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.
Ko
Michael A
MA
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave. R988, Toronto, Ontario M5G 1X5, Canada.
Rosario
Carla O
CO
Hudson
John W
JW
Kulkarni
Sarang
S
Pollett
Aaron
A
Dennis
James W
JW
Swallow
Carol J
CJ
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D006239:Haplotypes; D006498:Hepatectomy; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000601:surgery; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
C088051:Plk4 protein, mouse; D017346:Protein Serine-Threonine Kinases