title: A Synthetic Dosage Lethal Genetic Interaction Between CKS1B and PLK1 Is Conserved in Yeast and Human Cancer Cells.
abstract: The CKS1B gene located on chromosome 1q21 is frequently amplified in breast, lung, and liver cancers. CKS1B codes 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 cerevisiae mutants to identify genes whose functions become essential only when CKS1 is 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 CKS1 with 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 PLK1 knockdown correlates with increased CKS1B expression in published tumor cell data sets, and this correlation was confirmed using shRNAs against PLK1 in tumor cell lines. In addition, we overexpressed CKS1B in multiple cell lines and found increased sensitivity to PLK1 knockdown 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.
authors: Department Genetics and Development, Columbia University Medical Center, New York, New York 10032.
authors: Robert J D
authors: RJ
authors: Reid
authors: Department of Medicine, Columbia University Medical Center, New York, New York 10032.
authors: Xing
authors: X
authors: Du
authors: Department Genetics and Development, Columbia University Medical Center, New York, New York 10032.
authors: Ivana
authors: I
authors: Sunjevaric
authors: Department of Medicine, Columbia University Medical Center, New York, New York 10032.
authors: Vinayak
authors: V
authors: Rayannavar
authors: Department of Biological Sciences, Columbia University, New York, New York 10027.
authors: John
authors: J
authors: Dittmar
authors: Department of Biological Sciences, Columbia University, New York, New York 10027.
authors: Eric
authors: E
authors: Bryant
authors: Department of Medicine, Columbia University Medical Center, New York, New York 10032.
authors: Matthew
authors: M
authors: Maurer
authors: Department Genetics and Development, Columbia University Medical Center, New York, New York 10032 rothstein@columbia.edu.
authors: Rodney
authors: R
authors: Rothstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D042846:CDC2-CDC28 Kinases / Q000096:biosynthesis / Q000235:genetics*; D017489:CDC28 Protein Kinase, S cerevisiae / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D017124:Conserved Sequence / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008938:Mitosis / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics; D000072020:Synthetic Lethal Mutations / Q000235:genetics; D000097869:Polo-Like Kinase 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D042846:CDC2-CDC28 Kinases; D017489:CDC28 Protein Kinase, S cerevisiae; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins; D000097869:Polo-Like Kinase 1; C081185:CKS1 protein, S cerevisiae; C093090:CKS1B protein, human; C099685:SWE1 protein, S cerevisiae; C499349:WEE1 protein, human; C081927:CDC5 protein, S cerevisiae
keywords: CKS1; cyclin-dependent kinase; polo-like kinase; synthetic dosage lethal