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General Information
Name
cancer, neural stem cell, centrosome dysfunction
FlyBase ID
FBhh0000780
Disease Ontology Term
Parent Disease
OMIM
Overview

Drosophila genes that affect centrosome function were assessed for capacity to produce tumors in a larval brain system. Candidate mutations were characterized using a tissue transplant assay for neoplastic capacity in which larval brain tissue is transplanted into the abdomens of wild-type adult female hosts. For loss-of-function mutations in Sas-4, polo, and aurA, brain tissue transplants exhibited unrestrained growth, filling the abdominal cavity, and killing a subset of the hosts; small colonies scattered on different parts of the host's anatomy (micrometastases) are observed. The tumors can be maintained by serial retransplantation; these tumor lines exhibit increasing amounts of polyploidy and chromosome instability (CIN).

Based on two additional observations, it has been postulated that development of tumors in neural tissues due to centrosome dysfunction is caused primarily by perturbation of the self-renewing asymmetric division of neural stem cells, rather than by CIN. First, other sources of CIN (genetic or environmental) did not result in significant tumorigenic phenotypes in the larval brain transplantation assay. Second, when imaginal disc (epithelial) tissues from loss-of-function mutations in Sas-4, polo, and aurA were transplanted into the abdomens of wild-type adult female hosts, no tumorous growth was observed.

See related human disease model reports 'cancer, models of chromosomal instability' (FBhh0000763) and 'microcephaly, centrosome-SAC dysfunction' (FBhh0000778).

[updated May 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, neural stem cell, centrosome dysfunction
OMIM report
Human gene(s) implicated
Symptoms and phenotype

Lack of centrosomes does not prevent spindle assembly, but spindle assembly is inefficient and accuracy of chromosome segregation may be compromised (FBrf0235458 and references cited therein).

Genetics

A number of the human genes implicated in primary microcephaly encode proteins that are components of centrosomes (Patwardhan, et al., 2018, pubmed:29352115; Alcantara and O'Driscoll, 2014, pubmed:24816482).

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 (3)
        Gene Snapshot
        Spindle assembly abnormal 4 (Sas-4) encodes a centriole protein that is essential for centriole assembly. It is recruited to centrioles through an interaction with the centriole protein encoded by ana2, and it helps recruit microtubules to the centriole. [Date last reviewed: 2019-03-14]
        Gene Groups / Pathways
          Comments on ortholog(s)

          High-scoring ortholog of human CENPJ (1 Drosophila to 1 human); additional low-scoring orthologs in human. Dmel\Sas-4 shares 24% identity and 39% similarity with the human CENPJ gene.

          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)

          High-scoring ortholog of human PLK1; low- to moderate-scoring ortholog of human PLK2 and PLK3 (1 Drosophila to 3 human). Dmel\polo shares 52% identity and 71% similarity with the human PLK1 gene.

          Orthologs and Alignments from DRSC
          DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
          Gene Snapshot
          aurora A (aurA) encodes a protein kinase required for proper neuroblast self-renewal by regulating assymmetric protein localization. It contributes to spindle orientation, centrosome separation and pole cell formation. [Date last reviewed: 2019-06-13]
          Gene Groups / Pathways
          Comments on ortholog(s)

          Moderate- to high-scoring ortholog of human AURKB, AURKC, and AURKA (2 Drosophila to 3 human). Dmel\aurA shares 48-55% identity and 64-74% 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 (80 groups)
          protein-protein
          Interacting group
          Assay
          References
          anti tag coimmunoprecipitation, anti tag western blot, x-ray crystallography, anti bait coimmunoprecipitation, western blot, two hybrid, pull down, bio-layer interferometry, predetermined participant, autoradiography
          anti bait coimmunoprecipitation, peptide massfingerprinting, western blot
          pull down, autoradiography, western blot, two hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, cosedimentation through density gradient, peptide massfingerprinting, anti tag western blot
          pull down, western blot, anti tag coimmunoprecipitation, anti bait coimmunoprecipitation, cosedimentation through density gradient
          anti tag coimmunoprecipitation, anti tag western blot, two hybrid, pull down, western blot, anti bait coimmunoprecipitation
          experimental knowledge based
          anti tag coimmunoprecipitation, peptide massfingerprinting
          two hybrid, pull down, western blot, anti bait coimmunoprecipitation, peptide massfingerprinting, anti tag western blot, cosedimentation through density gradient, anti tag coimmunoprecipitation
          anti tag coimmunoprecipitation, western blot, pull down, anti bait coimmunoprecipitation, peptide massfingerprinting
          anti bait coimmunoprecipitation, cosedimentation through density gradient, western blot, pull down, anti tag coimmunoprecipitation
          anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, pull down, cosedimentation through density gradient
          anti bait coimmunoprecipitation, western blot, cosedimentation through density gradient
          anti bait coimmunoprecipitation, cosedimentation through density gradient, western blot
          anti bait coimmunoprecipitation, western blot, cosedimentation through density gradient
          anti bait coimmunoprecipitation, western blot, pull down, cosedimentation through density gradient, peptide massfingerprinting
          anti bait coimmunoprecipitation, cosedimentation through density gradient, western blot
          anti bait coimmunoprecipitation, western blot, two hybrid, anti tag coimmunoprecipitation, cosedimentation through density gradient, pull down, peptide massfingerprinting
          pull down, anti tag western blot, isothermal titration calorimetry, predetermined participant, anti tag coimmunoprecipitation
          experimental knowledge based
          RNA-protein
          Interacting group
          Assay
          References
          pull down, Identification by mass spectrometry
          pull down, Identification by mass spectrometry
          pull down, Identification by mass spectrometry
          pull down, Identification by mass spectrometry
          pull down, Identification by mass spectrometry
          pull down, Identification by mass spectrometry
          anti bait coimmunoprecipitation, primer specific pcr
          pull down, Identification by mass spectrometry
          pull down, Identification by mass spectrometry
          pull down, Identification by mass spectrometry
          pull down, Identification by mass spectrometry
          protein-protein
          Interacting group
          Assay
          References
          pull down, western blot, bioluminescence resonance energy transfer, fluorescence technology, enzymatic study, autoradiography
          enzymatic study, autoradiography
          protein kinase assay, autoradiography
          anti tag coimmunoprecipitation, peptide massfingerprinting, western blot
          anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
          anti tag coimmunoprecipitation, peptide massfingerprinting, western blot
          anti tag coimmunoprecipitation, western blot, peptide massfingerprinting, enzymatic study, autoradiography
          anti tag coimmunoprecipitation, anti tag western blot, proximity ligation assay, fluorescence microscopy, pull down, autoradiography
          protein kinase assay, molecular weight estimation by staining
          anti tag coimmunoprecipitation, anti tag western blot
          pull down, western blot, anti tag coimmunoprecipitation, Identification by mass spectrometry, coimmunoprecipitation, anti tag western blot, experimental knowledge based, anti bait coimmunoprecipitation
          anti bait coimmunoprecipitation, anti tag western blot
          two hybrid, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, affinity chromatography technology, multidimensional protein identification technology, fluorescence correlation spectroscopy
          experimental knowledge based
          pull down, autoradiography
          enzymatic study, autoradiography, pull down, western blot
          enzymatic study, autoradiography
          protein kinase assay, molecular weight estimation by staining
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, western blot, anti tag western blot
          two hybrid, fluorescent resonance energy transfer, fluorescence microscopy
          protein-protein
          Interacting group
          Assay
          References
          enzymatic study, autoradiography
          enzymatic study, autoradiography
          pull down, autoradiography, enzymatic study, anti tag coimmunoprecipitation, anti tag western blot
          two hybrid, anti tag coimmunoprecipitation, western blot, pull down, autoradiography
          enzymatic study, autoradiography, anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, western blot
          enzymatic study, autoradiography
          enzymatic study, autoradiography
          enzymatic study, autoradiography
          anti bait coimmunoprecipitation, western blot, two hybrid, enzymatic study, autoradiography, anti tag coimmunoprecipitation
          Alleles Reported to Model Human Disease (Disease Ontology) (0 alleles)
          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
          loss of function allele
          P-element activity
          amorphic allele - molecular evidence
          CRISPR/Cas9
          amorphic allele - molecular evidence
          CRISPR/Cas9
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          References (9)