| Autor: |
Reid, Robert J D, Du, Xing, Sunjevaric, Ivana, Rayannavar, Vinayak, Dittmar, John, Bryant, Eric, Maurer, Matthew, Rothstein, Rodney |
| Zdroj: |
Genetics; October 2016, Vol. 204 Issue: 2 p807-819, 13p |
| Abstrakt: |
The CKS1Bgene located on chromosome 1q21 is frequently amplified in breast, lung, and liver cancers. CKS1Bcodes for a conserved regulatory subunit of cyclin–CDK complexes that function at multiple stages of cell cycle progression. We used a high throughput screening protocol to mimic cancer-related overexpression in a library of Saccharomyces cerevisiaemutants to identify genes whose functions become essential only when CKS1is overexpressed, a synthetic dosage lethal (SDL) interaction. Mutations in multiple genes affecting mitotic entry and mitotic exit are highly enriched in the set of SDL interactions. The interactions between Cks1 and the mitotic entry checkpoint genes require the inhibitory activity of Swe1 on the yeast cyclin-dependent kinase (CDK), Cdc28. In addition, the SDL interactions of overexpressed CKS1with mutations in the mitotic exit network are suppressed by modulating expression of the CDK inhibitor Sic1. Mutation of the polo-like kinase Cdc5, which functions in both the mitotic entry and mitotic exit pathways, is lethal in combination with overexpressed CKS1. Therefore we investigated the effect of targeting the human Cdc5 ortholog, PLK1, in breast cancers with various expression levels of human CKS1B. Growth inhibition by PLK1knockdown correlates with increased CKS1Bexpression in published tumor cell data sets, and this correlation was confirmed using shRNAs against PLK1in tumor cell lines. In addition, we overexpressed CKS1Bin multiple cell lines and found increased sensitivity to PLK1knockdown and PLK1 drug inhibition. Finally, combined inhibition of WEE1 and PLK1 results in less apoptosis than predicted based on an additive model of the individual inhibitors, showing an epistatic interaction and confirming a prediction of the yeast data. Thus, identification of a yeast SDL interaction uncovers conserved genetic interactions that can affect human cancer cell viability. |
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