@article{25c212ff999345539dc58aae1a426abf,
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.",
keywords = "Centrosome amplification, P53, Plk4 kinase, Tumorigenesis",
author = "Benjamin Vitrea and Holland, {Andrew J.} and Anita Kulukian and Ofer Shoshani and Maretoshi Hirai and Yin Wanga and Marcus Maldonado and Thomas Cho and Jihane Boubaker and Swing, {Deborah A.} and Lino Tessarollo and Evans, {Sylvia M.} and Elaine Fuchs and Cleveland, {Don W.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Dr. Nissi Varki (University of California at San Diego Pathology Core) for histology sample preparation and analysis, and Melissa McAlonis-Downes (Ludwig Institute for Cancer Research) for valuable assistance in the management of the Cleveland laboratory mouse colony. We also thank N. Stokes, A. Aldeguer, and S. Hacker for valuable assistance with the DMBA/TPA treatments. B.V. was supported by a Human Funding Information: We thank Dr. Nissi Varki (University of California at San Diego Pathology Core) for histology sample preparation and analysis, and Melissa McAlonis-Downes (Ludwig Institute for Cancer Research) for valuable assistance in the management of the Cleveland laboratory mouse colony. We also thank N. Stokes, A. Aldeguer, and S. Hacker for valuable assistance with the DMBA/TPA treatments. B.V. was supported by a Human Frontier Science Program Long-Term Fellowship (LT000855/2010). A.J.H. was supported by a Leukemia Lymphoma Society Special Fellowship. A.K. was funded by a Jane Coffins Child postdoctoral fellowship. This work was supported by National Institutes of Health (NIH) Grants GM29513 (to D.W.C.) and GM114119 (toA.J.H),aMethodtoExtendResearchinTime(MERIT)AwardR37-AR27883 (to E.F.), and Grant DP1HL117649 from the NIH (to S.M.E.).",
year = "2015",
month = nov,
day = "17",
doi = "10.1073/pnas.1519388112",
language = "English (US)",
volume = "112",
pages = "E6321--E6330",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "46",
}