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General Information
Name
cancer, epithelial, Notch signaling, Hedgehog signaling
FlyBase ID
FBhh0001075
Disease Ontology Term
Parent Disease
OMIM
Overview

Much of the work in flies investigating the role of the Notch pathway in development of cancer has involved combining Notch signaling dysregulation with other genes postulated to have a role in tumorigenesis. This is typically achieved by using targeted expression of an activated form of Notch (N) or overexpression of one of the Notch ligands, Delta (Dl) or Serrate (Ser); see the human disease model report 'cancer, multiple, Notch signaling pathway' (FBhh0000766).

Overexpression of Dl in the adult eye results in a mild overgrowth phenotype; mutations of interacting genes have been identified that enhance this phenotype and result in much increased, tumorous overgrowth. In one such screen, assessing genes in a gain-of-expression system, the microRNA mir-7 was identified; Dmel\mir-7 is orthologous to human microRNAs MIR7-1 MIR7-2, MIR7-3. Knockdowns of predicted mir-7 target genes were then tested in the same assay; of the 39 genes tested, only downregulation ihog via RNAi fully mimicked the effect of mir-7 overexpression, i.e., the transformation of Dl-induced mild overgrowth into severe overgrowth or tumor-like growth.

Since ihog is a core component of the Hedgehog Signaling Pathway (FBgg0000979), other members of this pathway were tested. Tumorigenesis was induced co-operatively following Notch activation (via Dl overexpression) combined with reduced Hedgehog signalling effected by different mechanisms: overexpression of the mir-7 microRNA; or down-regulation of ihog, hh, smo, or ci; or overexpression of the ci repressor form.

See also the human disease model report 'basal cell carcinoma, SMO-related' (FBhh0001201).

[updated Feb. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, Notch signaling, Hedgehog signaling
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (6)
      Gene Snapshot
      Delta (Dl) encodes a single pass transmembrane EGF family protein and one of two ligands of the Notch signaling pathway. It regulates cell fate decisions and cell proliferation. Post transcriptional modification (such as by fucosylation, ubiquitination and proteolysis) of the product of Dl is key for its functions. [Date last reviewed: 2019-03-07]
      Gene Groups / Pathways
      Comments on ortholog(s)

      Moderate- to high-scoring ortholog of human DLL1 and DLL4 (1 Drosophila to 2 human); additional less closely related genes in human.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      interference hedgehog (ihog) encodes a type 1 membrane protein that acts as a co-receptor for the product of hh upstream or at the level of the receptor encoded by ptc. It interacts with the products of disp, dlp, dally and shf. It is involved in imaginal pattern formation and embryonic cuticle pattern formation. [Date last reviewed: 2018-11-15]
      Gene Groups / Pathways
      Comments on ortholog(s)

      Moderate-scoring ortholog of human BOC and CDON (2 human to 2 Drosophila); the other Drosophila gene is boi.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      hedgehog (hh) encodes the Hh signaling pathway ligand. It acts as a morphogen contributing to segment polarity determination, stem cells maintenance and cell migration. Post-translational modifications of the product of hh are essential for its restrictive spreading and signaling activity. [Date last reviewed: 2019-03-07]
      Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human SHH, DHH, and IHH (3 human to 1 Drosophila).

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      smoothened (smo) encodes a critical component of the Hedgehog signaling pathway. It is regulated by phosphorylation, dimerization, and cell-surface accumulation upon Hedgehog stimulation. The product of smo is also regulated by ubiquitin and other small molecules such as phospholipids. [Date last reviewed: 2019-03-14]
      Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human SMO (1 human to 1 Drosophila).

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      cubitus interruptus (ci) encodes a Zn-finger family of transcription factor. It contributes to Hedgehog (Hh) signaling pathway that is involved in pattern formation and growth control. The product of ci undergoes limited proteolysis to be converted into a truncated form that function as a transcription repressor in the absence of the ligand encoded by hh but is converted into a full-length transcription activator in the presence of the product of hh. [Date last reviewed: 2019-03-07]
      Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human GLI3 and GLI2; moderate-scoring ortholog of GLI1 (3 human to 1 Drosophila).

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

          Orthologous to human MIR7-1 MIR7-2, MIR7-3 (FBrf0242402 and miRBase).

