title: Chronic centrosome amplification without tumorigenesis.
abstract: Centrosomes are microtubule-organizing centers that facilitate bipolar mitotic spindle assembly and chromosome segregation. Recognizing that centrosome amplification is a common feature of aneuploid cancer cells, we tested whether supernumerary centrosomes are sufficient to drive tumor development. To do this, we constructed and analyzed mice in which centrosome amplification can be induced by a Cre-recombinase-mediated increase in expression of Polo-like kinase 4 (Plk4). Elevated Plk4 in mouse fibroblasts produced supernumerary centrosomes and enhanced the expected mitotic errors, but proliferation continued only after inactivation of the p53 tumor suppressor. Increasing Plk4 levels in mice with functional p53 produced centrosome amplification in liver and skin, but this did not promote spontaneous tumor development in these tissues or enhance the growth of chemically induced skin tumors. In the absence of p53, Plk4 overexpression generated widespread centrosome amplification, but did not drive additional tumors or affect development of the fatal thymic lymphomas that arise in animals lacking p53. We conclude that, independent of p53 status, supernumerary centrosomes are not sufficient to drive tumor formation.
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vitre
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Holland
authors.affiliation: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065;
authors.forename: Anita
authors.initials: A
authors.lastname: Kulukian
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093;
authors.forename: Ofer
authors.initials: O
authors.lastname: Shoshani
authors.affiliation: Skaggs School of Pharmacy, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Maretoshi
authors.initials: M
authors.lastname: Hirai
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093;
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093;
authors.forename: Marcus
authors.initials: M
authors.lastname: Maldonado
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093;
authors.forename: Thomas
authors.initials: T
authors.lastname: Cho
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093;
authors.forename: Jihane
authors.initials: J
authors.lastname: Boubaker
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702;
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Swing
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702;
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Skaggs School of Pharmacy, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065;
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093 dcleveland@ucsd.edu.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018385:Centrosome / Q000378:metabolism*; D005786:Gene Expression Regulation; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C088051:Plk4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Plk4 kinase; centrosome amplification; p53; tumorigenesis