| First Author | Ko MA | Year | 2005 |
| Journal | Nat Genet | Volume | 37 |
| Issue | 8 | Pages | 883-8 |
| PubMed ID | 16025114 | Mgi Jnum | J:100110 |
| Mgi Id | MGI:3586954 | Doi | 10.1038/ng1605 |
| Citation | Ko MA, et al. (2005) Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet 37(8):883-8 |
| abstractText | 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. |