          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 (115 groups)
          RNA-RNA
          Interacting group
          Assay
          References
          luminiscence technology, immunohistochemistry
          protein-protein
          Interacting group
          Assay
          References
          bead aggregation assay, fluorescence microscopy, inferred by author, atomic force microscopy
          protease assay, western blot, inferred by author
          anti tag coimmunoprecipitation, anti tag western blot, enzymatic study
          fluorescence microscopy, inferred by author, pull down, tag visualisation by alkaline phosphatase activity, affinity technology, tag visualisation, bead aggregation assay, anti bait coimmunoprecipitation, western blot, atomic force microscopy, phenotype-based detection assay, enzyme linked immunosorbent assay
          anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot, enzymatic study
          anti tag coimmunoprecipitation, anti tag western blot
          coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, affinity technology, fluorescence microscopy, anti bait coimmunoprecipitation
          RNA-RNA
          Interacting group
          Assay
          References
          luminiscence technology, necessary binding region, fluorescence technology, quantitative reverse transcription pcr
          protein-protein
          Interacting group
          Assay
          References
          molecular sieving, predetermined participant, cosedimentation, anti tag coimmunoprecipitation, anti tag western blot
          x-ray crystallography, predetermined participant, anti bait coimmunoprecipitation, western blot, surface plasmon resonance, pull down, anti tag western blot, inferred by author, affinity technology, tag visualisation, molecular sieving, cosedimentation, molecular weight estimation by staining
          anti bait coimmunoprecipitation, anti tag western blot, western blot
          anti tag coimmunoprecipitation, anti tag western blot
          enzyme linked immunosorbent assay
          protein-protein
          Interacting group
          Assay
          References
          molecular sieving, molecular weight, anti tag coimmunoprecipitation, western blot
          cosedimentation, anti tag western blot, anti bait coimmunoprecipitation, western blot
          anti bait coimmunoprecipitation, western blot
          pull down, anti tag western blot, western blot
          anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, western blot
          electron microscopy, anti bait coimmunoprecipitation, anti tag western blot, microscale thermophoresis
          anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot
          cosedimentation, western blot
          x-ray crystallography, predetermined participant, anti bait coimmunoprecipitation, western blot, surface plasmon resonance, pull down, anti tag western blot, inferred by author, affinity technology, tag visualisation, molecular sieving, cosedimentation, molecular weight estimation by staining
          affinity technology, fluorescence microscopy, inferred by author, anti bait coimmunoprecipitation, western blot, tag visualisation, pull down, anti tag western blot
          enzymatic study, autoradiography
          anti tag coimmunoprecipitation, western blot
          cosedimentation, western blot
          protein-protein
          Interacting group
          Assay
          References
          pull down, anti tag western blot, fluorescent resonance energy transfer, fluorescence microscopy, bioluminescence resonance energy transfer, fluorescence technology, anti tag coimmunoprecipitation, anti bait coimmunoprecipitation, western blot, autoradiography
          anti bait coimmunoprecipitation, peptide massfingerprinting, western blot
          fluorescent resonance energy transfer, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, tag visualisation, pull down, two hybrid, peptide massfingerprinting, bioluminescence resonance energy transfer, fluorescence technology
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, western blot
          anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, bimolecular fluorescence complementation, fluorescence microscopy, two hybrid, peptide massfingerprinting
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot, pull down, fluorescent resonance energy transfer, fluorescence microscopy
          anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot, western blot
          anti tag coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, anti tag western blot
          bimolecular fluorescence complementation, fluorescence microscopy, anti tag coimmunoprecipitation, western blot, anti tag western blot, anti bait coimmunoprecipitation
          anti tag coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, western blot
          pull down, anti tag western blot, anti tag coimmunoprecipitation
          anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation
          two hybrid, anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, covalent binding, anti tag western blot
          anti tag coimmunoprecipitation, covalent binding, anti tag western blot
          anti bait coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot, pull down
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, western blot, pull down
          RNA-RNA
          Interacting group
          Assay
          References
          fluorescence technology, immunohistochemistry, luminiscence technology, necessary binding region
          immunocytochemistry, fluorescence technology, luminiscence technology, necessary binding region
          protein-protein
          Interacting group
          Assay
          References
          anti tag coimmunoprecipitation, anti tag western blot, fluorescent resonance energy transfer, fluorescence microscopy
          anti tag coimmunoprecipitation, peptide massfingerprinting
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          pull down, anti tag western blot, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, two hybrid, autoradiography, molecular sieving, peptide massfingerprinting
