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General Information
Name
cancer, multiple, CCR4-NOT complex
FlyBase ID
FBhh0000939
Disease Ontology Term
Parent Disease
OMIM
Overview

This report describes a Drosophila model used to characterize the role CNOT3 and other components of the CCR4-NOT complex in the development of T-cell acute lymphoblastic leukemia (T-ALL) and other cancers. The fly model was developed when CNOT3 emerged as a candidate tumor suppressor gene in whole exome sequencing of (T-ALL) patients. The CCR4-NOT complex contributes to regulation of RNA metabolism at all steps, including transcription, mRNA stability, and eventual degradation in the cytoplasm. There is a single gene orthologous to CNOT3 in Drosophila, Dmel\Not3, for which RNAi targeting constructs and an allele caused by insertional mutagenesis have been generated.

None of the human CCR4-NOT complex genes has been introduced into flies.

Like all invertebrates, flies lack cells analogous to the hematopoietic lymphoid lineage. However, based on the knowledge that activating mutations of NOTCH1 are frequently associated with T-ALL, a fly model in which the Notch ligand Dl is overexpressed in the developing eyes was used as a sensitized system to characterize the impact of Dmel\Not3 mutations. This emulates the multi-step progression of most cancers, including ALL. Dl overexpression in eyes results in slightly enlarged but otherwise normal-appearing eyes. Dl overexpression combined with knockdown of Not3, effected by RNAi, results in dramatic hyperproliferative eye phenotypes.

Other subunits of the Drosophila CCR4-NOT complex have been tested in this system. Reduction in expression of Not1 (orthologous to human CNOT1), Rga (orthologous to CNOT2), or Pop2 (orthologous to CNOT7 and CNOT8) in combination with Dl overexpression results in hyperproliferative eye phenotypes. Reduction in expression of twin (orthologous to CNOT6 and CNOT6L) in combination with Dl overexpression results in metastatic, as well as hyperproliferative, phenotypes. Physical and genetic interactions have been described for these fly genes; see below and in the respective gene reports.

See also the human disease model report 'cancer, multiple, Notch signaling pathway' (FBhh0000766).

