Cisplatin sensitivity correlates with its ability to cause cell cycle arrest via a wee1 kinase-dependent pathway in Schizosaccharomyces pombe.
Mutants of Schizosaccharomyces pombe were used to define genes involved in the cell cycle arrest produced by cisplatin (DDP), an agent that causes both DNA damage and inhibition of DNA synthesis. Previous work has demonstrated that strains with defective or absent wee1+ function fail to arrest in G2 when DNA is damaged, but do arrest when DNA synthesis is inhibited (Rowley et al., 1992a, Nature, 356:353-355). Strains defective in wee1+ function, or in the ability of the wee1+ kinase to regulate cdc2, failed to arrest following DDP exposure, as did a rad1-1 mutant. All strains failing to arrest in G2 were hypersensitive to DDP. Thus, DNA damage rather than inhibition of DNA synthesis is causative of DDP-induced cell cycle arrest. In addition, this work shows that the wee1+ and rad1+ gene products are required for successful DDP-induced arrest, and suggests that the ability of S. pombe to arrest is a major determinant of sensitivity to DDP.
Thiebaut
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F
Department of Medicine, University of California, San Diego, La Jolla 92093.
Enns
R
R
Howell
S B
SB
D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000633:toxicity*; D004271:DNA, Fungal / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005800:Genes, Fungal; D005838:Genotype; D007700:Kinetics; D008954:Models, Biological; D009687:Nuclear Proteins; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D029702:Schizosaccharomyces pombe Proteins; D013045:Species Specificity; D013997:Time Factors
D018797:Cell Cycle Proteins; D004271:DNA, Fungal; D009687:Nuclear Proteins; D029702:Schizosaccharomyces pombe Proteins; D011494:Protein Kinases; C068689:wee1 protein, S pombe; D011505:Protein-Tyrosine Kinases; D002945:Cisplatin