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General Information
Name
cancer, epithelial, NOTCH-SCRIB-related
FlyBase ID
FBhh0000679
Disease Ontology Term
Parent Disease
OMIM
Overview

A model of cancer initiation and progression has been developed using the Drosophila scrib gene in combination with the Drosophila Notch (N) gene. See also the human disease model reports 'cancer, epithelial, SCRIB-related' (FBhh0000587), and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).

The Scribble polarity complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. The eponymous Drosophila scrib gene is a cell polarity regulator and neoplastic tumor suppressor; there are two orthologous genes in human, SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. Dmel\scrib is well characterized genetically: classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. A tagged wild-type transgene of human Hsap\SCRIB has been introduced into flies; partial heterologous rescue (functional complementation) of homozygous Dmel\scrib loss-of-function phenotypes is observed.

Animals homozygous for loss-of-function mutations of Dmel\scrib typically die during the larval stage; imaginal discs exhibit morphology defects, such as increase in size (due to increased cell numbers) and disruption of monolayered epithelial organization. To create a context that more accurately emulates the clonal development of tumors, somatic clones have been used; somatic clones that are homozygous for loss-of-function mutations of scrib exhibit overgrowth phenotypes. Many physical and genetic interactions for Dmel\scrib have been described; see below and in the gene report for scrib.

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 activate 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.

Expression of scrib loss-of-function alleles in somatic clones in combination with a constitutively active N transgene results in a more extreme overproliferation of the clonal cells than is observed with either modification alone, resulting in dramatic tissue overgrowth.

[updated Dec. 2017 by FlyBase; FBrf0222196]

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

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
Search term: neoplastic phenotype(s)
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second human gene is LRRC1.

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

Many to one (4 human to 1 Drosophila). The human genes are NOTCH1, NOTCH2, NOTCH3 and NOTCH4.

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

Many to one (4 human to 1 Drosophila). The human genes are NOTCH1, NOTCH2, NOTCH3 and NOTCH4.

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

Many to one (4 human to 1 Drosophila). The human genes are NOTCH1, NOTCH2, NOTCH3 and NOTCH4.

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

Many to one (4 human to 1 Drosophila). The human genes are NOTCH1, NOTCH2, NOTCH3 and NOTCH4.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    scribble (scrib) encodes a scaffolding protein that is part of the conserved machinery regulating apicobasal polarity. It acts with the products of dlg1 and l(2)gl to distinguish the basolateral domain of epithelial cells and neuroblasts, via reciprocally antagonistic interactions with the aPKC/par-6 complex that impacts vesicle trafficking. The product of scrib also organizes synaptic architecture and is implicated in learning and memory. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.

    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 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
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (65 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      proximity ligation assay, fluorescence microscopy
      colocalization, fluorescence microscopy, inferred by author, anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, proximity ligation assay
      proximity ligation assay, fluorescence microscopy
      x-ray crystallography, isothermal titration calorimetry, predetermined participant, anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, western blot, anti tag coimmunoprecipitation
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, autoradiography
      anti tag coimmunoprecipitation, western blot
      pull down, autoradiography, two hybrid
      protein-protein
      Interacting group
      Assay
      References
      two hybrid, enzyme linked immunosorbent assay, electron microscopy, molecular weight
      anti tag coimmunoprecipitation, anti tag western blot, 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
      pull down, western blot, anti tag coimmunoprecipitation
      anti tag coimmunoprecipitation, autoradiography, western blot, two hybrid, anti bait coimmunoprecipitation
      proximity ligation assay, fluorescence microscopy
      affinity technology, tag visualisation by alkaline phosphatase activity
      pull down, autoradiography, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
      anti bait coimmunoprecipitation, western blot, bead aggregation assay, fluorescence microscopy, inferred by author, affinity technology, atomic force microscopy, pull down, tag visualisation by alkaline phosphatase activity, tag visualisation, enzyme linked immunosorbent assay, phenotype-based detection assay
      two hybrid, pull down, western blot, anti bait coimmunoprecipitation, autoradiography
      two hybrid, anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, two hybrid, anti tag western blot
      anti tag coimmunoprecipitation, western blot, two hybrid, pull down
      protease assay, western blot, inferred by author
      anti tag coimmunoprecipitation, anti tag western blot
      protein three hybrid, three hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting
      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
      affinity technology, tag visualisation by alkaline phosphatase activity, fluorescence microscopy, inferred by author, tag visualisation, bead aggregation assay, pull down, anti tag coimmunoprecipitation, western blot, confocal microscopy
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot, pull down, anti bait coimmunoprecipitation, western blot
      pull down, autoradiography, molecular weight estimation by staining, western blot, isothermal titration calorimetry, predetermined participant, nuclear magnetic resonance
      two hybrid, cosedimentation, protein three hybrid, pull down, autoradiography, anti tag coimmunoprecipitation, western blot, electron microscopy, anti tag western blot, anti bait coimmunoprecipitation, peptide massfingerprinting, isothermal titration calorimetry, predetermined participant, coimmunoprecipitation, three hybrid, electrophoretic mobility shift assay, electrophoretic mobility supershift assay, molecular sieving, molecular weight estimation by staining
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, western blot, two hybrid, 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) (18 alleles)
      Models Based on Experimental Evidence ( 6 )
      Modifiers Based on Experimental Evidence ( 6 )
      Allele
      Disease
      Interaction
      References
      model of  carcinoma
      is ameliorated by licGD7546
      is ameliorated by licJF01433
      Models Based on Experimental Evidence ( 4 )
      Modifiers Based on Experimental Evidence ( 9 )
      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
      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
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      References (20)