)
        RNA-RNA
        Interacting group
        Assay
        References
        fluorescence technology, luminiscence technology
        fluorescence technology, luminiscence technology
        luminiscence technology, fluorescence technology
        quantitative reverse transcription pcr, luminiscence technology
        luminiscence technology, necessary binding region
        immunohistochemistry, luminiscence technology, fluorescence technology, necessary binding region
        quantitative reverse transcription pcr, luminiscence technology, necessary binding region
        RNA-protein
        Interacting group
        Assay
        References
        electrophoretic mobility shift assay, autoradiography
        protein-protein
        Interacting group
        Assay
        References
        cross-linking study, molecular weight estimation by staining
        pull down, western blot, far western blotting, anti tag western blot, isothermal titration calorimetry, predetermined participant, autoradiography, molecular sieving, molecular weight estimation by staining, colocalization, fluorescence microscopy, inferred by author, anti tag coimmunoprecipitation
        pull down, western blot, anti tag western blot
        pull down, molecular weight estimation by staining, autoradiography, colocalization, fluorescence microscopy, inferred by author, anti tag coimmunoprecipitation, anti tag western blot
        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, 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
        anti tag coimmunoprecipitation, anti tag western blot, two hybrid, 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
        enzymatic study, molecular weight estimation by staining, molecular sieving, molecular weight, cosedimentation, cleavage assay, western blot
        experimental knowledge based
        experimental knowledge based
        anti tag coimmunoprecipitation, anti tag western blot, western blot
        anti tag coimmunoprecipitation, anti tag western blot
        pull down, western blot, molecular sieving, anti tag coimmunoprecipitation, anti tag western blot, molecular weight estimation by staining, electron microscopy
        experimental knowledge based
        anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot, enzymatic study, pull down, cleavage assay, molecular weight estimation by staining
        enzymatic study, molecular weight estimation by staining, anti tag western blot, cleavage assay, autoradiography
        anti tag coimmunoprecipitation, anti tag western blot
        anti tag coimmunoprecipitation, anti tag western blot
        experimental knowledge based
        experimental knowledge based
        anti tag coimmunoprecipitation, western blot, phenotype-based detection assay, fluorescence microscopy, inferred by author
        anti tag coimmunoprecipitation, anti tag western blot
        experimental knowledge based
        anti tag coimmunoprecipitation, western blot, anti tag western blot
        anti tag coimmunoprecipitation, western blot, anti tag western blot
        anti tag coimmunoprecipitation, anti tag western blot
        RNA-RNA
        Interacting group
        Assay
        References
        protein-protein
        Interacting group
        Assay
        References
        anti tag coimmunoprecipitation, Identification by mass spectrometry
        experimental knowledge based
        experimental knowledge based
        enzymatic study, western blot, autoradiography
        molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot, cleavage assay
        anti tag coimmunoprecipitation, western blot
        enzymatic study, molecular weight estimation by staining, anti tag western blot, cleavage assay, autoradiography
        enzymatic study, western blot
        experimental knowledge based
        experimental knowledge based
        experimental knowledge based
        anti bait coimmunoprecipitation, western blot
        experimental knowledge based
        experimental knowledge based
        anti tag coimmunoprecipitation, anti tag western blot
        protein-protein
        Interacting group
        Assay
        References
        anti tag coimmunoprecipitation, anti tag western blot
        Alleles Reported to Model Human Disease (Disease Ontology) (25 alleles)
        Models Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Interaction
        References
        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 Sec15GD12109
        is ameliorated by Sec151
        is ameliorated by Src64BGD12263
        is exacerbated by Nek2UAS.GFP
        is ameliorated by JraNIG.2275R
        is ameliorated by bskDN.UAS
        is ameliorated by bskHMS00777
        is exacerbated by hepAct.UAS
        is exacerbated by imdUAS.cGa
        is ameliorated by TimpUAS.cPa
        ameliorates  cancer
        model of  prostate cancer
        model of  kidney cancer
        is ameliorated by Pka-C1B3
        is ameliorated by TorΔP
        Models Based on Experimental Evidence ( 2 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 3 )
        Models Based on Experimental Evidence ( 0 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 2 )
        Allele
        Disease
        Interaction
        References
        Models Based on Experimental Evidence ( 1 )
        Modifiers Based on Experimental Evidence ( 3 )
        Allele
        Disease
        Interaction
        References
        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
        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
        amorphic allele - genetic evidence
        P-element activity
        ethyl methanesulfonate
        amorphic allele - genetic evidence
        gamma ray
        loss of function allele
        ethyl methanesulfonate
        amorphic allele - genetic evidence
        ethyl methanesulfonate
        amorphic allele - genetic evidence
        ethyl methanesulfonate
        amorphic allele - genetic evidence
        Delta2-3 transposase
        loss of function allele
        loss of function allele
        P-element activity
        amorphic allele - genetic evidence
        amorphic allele - molecular evidence
        P-element activity
        amorphic allele - molecular evidence
        P-element activity
        amorphic allele - molecular evidence
        P-element activity
        loss of function allele
        ethyl methanesulfonate
        loss of function allele
        ethyl methanesulfonate
        loss of function allele
        ethyl methanesulfonate
        loss of function allele
        ethyl methanesulfonate
        loss of function allele
        ethyl methanesulfonate
        loss of function allele
        ethyl methanesulfonate
        References (14)