          anti tag coimmunoprecipitation, anti tag western blot
          pull down, anti tag western blot, enzymatic study, peptide massfingerprinting
          enzymatic study, peptide massfingerprinting
          anti bait coimmunoprecipitation, anti tag western blot, two hybrid, pull down, autoradiography, anti tag coimmunoprecipitation
          enzymatic study, autoradiography, interologs mapping, inferred by curator
          enzymatic study, western blot
          anti bait coimmunoprecipitation, western blot, two hybrid, protein three hybrid, anti tag coimmunoprecipitation, anti tag western blot, enzymatic study, molecular sieving
          anti tag coimmunoprecipitation, anti tag western blot, two hybrid, pull down
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          coimmunoprecipitation, western blot
          pull down, autoradiography
          anti tag coimmunoprecipitation, anti tag western blot, two hybrid
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, anti tag western blot, two hybrid, pull down, molecular weight estimation by staining, lambda phage display
          pull down, western blot
          anti tag coimmunoprecipitation, anti tag western blot, bimolecular fluorescence complementation, fluorescence microscopy
          anti bait coimmunoprecipitation, western blot
          anti bait coimmunoprecipitation, western blot, anti tag western blot, pull down, anti tag coimmunoprecipitation
          anti tag coimmunoprecipitation, anti tag western blot, two hybrid, enzymatic study, peptide massfingerprinting, pull down, western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          pull down, anti tag western blot
          pull down, autoradiography, anti tag western blot, enzymatic study, peptide massfingerprinting
          anti bait coimmunoprecipitation, peptide massfingerprinting, western blot
          anti tag coimmunoprecipitation, anti tag western blot, pull down, Identification by mass spectrometry
          anti tag coimmunoprecipitation, anti tag western blot
          two hybrid, anti tag coimmunoprecipitation, anti tag western blot, pull down, fluorescent resonance energy transfer, autoradiography, fluorescence microscopy, molecular sieving, western blot, isothermal titration calorimetry, predetermined participant, anti bait coimmunoprecipitation
          anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, anti tag western blot, pull down
          anti tag coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, anti tag western blot, pull down
          anti tag coimmunoprecipitation, anti tag western blot
          RNA-RNA
          Interacting group
          Assay
          References
          immunohistochemistry, fluorescence technology, necessary binding region
          fluorescence technology, anti tag western blot
          fluorescence technology
          fluorescence technology, necessary binding region
          luminiscence technology, necessary binding region
          luminiscence technology, fluorescence technology, necessary binding region
          fluorescence technology
          fluorescence technology
          luminiscence technology
          fluorescence technology
          luminiscence technology, necessary binding region, fluorescence technology, quantitative reverse transcription pcr
          fluorescence technology
          immunohistochemistry
          RNA-protein
          Interacting group
          Assay
          References
          anti tag coimmunoprecipitation, quantitative reverse transcription pcr
          Alleles Reported to Model Human Disease (Disease Ontology) (16 alleles)
          Models Based on Experimental Evidence ( 2 )
          Modifiers Based on Experimental Evidence ( 6 )
          Models Based on Experimental Evidence ( 1 )
          Allele
          Disease
          Evidence
          References
          Modifiers Based on Experimental Evidence ( 4 )
          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 ( 1 )
          Allele
          Disease
          Evidence
          References
          Modifiers Based on Experimental Evidence ( 3 )
          Allele
          Disease
          Interaction
          References
          DOES NOT ameliorate  cancer
          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
          amorphic allele - molecular evidence
          FLPase
          amorphic allele - molecular evidence
          ends-out gene targeting
          P-element activity
          amorphic allele - genetic evidence
          X ray
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          spontaneous
          loss of function allele
          X ray
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          spontaneous
          amorphic allele - genetic evidence
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          X ray
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          X ray
          amorphic allele - genetic evidence
          X ray
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          spontaneous
          loss of function allele
          Delta2-3 transposase
          loss of function allele
          gamma ray
          loss of function allele
          X ray
          loss of function allele
          Delta2-3 transposase
          loss of function allele
          CRISPR/Cas9
          loss of function allele
          CRISPR/Cas9
          loss of function allele
          CRISPR/Cas9
          loss of function allele
          CRISPR/Cas9
          loss of function allele
          CRISPR/Cas9
          loss of function allele
          CRISPR/Cas9
          P-element activity
          loss of function allele
          Delta2-3 transposase
          amorphic allele - genetic evidence
          Delta2-3 transposase
          amorphic allele - genetic evidence
          Delta2-3 transposase
          loss of function allele
          Delta2-3 transposase
          amorphic allele - genetic evidence
          gamma ray
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          gamma ray
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          CRISPR/Cas9
          References (6)