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Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis.

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 approximately 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 (approximately 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.

Pubmed ID: 16025114

Authors

  • Ko MA
  • Rosario CO
  • Hudson JW
  • Kulkarni S
  • Pollett A
  • Dennis JW
  • Swallow CJ

Journal

Nature genetics

Publication Data

August 28, 2005

Associated Grants

None

Mesh Terms

  • Animals
  • Cell Transformation, Neoplastic
  • Haplotypes
  • Hepatectomy
  • Liver Neoplasms, Experimental
  • Lung Neoplasms
  • Mice
  • Mice, Mutant Strains
  • Mitosis
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases