Open Close
General Information
Name
cancer, epithelial, TNF-DLG1-related
FlyBase ID
FBhh0000928
Disease Ontology Term
Parent Disease
OMIM
Overview

This Drosophila model of epithelial cancer makes use of the fly polarity gene dlg1 and the fly tumor necrosis factor (TNF) family gene egr. Classical loss-of-functions mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\dlg1. RNAi-targeting constructs, alleles caused by insertional mutagenesis, and loss-of-function mutations resulting from imprecise excision of TE insertions have been generated for Dmel\egr.

Loss of apical-basal polarity is an early event in the development of epithelial cancers; genes of the Scribble polarity complex have been used extensively in Drosophila models of epithelial cancer (see FBhh0000586). The fly gene dlg1 is orthologous to four genes in human, DLG1 (a component of the Scribble polarity complex), DLG2, DLG3, and DLG4. Animals homozygous for loss-of-function mutations of Dmel\dlg1 typically die during the larval stage; tumors of the brain and imaginal discs are observed; defects associated with neuromuscular junctions are observed. Knockdown of dlg1 in larval imaginal discs, effected by RNAi, results in apoptosis and an invasion-like phenotype in which cells delaminated and migrated away from the site of origin within the wing disc epithelium; however, most of these animals survive to adulthood, displaying scars along the anterior/posterior boundary of the wing blade, indicating that a mechanism to eliminate the abnormal cells comes into play. (See the human disease model report 'cancer, epithelial, DLG1-related' FBhh0000678).

Tumor necrosis factor (TNF) proteins are transmembrane proteins that can be released from the cell membrane by extracellular proteolytic cleavage; they can act via both autocrine and paracrine signaling. This is a large gene family in human; in Drosophila there is a single TNF family gene, eiger (egr). Animals homozygous for the loss-of-function mutation of egr1 are viable and fertile, with minor feeding and immune response phenotypes. Using the dlg1 model, egr has been found to play a significant role in tumorigenesis in that system. In contrast to the result in wild-type egr animals, in egr1 animals knockdown of dlg1 in larval imaginal discs, effected by RNAi, fails to result in apoptosis, the invasion-like phenotype is more extensive, and all animals die during the pupal stage. Thus presence of wild-type egr is these experiments serves an anti-tumor function.

The role of hemocyte-derived egr has been investigated using overexpression of egr or knockdown by RNAi in hemocytes of dlg1 mutants; tumor size and amount of tumor-related apoptosis in imaginal discs were assayed. The role of hemocytes has also been investigated in related models; see 'cancer, epithelial, TNF-SCRIB-RAS-related' (FBhh0000927).

Multiple physical and genetic interactions have been described for both Dmel\egr and Dmel\dlg1; see below and in the respective gene reports.

[updated Nov. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, TNF-DLG1-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information

DLG1 encodes an essential multidomain scaffolding protein with multiple roles in normal development. It recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells, and may play roles in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. [from Gene Cards, DLG1; 2017.08.01]

The tumor necrosis factor (TNF) superfamily is a protein superfamily of type II transmembrane proteins containing TNF homology domain and forming trimers. Members of this superfamily can be released from the cell membrane by extracellular proteolytic cleavage. TNF proteins are expressed predominantly by immune cells and regulate diverse cell functions, including regulation of immune response and inflammation, but also proliferation, differentiation, apoptosis and embryogenesis. The superfamily contains 19 members that bind to 29 members of TNF receptor superfamily. [https://en.wikipedia.org/wiki/Tumor_necrosis_factor_superfamily] This protein family is also called the TNF ligand family.

TNF proteins can act via both autocrine and paracrine signaling (Caldwell et al., 2014; pubmed:25274725).

HGNC currently lists 18 genes in the Tumor Necrosis Factor Superfamily (https://www.genenames.org/data/genegroup/#!/group/781)

External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (2)
      Gene Snapshot
      eiger (egr) encodes the TNF superfamily ligand that activates the intracellular JNK pathway through its receptor encoded by grnd or wgn. Its roles include cell death, tumor suppression, tumor promotion, growth regulation, host defense, pain sensitization, and nutrient response. [Date last reviewed: 2018-10-11]
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)

      Sole TNF family gene in Drosophila (1 Drosophila to many human); Dmel\egr is most closely related to human EDA, TNFSF13, and TNFSF13B.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Groups / Pathways
      Comments on ortholog(s)

      Moderate- to high-scoring ortholog of human DLG1, DLG4, DLG2, and DLG3 (1 Drosophila to 4 human). Dmel\dlg1 shares 40-49% identity and 55-63% 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
      Other Genes Used: Viral, Bacterial, Synthetic (0)
        Summary of Physical Interactions (35 groups)
        protein-protein
        Interacting group
        Assay
        References
        pull down, western blot
        anti tag coimmunoprecipitation, anti tag western blot
        anti bait coimmunoprecipitation, western blot
        anti bait coimmunoprecipitation, western blot
        anti bait coimmunoprecipitation, western blot
        anti tag coimmunoprecipitation, anti tag western blot
        protein-protein
        Interacting group
        Assay
        References
        pull down, western blot, molecular sieving, molecular weight, x-ray crystallography, cosedimentation, two hybrid, anti tag coimmunoprecipitation
        anti bait coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy
        anti bait coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy
        enzymatic study, Identification by mass spectrometry
        proximity ligation assay, fluorescence microscopy
        anti bait coimmunoprecipitation, western blot, enzymatic study, autoradiography
        pull down, anti tag western blot, anti tag coimmunoprecipitation, western blot
        two hybrid, anti bait coimmunoprecipitation, western blot
        anti bait coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, pull down
        two hybrid, pull down, western blot, anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation
        anti bait coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy
        pull down, molecular weight estimation by staining, western blot, anti tag coimmunoprecipitation
        pull down, anti tag western blot
        anti bait coimmunoprecipitation, western blot
        proximity ligation assay, fluorescence microscopy
        enzymatic study, autoradiography
        pull down, molecular weight estimation by staining, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, two hybrid, anti tag western blot
        anti tag coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy, anti bait coimmunoprecipitation, colocalization, inferred by author
        two hybrid, pull down, molecular weight estimation by staining, isothermal titration calorimetry, predetermined participant, surface plasmon resonance, anti tag western blot
        two hybrid, anti bait coimmunoprecipitation, western blot
        pull down, western blot, two hybrid, anti bait coimmunoprecipitation, autoradiography
        anti bait coimmunoprecipitation, western blot, two hybrid
        anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot
        anti bait coimmunoprecipitation, western blot
        RNA-RNA
        Interacting group
        Assay
        References
        luminiscence technology, necessary binding region, western blot, anti tag western blot
        RNA-protein
        Interacting group
        Assay
        References
        electrophoretic mobility shift assay, autoradiography
        anti bait coimmunoprecipitation, quantitative reverse transcription pcr
        anti tag coimmunoprecipitation, quantitative reverse transcription pcr
        Alleles Reported to Model Human Disease (Disease Ontology) (14 alleles)
        Models Based on Experimental Evidence ( 2 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 6 )
        Models Based on Experimental Evidence ( 6 )
        Modifiers Based on Experimental Evidence ( 5 )
        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
        Delta2-3 transposase
        amorphic allele - molecular evidence
        P-element activity
        amorphic allele - molecular evidence
        Delta2-3 transposase
        loss of function allele
        X ray
        loss of function allele
        ethyl methanesulfonate
        Delta2-3 transposase
        amorphic allele - molecular evidence
        ethyl methanesulfonate
        References (13)