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(1). 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 similar to 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 (similar to 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.