Human Disease Model Report: cancer, neural stem cell, centrosome dysfunction

General Information

Name

cancer, neural stem cell, centrosome dysfunction

FlyBase ID

FBhh0000780

Disease Ontology Term

brain cancer

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).

(FlyBase Curators, 2013-)

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).

(FlyBase Curators, 2013-)

Cellular phenotype and pathology

Molecular information

External links

Disease synonyms

Related Diseases

Related human health report(s)

cancer, malignant glioma, AURKA/WDR62-related

cancer, models of chromosomal instability

microcephaly, centrosome-SAC dysfunction

Ortholog Information

Human gene(s) in FlyBase

Other mammalian ortholog(s) used

D. melanogaster Gene Information (3)

Dmel\Sas-4

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]

Molecular function (GO)

Cellular component (GO)

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

H. sapiens (Human)

Dmel\polo

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

PK-U

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

H. sapiens (Human)

Dmel\aurA

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]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

PK-U

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

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (85 groups)

Sas-4

protein-protein

Interacting group

Assay

References

Sas-4

two hybrid

(Galletta et al., 2016)

Sas-4 - ana1

two hybrid

(Galletta et al., 2016)

Sas-4 - ana2

x-ray crystallography, two hybrid, pull down, anti tag western blot, anti bait coimmunoprecipitation, western blot, autoradiography, anti tag coimmunoprecipitation, bio-layer interferometry, predetermined participant

(McLamarrah et al., 2020, Moyer and Holland, 2019, McLamarrah et al., 2018, Galletta et al., 2016, Dzhindzhev et al., 2014, Zheng et al., 2014, Cottee et al., 2013)

Sas-4 - ana3

anti bait coimmunoprecipitation, western blot, peptide massfingerprinting

(Gopalakrishnan et al., 2011)

Sas-4 - asl

anti bait coimmunoprecipitation, anti tag western blot, two hybrid, western blot, anti tag coimmunoprecipitation, pull down, peptide massfingerprinting, autoradiography, cosedimentation through density gradient

(Galletta et al., 2016, Galletta et al., 2016, Klebba et al., 2015, Zheng et al., 2014, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011, Conduit et al., 2010, Dzhindzhev et al., 2010)

Sas-4 - aurA

two hybrid

(Galletta et al., 2016)

Sas-4 - βTub56D

pull down, western blot, anti tag coimmunoprecipitation, anti bait coimmunoprecipitation, cosedimentation through density gradient

(Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)

Sas-4 - Cep135

anti bait coimmunoprecipitation, western blot, pull down, anti tag coimmunoprecipitation, anti tag western blot, two hybrid

(Galletta et al., 2016, Zheng et al., 2014)

Sas-4 - CG13920

experimental knowledge based

(Guruharsha et al., 2011)

Sas-4 - Cnb

anti tag coimmunoprecipitation, peptide massfingerprinting

(Januschke et al., 2013)

Sas-4 - cnn

two hybrid, anti bait coimmunoprecipitation, western blot, peptide massfingerprinting, anti tag coimmunoprecipitation, pull down, anti tag western blot, cosedimentation through density gradient

(Galletta et al., 2016, Conduit et al., 2015, Zheng et al., 2014, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011, Conduit et al., 2010)

Sas-4 - Cp110

two hybrid

(Galletta et al., 2016)

Sas-4 - Cp190

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, pull down, peptide massfingerprinting

(Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)

Sas-4 - γTub23C

pull down, western blot, anti bait coimmunoprecipitation, cosedimentation through density gradient, anti tag coimmunoprecipitation

(Conduit et al., 2015, Zheng et al., 2014, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)

Sas-4 - γTub37C

anti bait coimmunoprecipitation, western blot, pull down, anti tag coimmunoprecipitation, cosedimentation through density gradient

(Conduit et al., 2015, Zheng et al., 2014, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)

Sas-4 - Grip75

anti bait coimmunoprecipitation, western blot, cosedimentation through density gradient

(Gopalakrishnan et al., 2012)

Sas-4 - Grip84

anti bait coimmunoprecipitation, western blot, cosedimentation through density gradient

(Gopalakrishnan et al., 2012)

Sas-4 - Grip91

anti bait coimmunoprecipitation, cosedimentation through density gradient, western blot

(Gopalakrishnan et al., 2012)

Sas-4 - Grip128

anti bait coimmunoprecipitation, western blot, cosedimentation through density gradient, pull down, peptide massfingerprinting

(Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)

Sas-4 - Grip163

anti bait coimmunoprecipitation, cosedimentation through density gradient, western blot

(Gopalakrishnan et al., 2012)

Sas-4 - Lk6

two hybrid

(Galletta et al., 2016)

Sas-4 - Nek2

two hybrid

(Galletta et al., 2016)

Sas-4 - Plp

anti bait coimmunoprecipitation, peptide massfingerprinting, pull down, western blot, cosedimentation through density gradient, two hybrid, anti tag coimmunoprecipitation

(Galletta et al., 2016, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)

Sas-4 - polo

two hybrid

(Galletta et al., 2016)

Sas-4 - SAK

isothermal titration calorimetry, predetermined participant, pull down, anti tag western blot, autoradiography, anti tag coimmunoprecipitation

(Ábrahám et al., 2023, McLamarrah et al., 2020)

Sas-4 - Sas-6

experimental knowledge based

(Guruharsha et al., 2011)

Sas-4 - spd-2

two hybrid

(Galletta et al., 2016)

Sas-4 - t-Grip91

two hybrid, pull down, autoradiography

(Alzyoud et al., 2024)

Sas-4 - t-Grip128

two hybrid, pull down, autoradiography

(Alzyoud et al., 2024)

polo

RNA-protein

Interacting group

Assay

References

polo - Ars2