1. Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis.
- Author
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Ko, Michael A., Rosario, Carla O., Hudson, John W., Kulkarni, Sarang, Pollett, Aaron, Dennis, James W., and Swallow, Carol J.
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CELL cycle ,CARCINOGENESIS ,PATHOLOGY ,CANCER ,LUNG cancer ,GROWTH factors - Abstract
The polo-like kinase Plk4 (also called Sak) is required for late mitotic progression, cell survival and postgastrulation embryonic development. 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. [ABSTRACT FROM AUTHOR]- Published
- 2005
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