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General Information
Name
cancer, epithelial, NOTCH-LLGL-related
FlyBase ID
FBhh0001055
Disease Ontology Term
Parent Disease
OMIM
Overview

A model of cancer of epidermal origin has been developed using the Drosophila l(2)gl gene in combination with an activated form of the Drosophila Notch (N) gene. See also the human disease model reports 'cancer, epithelial, LLGL-related' (FBhh0000591), and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).

l(2)gl encodes a component of the Scribble polarity complex; this complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. In human, there are two genes orthologous to Dmel\l(2)gl, the cytoskeletal proteins LLGL1 and LLGL2. Animals homozygous for loss-of-function mutations of Dmel\l(2)gl typically die during the larval stage and exhibit abnormal overproliferation of tissues, including in the brain, imaginal discs, and hematopoietic organs; cell-polarity defects are observed. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\l(2)gl.

The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. In human, there are 4 known genes that encode NOTCH family proteins; there is a single orthologous gene in Drosophila (the founding member of this gene family), Notch or N. In flies, most work relevant to cancer has been done with a constitutively active N transgene; ectopic expression of constitutively active N in somatic clones surrounded by wild-type tissue results in hyperproliferative effects. N is one the most thoroughly studied genes in Drosophila: hundreds of alleles, extensive physical interactions, and an unwieldy number of genetic interactions have been described; see below and in the gene report for N.

In eye discs, RNAi-mediated knockdown of l(2)gl in combination with constitutively active N results in more extreme overproliferation than is observed with either modification alone, resulting in dramatic tissue overgrowth. MMP1 (a reporter for JNK signaling) upregulation and loss of epithelial integrity are observed.

[updated Jun. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, NOTCH-LLGL-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
LLGL1 and LLGL2 encode cortical cytoskeleton proteins found in a complex involved in maintaining cell polarity and epithelial integrity, the Scribble Cell Polarity Complex. This complex plays a role in the initial phase of the establishment of epithelial cell polarity; it is involved in the regulation of mitotic spindle orientation, proliferation, differentiation, and tissue organization of neuroepithelial cells. [Gene Cards, LLGL1, LLGL2; 2017.08.01]
In human, there are 4 known genes encoding the NOTCH family of proteins, a group of receptors involved in the Notch signaling pathway. NOTCH proteins are characterized by N-terminal EGF-like repeats followed by LNR domains which form a complex with ligands to prevent signaling. The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. [Gene Cards, NOTCH1; 2017.12.06]
External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    lethal (2) giant larvae (l(2)gl) encodes a tumor suppressor protein that regulates cell polarity and asymmetric cell division. It acts on the basolateral side of epithelial cells, antagonizing the activity of apical complex proteins encoded by baz, par-6 and aPKC. [Date last reviewed: 2019-09-26]
    Gene Groups / Pathways
    Comments on ortholog(s)
    Moderate- to high-scoring ortholog of human LLGL1 and LLGL2 (1 Drosophila to 2 human). Dmel\l(2)gl shares 34-36% identity and 51-54% 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
    In progress.Contributions welcome.
    Gene Groups / Pathways
    Comments on ortholog(s)
    Moderate- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3 and NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 33-44% identity and 44-57% 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
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (62 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation
    anti bait coimmunoprecipitation, western blot, experimental knowledge based, pull down, autoradiography, anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot
    proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, anti tag western blot, pull down, Identification by mass spectrometry
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    protein-protein
    Interacting group
    Assay
    References
    two hybrid, enzyme linked immunosorbent assay, electron microscopy, molecular weight
    anti tag coimmunoprecipitation, western blot, anti tag western blot
    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
    pull down, western blot
    experimental knowledge based
    anti tag coimmunoprecipitation, western blot, pull down
    anti tag coimmunoprecipitation, autoradiography, two hybrid, anti bait coimmunoprecipitation, western blot
    proximity ligation assay, fluorescence microscopy
    affinity technology, tag visualisation by alkaline phosphatase activity
    pull down, autoradiography, western blot, anti tag coimmunoprecipitation, anti bait coimmunoprecipitation
    bead aggregation assay, fluorescence microscopy, inferred by author, affinity technology, enzyme linked immunosorbent assay, tag visualisation by alkaline phosphatase activity, phenotype-based detection assay, anti bait coimmunoprecipitation, western blot, atomic force microscopy, pull down, tag visualisation
    pull down, western blot, autoradiography, two hybrid, anti bait coimmunoprecipitation
    two hybrid, anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, anti tag western blot, western blot, anti tag coimmunoprecipitation, two hybrid
    two hybrid, pull down, western blot, anti tag coimmunoprecipitation
    protease assay, western blot, inferred by author
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting, protein three 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, anti tag western blot, 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
    affinity technology, tag visualisation by alkaline phosphatase activity, inferred by author, confocal microscopy, bead aggregation assay, fluorescence microscopy, tag visualisation, anti tag coimmunoprecipitation, western blot, pull down
    anti bait coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot, pull down, anti bait coimmunoprecipitation, western blot
    isothermal titration calorimetry, predetermined participant, pull down, molecular weight estimation by staining, western blot, nuclear magnetic resonance, autoradiography
    molecular sieving, molecular weight estimation by staining, isothermal titration calorimetry, predetermined participant, two hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting, coimmunoprecipitation, western blot, protein three hybrid, cosedimentation, electron microscopy, anti bait coimmunoprecipitation, anti tag western blot, pull down, autoradiography, electrophoretic mobility shift assay, electrophoretic mobility supershift assay
    two hybrid, pull down, western blot, anti tag coimmunoprecipitation
    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
    inferred by author, confocal microscopy, bead aggregation assay
    RNA-protein
    Interacting group
    Assay
    References
    anti bait coimmunoprecipitation, quantitative reverse transcription pcr, nucleic acid uv cross-linking assay, autoradiography
    pull down, quantitative reverse transcription pcr
    Alleles Reported to Model Human Disease (Disease Ontology) (6 alleles)
    Models Based on Experimental Evidence ( 3 )
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 1 )
    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
    amorphic allele - genetic evidence
    P-element activity
    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
    natural population
    amorphic allele - genetic evidence
    spontaneous
    amorphic allele - molecular evidence
    ends-out gene targeting
    References (4)