FB2026_01 , released March 12, 2026
FB2026_01 , released March 12, 2026
Human Disease Model Report: HPV-related carcinoma, E5-E6-E7-UBE3A models
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General Information
Name
HPV-related carcinoma, E5-E6-E7-UBE3A models
FlyBase ID
FBhh0001073
Disease Ontology Term
Parent Disease
OMIM
Overview

A Drosophila model of HPV-related carcinoma has been developed using the papillomavirus E6 gene HPV18\E6 plus the human ubiquitin ligase gene Hsap\UBE3A expressed in the eye or wing disc. Co-expression of HPV18\E6 and Hsap\UBE3A results in visible phenotypes in disc-derived tissues not observed for expression of either gene alone; however, phenotypes indicative of cellular transformation or tumorigenesis are not observed. When, in addition, activated Ras85D or activated Notch N is expressed, tumorigenic phenotypes and evidence of metastatic cell migration are observed. This model has been extended using the papillomavirus E5, E6, and E7 genes HPV16\E5, HPV16\E6, and HPV16\E7 genes, in which all three genes are co-expressed in the eye disc with Hsap\UBE3A.

Using the eye phenotype, this system has been used to identify the signaling pathways involved in E6 + UBE3A phenotypes; a dominant negative form of the insulin receptor InR exacerbates the phenotype, implicating insulin signaling in this process. Effects upon Drosophila orthologs of known targets of E6 in human cells have been assessed; of the genes tested, the most significant effect was upon the molecular scaffolding protein Dmel\Magi (orthologous to human MAGI1, MAGI2, and MAGI3). A genetic screen identified Dmel\IKKβ as a modifier of the eye phenotype; this interaction is conserved in human cells.

UBE3A acts in the ubiquitin proteasome pathway and as a transcriptional coactivator. There is a single orthologous gene in Drosophila, Dmel\Ube3a, for which classical amorphic alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. In analogous experiments, HPV18\E6 co-expressed with the fly Dmel\Ube3a gene in discs fails to produce visible phenotypes, and thus has not been used in this model.

The constitutively active Ras85D mutation, Ras85DV12, is analogous to oncogenic mutations found in human RAS proteins. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G12V in the fly Ras85D gene (corresponds to G12V in the human KRAS and HRAS genes). See also the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474). Much of the work in flies investigating the role of the Notch pathway in development of cancer has involved combining Notch signaling dysregulation with another cancer model. This is typically achieved by using targeted expression of an activated form of Notch (N); see also the human disease model report 'cancer, multiple, Notch signaling pathway' (FBhh0000766).

[updated Jan. 2023 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: HPV-related carcinoma, E5-E6-E7-UBE3A models
OMIM report
Human gene(s) implicated
Symptoms and phenotype

HPV is thought to be responsible for more than 90% of anal and cervical cancers, about 70% of vaginal and vulvar cancers, and 60% of penile cancers. Cancers of the oropharynx (back of the throat, including the base of the tongue and tonsils) traditionally have been associated with use of tobacco and alcohol, but recent studies show that about 60% to 70% of cancers of the oropharynx may be linked to HPV (https://www.cdc.gov/cancer/hpv/basic_info/cancers.htm).

Human papillomaviruses (HPVs) are the etiological agents in nearly all cases (99.7%) of cervical cancer, and the HPV E6 protein is one of two viral oncoproteins that is expressed in virtually all HPV-positive cancers. HPV16 and HPV18 are the high-risk types most frequently associated with cervical squamous cell carcinomas (50% and 20%, respectively). The HPV E6 and E7 proteins are the only two viral genes expressed in virtually all HPV-positive cervical carcinomas (Beaudenon and Huibregtse, 2008; pubmed:19007434).

Genetics

E7 is the major transforming oncoprotein of HPV. It promotes increased cell proliferation by dysregulating the G1/S transition, and delays cell differentiation. E6 and E7 can each immortalize cells, but appear to act cooperatively in tumor formation, with E7 being involved in the early stages and E6 accelerating progression to malignancy. A third HPV protein, E5, expressed early in the HPV life cycle, provides support for viral infection and transformation of cells. E5 enhances the oncogenic abilities of E6 and E7 in cellular transformation and tumor formation. (Hashemi, et al., 2022, pubmed:36508448; FBrf0255248 and references cited therein).

Cellular phenotype and pathology
Molecular information

High-risk HPV E6 proteins bind directly to the cellular ubiquitin ligase E6AP/UBE3A, causing its substrate specificity to be altered so that it stably associates with and polyubiquitylates TP53, resulting in degradation of TP53 (Beaudenon and Huibregtse, 2008; pubmed:19007434).

Multiple functions of E6, including interaction with UBE3A, TP53 and PDZ domain-containing substrates, appear to be required for its ability to bring about cell transformation and to contribute towards malignancy in animal models (Beaudenon and Huibregtse, 2008, pubmed:19007434; FBrf0233222 and references cited therein).

External links
Disease synonyms
HPV 18 E6 model
HPV-related carcinoma, E6-UBE3A models
human papillomavirus-related carcinoma
Search term: HPV-related cervical cancer
Search term: HPV-related cervical carcinoma
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

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    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 Groups / Pathways
    Comments on ortholog(s)

    Moderate- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3, NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 43-44% identity and 56-57% similarity with NOTCH1 and NOTCH2.

