title: APC/C is an essential regulator of centrosome clustering.
abstract: Centrosome amplification has been extensively associated with cancer. Cancer cells with extra centrosomes have the ability to cluster the extra centrosomes and divide in a bipolar fashion. Although a number of proteins have been shown to be involved in centrosome clustering, a mechanistic understanding of how this process is coordinated is not yet well defined. Here, to reveal regulators of centrosome clustering, we perform small interfering RNA (siRNA) screens with multiple assay readouts in a human isogenic cellular model. We find that APC/C activity is essential for centrosome clustering. We show that the motor kinesin Eg5 is a substrate of APC/C-CDH1, and that inhibition of APC/C results in stabilization of Eg5. Increased Eg5 protein levels disturb the balance of forces on the spindle and prevent centrosome clustering. This process is completely reversed after a short treatment with the Eg5 inhibitor, monastrol. These data advance our understanding of the regulation of centrosome clustering.
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Drosopoulos
authors.affiliation: 1] Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK [2].
authors.forename: Chan
authors.initials: C
authors.lastname: Tang
authors.affiliation: 1] Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK [2].
authors.forename: William C H
authors.initials: WC
authors.lastname: Chao
authors.affiliation: 1] Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK [2] Cancer Research UK, Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018385:Centrosome; D017491:Genes, APC; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D055550:Protein Stability; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering; D017386:Sequence Homology, Amino Acid; D013871:Thiones / Q000494:pharmacology
chemical_list: C470243:KIF11 protein, human; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013871:Thiones; C400223:monastrol; D016547:Kinesins