Nature Genetics
37, 883 - 888 (2005)
Published online: 17 July 2005; | doi:10.1038/ng1605
Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesisMichael A Ko1, 2, Carla O Rosario1, 3, John W Hudson4, Sarang Kulkarni1, Aaron Pollett5, James W Dennis1, 3
& Carol J Swallow1, 21
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave. R988, Toronto, Ontario
M5G 1X5, Canada. 2
Department of Surgery, University of Toronto, Ontario, Canada. 3
Departments of Microbiology and Medical Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. 4
Department of Biological Sciences, University of Windsor, Ontario, Canada. 5
Department of Pathology, University of Toronto, Ontario, Canada.
Correspondence should be addressed to James W Dennis dennis@mshri.on.ca The polo-like kinase Plk4 (also called Sak) is required for late mitotic progression, cell survival and postgastrulation embryonic development1. Here we identified a phenotype resulting from Plk4 haploinsufficiency in Plk4 heterozygous cells and mice. Plk4+/- embryonic fibroblasts had increased centrosomal amplification, multipolar spindle formation and aneuploidy compared with wild-type cells. The incidence of spontaneous liver and lung cancers was  15 times high in elderly Plk4+/- mice than in Plk4+/+ littermates. Using the in vivo model of partial hepatectomy to induce synchronous cell cycle entry, we determined that the precise regulation of cyclins D1, E and B1 and of Cdk1 was impaired in Plk4+/- regenerating liver, and p53 activation and p21 and BubR1 expression were suppressed. These defects were associated with progressive cell cycle delays, increased spindle irregularities and accelerated hepatocellular carcinogenesis in Plk4+/- mice. Loss of heterozygosity occurs frequently (60%) at polymorphic markers adjacent to the PLK4 locus in human hepatoma. Reduced Plk4 gene dosage increases the probability of mitotic errors and cancer development.
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