    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 (2)
    Summary of Physical Interactions (87 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    pull down, anti tag western blot
    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
    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
    pull down, covalent binding, western blot, anti tag coimmunoprecipitation, Identification by mass spectrometry
    protein-protein
    Interacting group
    Assay
    References
    two hybrid, enzyme linked immunosorbent assay, electron microscopy, molecular weight
    anti bait coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot, anti tag western blot
    anti bait coimmunoprecipitation, western blot
    proximity ligation assay, fluorescence microscopy
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    pull down, western blot
    experimental knowledge based
    anti tag coimmunoprecipitation, western blot, pull down
    anti tag coimmunoprecipitation, western blot, autoradiography, anti bait coimmunoprecipitation, two hybrid
    proximity ligation assay, fluorescence microscopy
    affinity technology, tag visualisation by alkaline phosphatase activity
    pull down, autoradiography, western blot, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation
    affinity technology, inferred by author, bead aggregation assay, fluorescence microscopy, enzyme linked immunosorbent assay, anti bait coimmunoprecipitation, western blot, tag visualisation, phenotype-based detection assay, cross-linking study, pull down, tag visualisation by alkaline phosphatase activity, atomic force microscopy
    pull down, western blot, autoradiography, anti bait coimmunoprecipitation, two hybrid
    anti tag coimmunoprecipitation, western blot, nuclear magnetic resonance, two hybrid, cosedimentation in solution, predetermined participant, anti tag western blot
    anti tag coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy
    anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, two hybrid, anti tag western blot
    two hybrid, pull down, western blot, anti tag coimmunoprecipitation
    protease assay, western blot, inferred by author
    anti tag coimmunoprecipitation, anti tag western blot
    three hybrid, protein three hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting
    anti bait coimmunoprecipitation, western blot, two hybrid
    pull down, western blot
    pull down, western blot
    pull down, western blot
    coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot
    pull down, western blot, anti tag coimmunoprecipitation
    two hybrid, pull down, autoradiography
    anti tag coimmunoprecipitation, western blot, anti tag western blot
    anti tag coimmunoprecipitation, western blot
    experimental knowledge based
    experimental knowledge based
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot
    inferred by author, anti bait coimmunoprecipitation, cross-linking study, western blot, pull down, tag visualisation by alkaline phosphatase activity, affinity technology, fluorescence microscopy, confocal microscopy, bead aggregation assay, tag visualisation, anti tag coimmunoprecipitation
    anti bait coimmunoprecipitation, western blot
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, pull down
    pull down, molecular weight estimation by staining, isothermal titration calorimetry, predetermined participant, autoradiography, nuclear magnetic resonance, western blot
    protein three hybrid, isothermal titration calorimetry, predetermined participant, two hybrid, pull down, autoradiography, anti tag coimmunoprecipitation, peptide massfingerprinting, anti bait coimmunoprecipitation, western blot, cosedimentation, molecular sieving, molecular weight estimation by staining, anti tag western blot, electrophoretic mobility shift assay, electrophoretic mobility supershift assay, coimmunoprecipitation, electron microscopy, three hybrid
    anti tag coimmunoprecipitation, anti tag western blot
    two hybrid, anti tag coimmunoprecipitation, western blot, pull down
    anti bait coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, cross-linking study, western blot
    inferred by author, confocal microscopy, bead aggregation assay
    proximity ligation assay, fluorescence microscopy
    anti bait coimmunoprecipitation, western blot, Identification by mass spectrometry, anti tag western blot
    RNA-protein
    Interacting group
    Assay
    References
    nucleic acid uv cross-linking assay, autoradiography, anti bait coimmunoprecipitation, quantitative reverse transcription pcr
    pull down, quantitative reverse transcription pcr
    Alleles Reported to Model Human Disease (Disease Ontology) (56 alleles)
    Models Based on Experimental Evidence ( 17 )
    Allele
    Disease
    Evidence
    References
    model of  cancer
    Modifiers Based on Experimental Evidence ( 19 )
    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 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  kidney cancer
    is ameliorated by Pka-C1B3
    is ameliorated by mTorΔP
    model of  cancer
    is exacerbated by Ptp61FΔ
    is exacerbated by exe1
    is exacerbated by M6W186stop
    is ameliorated by Ptip3804
    is exacerbated by p53UAS.cUa
    is ameliorated by Ilp8MI00727
    is exacerbated by Clbn1Q
    exacerbates  carcinoma
    model of  carcinoma
    is exacerbated by NkapGD11807
    Models Based on Experimental Evidence ( 13 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 22 )
    Allele
    Disease
    Interaction
    References
    is exacerbated by CatHMS00990
    is ameliorated by CatUAS.cUa
    is ameliorated by Sod2UAS.cMa
    is exacerbated by cncHMS00650
    is exacerbated by Sod2HMS00499
    is ameliorated by cncUAS.cSa
    ameliorates  carcinoma
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 0 )
    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
    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
    amorphic allele - genetic evidence
    Delta2-3 transposase
    loss of function allele
    spontaneous
    loss of function allele
    spontaneous
    amorphic allele - genetic evidence
    X ray
    loss of function allele
    X ray
    loss of function allele
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    gamma ray
    loss of function allele
    X ray
    loss of function allele
    X ray
    loss of function allele
    X ray
    loss of function allele
    X ray
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    X ray
    loss of function allele
    X ray
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    loss of function allele
    X ray
    loss of function allele
    X ray
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    X ray
    loss of function allele
    X ray
    loss of function allele
    loss of function allele
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    X ray
    amorphic allele - genetic evidence
    loss of function allele
    spontaneous
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    X ray
    loss of function allele
    X ray
    loss of function allele
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    loss of function allele
    loss of function allele
    P-element activity
    amorphic allele - genetic evidence
    References (7)