PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis
- 29 December 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (5), 1293-1307
- https://doi.org/10.1158/0008-5472.can-20-1377
Abstract
Polo-like kinase 1 (PLK1) is an essential cell cycle regulator that is frequently overexpressed in various human cancers. To determine whether Plk1 overexpression drives tumorigenesis, we established transgenic mouse lines that ubiquitously express increased levels of Plk1. High Plk1 levels were a driving force for different types of spontaneous tumors. Increased Plk1 levels resulted in multiple defects in mitosis and cytokinesis, supernumerary centrosomes, and compromised cell cycle checkpoints, allowing accumulation of chromosomal instability (CIN) which resulted in aneuploidy and tumor formation. Clinically, higher expression of PLK1 positively associated with an increase in genome-wide copy number alterations in multiple human cancers. This study provides in vivo evidence that aberrant expression of PLK1 triggers CIN and tumorigenesis and highlights potential therapeutic opportunities for CIN-positive cancers.Other Versions
Funding Information
- American Cancer Society (127626-RSG-15-005-01-CCG)
- NIH (R01 CA191002)
- NIH NCI (P30 CA016059)
- NIH NCI (P30 CA016059)
This publication has 52 references indexed in Scilit:
- Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast CancerCancer Research, 2013
- Micronuclei in genotoxicity assessment: from genetics to epigenetics and beyondFrontiers in Genetics, 2013
- A Comparison of Exogenous Promoter Activity at the ROSA26 Locus Using a PhiC31 Integrase Mediated Cassette Exchange Approach in Mouse ES CellsPLOS ONE, 2011
- Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivationThe Journal of cell biology, 2011
- Real-Time Dynamic Imaging of Virus Distribution In VivoPLOS ONE, 2011
- Oncogenes and Tumor Suppressor GenesCold Spring Harbor Perspectives in Biology, 2010
- A Mitotic Phosphorylation Feedback Network Connects Cdk1, Plk1, 53BP1, and Chk2 to Inactivate the G2/M DNA Damage CheckpointPLoS Biology, 2010
- Whole Chromosome Instability Caused by Bub1 Insufficiency Drives Tumorigenesis through Tumor Suppressor Gene Loss of HeterozygosityCancer Cell, 2009
- Genetic Factors on Mouse Chromosome 18 Affecting Susceptibility to Testicular Germ Cell Tumors and Permissiveness to Embryonic Stem Cell DerivationCancer Research, 2009
- The spindle-assembly checkpoint in space and timeNature Reviews Molecular Cell Biology, 2007