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General Information
Name
cancer, epithelial, ESCRT-complexes-related
FlyBase ID
FBhh0000968
Disease Ontology Term
Parent Disease
OMIM
Overview

Mutations of several Drosophila genes that encode components of ESCRT-complexes have been observed to produce overproliferation phenotypes. A part of the endosomal-lysosomal network, the ESCRT complexes, acting sequentially at the endosomal membrane, recognize and sort ubiquitinated endosomal proteins for degradation. Two Drosophila ESCRT-complex genes, TSG101 (orthologous to human TSG101) and Vps25 (orthologous to human VPS25) have been investigated in the context of a cancer model. Classical loss-of-functions mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes.

A UAS construct of the human Hsap\TSG101 has been introduced into flies, but has not been characterized in the context of this disease model.

Animals homozygous for loss-of-function mutations of Dmel\TSG101 typically die during the larval stage. Loss-of-function mutations of the Drosophila TSG101 gene result in overgrowth phenotypes in two different contexts: first, clones of TSG101 cells promote the overgrowth of surrounding wild-type tissue; second, eye discs composed almost entirely of TSG101 mutant tissue continue to grow during an extended larval stage, failing to respond to signals that normally sense and restrict organ size, and becoming tumorous masses.

Animals homozygous for loss-of-function mutations of Dmel\Vps25 typically die in the late embryonic or larval stages. Lack of Vps25 function in somatic clones causes at least phenotypes related to abnormal patterns of growth: non-autonomous proliferation, non-autonomous resistance to cell death, and autonomous apoptosis. As the mutant cells proliferate, they lose their epithelial organization and undergo apoptosis.

See the FlyBase gene group report ENDOSOMAL SORTING COMPLEXES REQUIRED FOR TRANSPORT (FBgg0000215) and the HGNC gene group reports under 'ESCRT complexes' (https://www.genenames.org/data/genegroup/#!/group/1111).

[updated Feb. 2019 by FlyBase; FBrf0222196]

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

Upon entering the endosomal-lysosomal network, internalized protein cargo has two potential destinies: either it is trafficked and delivered to the late endosomes and terminally, to lysosomes for degradation (via the ESCRT system); or, it is sorted and transported to the trans-Golgi network or the plasma membrane for reuse (via the retromer). At the endosomal membrane, the ESCRT complexes, acting sequentially, recognize and sort ubiquitinated endosomal proteins for degradation. (Hu et al., 2015; pubmed:26448863)

External links
Disease synonyms
Search term: endolysosomal sorting
Search term: endolysosomal trafficking
Search term: endosomal trafficking
Search term: hyperplastic phenotypes
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    Tumor susceptibility gene 101 (TSG101) encodes an ESCRT-I complex component that acts as an adapter for membrane rearrangements operated by ESCRT-III. Its roles include endosomal sorting of ubiquitinated cargoes, which is important for signaling regulation, cytokinesis, and budding of viruses and exovesicles. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    High-scoring ortholog of human TSG101 (VPS23) (1 Drosophila to 1 human). Dmel\TSG101 shares 50% identity and 66% 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
    Vacuolar protein sorting 25 (Vps25) encodes a member of the ESCRT-II complex, which sorts certain endocytosed receptors for degradation via the multivesicular body. As part of this complex, the product of Vps25 also has a role in bcd RNA localization. [Date last reviewed: 2019-03-21]
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    High-scoring ortholog of human VPS25 (1 Drosophila to 1 human). Dmel\Vps25 shares 43% identity and 66% 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
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (6 groups)
      protein-protein
      Interacting group
      Assay
      References
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based, anti bait coimmunoprecipitation, anti tag western blot
      experimental knowledge based
      protein-protein
      Interacting group
      Assay
      References
      Alleles Reported to Model Human Disease (Disease Ontology) (6 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 ( 5 )
      Modifiers Based on Experimental Evidence ( 2 )
      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
      ethyl methanesulfonate
      ethyl methanesulfonate
      ethyl methanesulfonate
      P-element activity
      References (15)