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Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis

Nature Genetics volume 37, pages 883–888 (2005)Cite this article

Abstract

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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Figure 1: Chromosomal instability and carcinogenesis in Plk4+/− cells and mice.
Figure 2: Mitotic failure in regenerating Plk4+/− hepatocytes.
Figure 3: Molecular markers of cell-cycle progression in regenerating livers of Plk4+/+ and Plk4+/− mice.
Figure 4: Plk4 haploinsufficiency in mice and 4q28 LOH in human hepatoma.

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Acknowledgements

We thank N. DiNicola and A. Sproule for technical assistance and S. Gallinger, I. McGilvray, L. Osborne, S. Scherer, R. Chetty, C McKerlie and T. Pawson for discussions. This work was supported by grants from the National Cancer Institute of Canada (J.W.D.) and the National Colorectal Cancer Campaign (C.J.S.).

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Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave. R988, Toronto, M5G 1X5, Ontario, Canada

    Michael A Ko, Carla O Rosario, Sarang Kulkarni, James W Dennis & Carol J Swallow

  2. Department of Surgery, University of Toronto, Ontario, Canada

    Michael A Ko & Carol J Swallow

  3. Departments of Microbiology and Medical Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada

    Carla O Rosario & James W Dennis

  4. Department of Biological Sciences, University of Windsor, Ontario, Canada

    John W Hudson

  5. Department of Pathology, University of Toronto, Ontario, Canada

    Aaron Pollett

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  1. Michael A Ko
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Correspondence to James W Dennis.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Slow growth, mitotic irregularities, and micronuclei in Sak+/− MEFs. (PDF 185 kb)

Supplementary Table 1

PCR primers and probes. (PDF 31 kb)

Supplementary Methods (PDF 83 kb)

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Ko, M., Rosario, C., Hudson, J. et al. Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet 37, 883–888 (2005). https://doi.org/10.1038/ng1605

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