[updated Dec. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, multiple, CCR4-NOT complex
OMIM report
Human gene(s) implicated
Symptoms and phenotype
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts for about 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. It is considered as a paradigm for the multistep nature of cancer initiation and progression (Durinck et al., 2015; pubmed:26123366).
Genetics
Cellular phenotype and pathology
Molecular information
Activating mutations in NOTCH1 are found in a large percentage of human T-ALL cases (Grabher et al., 2006; pubmed:16612405).
The CCR4-NOT complex is a multisubunit protein complex that is conserved in all eukaryotes and contributes to regulation of RNA metabolism at all steps, from synthesis to degradation in the cytoplasm (Collart, 2016; pubmed:26821858).
External links
Disease synonyms
cancer, multiple, CNOT3-related
Search term: T-cell acute lymphoblastic leukemia
Search term: T-ALL
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 (6)
      Gene Snapshot
      CCR4-NOT transcription complex subunit 3 (Not3) encodes a poly(A)-specific ribonuclease involved in translation inhibition. [Date last reviewed: 2019-08-01]
      Gene Groups / Pathways
      Comments on ortholog(s)
      Moderate-scoring ortholog of human CNOT3 (1 Drosophila to 1 human). Dmel\Not3 shares 40% identity and 54% 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
      twin (twin) encodes the CCR4 deadenylase, one of two enzymes in the CCR4-NOT complex that degrade mRNA poly(A) tails. It is required during oogenesis in germline stem cell self-renewal, synchronous germ cell division and prevention of cell death, as well as in early embryonic patterning through the deadenylation of specific maternal mRNAs. [Date last reviewed: 2018-09-13]
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human CNOT6 and CNOT6L (1 Drosophila to 2 human). Dmel\twin shares 57% identity and 72-73% 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
      Not1 (Not1) encodes a poly(A)-specific ribonuclease involved in translation inhibition and ovarian follicle cell development. [Date last reviewed: 2019-08-01]
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human CNOT1 (1 Drosophila to 1 human). Dmel\Not1 shares 46% identity and 62% 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
      In progress.Contributions welcome.
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human CNOT2 (2 Drosophila to 1 human). Dmel\Rga shares 33% identity and 46% similarity with the human gene. The second orthologous gene in Drosophila, CG15262, is expressed primarily in testis.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      Pop2 (Pop2) encodes a poly(A)-specific ribonuclease involved in translation inhibition. [Date last reviewed: 2019-08-01]
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human CNOT8 and CNOT7 (1 Drosophila to 2 human). Dmel\Pop2 shares 68% identity and 84% similarity with CNOT8; it shares 56% identity and 68% similarity with CNOT7.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      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. Dmel\Dl shares 39% identity and 51-53% similarity with human DLL1 and DLL4.
      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 (88 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, western blot, anti bait coimmunoprecipitation
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, Identification by mass spectrometry, western blot, experimental knowledge based, 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
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      protein-protein
      Interacting group
      Assay
      References
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot, anti tag western blot, anti bait coimmunoprecipitation
      anti tag coimmunoprecipitation, anti tag western blot, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      anti bait coimmunoprecipitation, Identification by mass spectrometry, experimental knowledge based, western blot, anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, 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, western blot, ion exchange chromatography, molecular sieving, experimental knowledge based
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      RNA-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, primer specific pcr
      protein-protein
      Interacting group
      Assay
      References
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot, pull down, molecular weight estimation by staining
      anti bait coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, 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, western blot
      anti tag coimmunoprecipitation, western blot
      pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, Identification by mass spectrometry, western blot, experimental knowledge based, anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, Identification by mass spectrometry, anti tag coimmunoprecipitation, anti tag western blot, western blot, experimental knowledge based
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot, experimental knowledge based, anti bait coimmunoprecipitation, western blot, Identification by mass spectrometry
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, western blot
      tandem affinity purification, Identification by mass spectrometry
      anti bait coimmunoprecipitation, Identification by mass spectrometry, experimental knowledge based, western blot, anti tag coimmunoprecipitation, anti tag western blot
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag 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 tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      anti tag coimmunoprecipitation, western blot
      pull down, molecular weight estimation by staining, western blot, Identification by mass spectrometry, anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot, experimental knowledge based, anti bait coimmunoprecipitation, western blot, Identification by mass spectrometry
      pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based, 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
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, western blot
      anti tag coimmunoprecipitation, western blot
      RNA-protein
      Interacting group
      Assay
      References
      pull down, molecular weight estimation by staining, western blot, Identification by mass spectrometry, anti tag coimmunoprecipitation, anti tag western blot
      protein-protein
      Interacting group
      Assay
      References
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, Identification by mass spectrometry, anti tag coimmunoprecipitation, anti tag western blot, western blot, experimental knowledge based
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, autoradiography, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      two hybrid, anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot, western blot, ion exchange chromatography, molecular sieving, experimental knowledge based
      RNA-protein
      Interacting group
      Assay
      References
      pull down, western blot, Identification by mass spectrometry
      RNA-RNA
      Interacting group
      Assay
      References
      luminiscence technology, immunohistochemistry
      protein-protein
      Interacting group
      Assay
      References
      atomic force microscopy, bead aggregation assay, fluorescence microscopy, inferred by author
      protease assay, western blot, inferred by author
      anti tag coimmunoprecipitation, anti tag western blot, enzymatic study
      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, anti tag coimmunoprecipitation, anti tag western blot, enzymatic study
      anti tag coimmunoprecipitation, anti tag western blot
      coimmunoprecipitation, western blot, affinity technology, fluorescence microscopy, anti tag coimmunoprecipitation, anti bait coimmunoprecipitation
      Alleles Reported to Model Human Disease (Disease Ontology) (11 alleles)
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 3 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 2 )
      Modifiers Based on Experimental Evidence ( 4 )
      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
      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
      References (4)