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Inactivation of the Saccharomyces cerevisiae SKY1 gene induces a specific modification of the yeast anticancer drug sensitivity profile accompanied by a mutator phenotype
- Source :
- Molecular Pharmacology, 61, 659-666. American Society for Pharmacology and Experimental Therapeutics
- Publication Year :
- 2002
-
Abstract
- The therapeutic potential of the highly active anticancer agent cisplatin is severely limited by the occurrence of cellular resistance. A better understanding of the molecular pathways involved in cisplatin-induced cell death could potentially indicate ways to overcome cellular unresponsiveness to the drug and thus lead to better treatment results. We used the budding yeast Saccharomyces cerevisiae as a model organism to identify and characterize novel genes involved in cisplatin-induced cell kill, and found that SKY1 (SR-protein-specific kinase from budding yeast) is a cisplatin sensitivity gene whose disruption conferred cisplatin resistance. In cross-resistance studies, we observed resistance of yeast sky1 Delta cells (i.e., cells from which the SKY1 gene had been disrupted) to cisplatin, carboplatin (but not oxaliplatin), doxorubicin and daunorubicin, and hypersensitivity to cadmium chloride and 5-fluorouracil. Furthermore, these cells did not display reduced platinum accumulation, DNA platination or doxorubicin accumulation, indicating that the resistance is unrelated to decreased drug import or increased drug export. Based on the modification of the anticancer drug sensitivity profile and our finding that sky1 Delta cells display a mutator phenotype, we propose that Sky1p might play a significant role in specific repair and/or tolerance pathways. Disruption of the S. cerevisiae SKY1 gene would thus result in deregulation of such mechanisms and, consequently, lead to altered drug sensitivity.
- Subjects :
- Saccharomyces cerevisiae Proteins
Drug export
Daunorubicin
Saccharomyces cerevisiae
Drug Resistance
Antineoplastic Agents
Drug resistance
Protein Serine-Threonine Kinases
Biology
DNA Adducts
chemistry.chemical_compound
medicine
Gene Silencing
Gene
Platinum
Pharmacology
Cisplatin
DNA
biology.organism_classification
Yeast
Carboplatin
Cell biology
Phenotype
chemistry
Biochemistry
Doxorubicin
Molecular Medicine
medicine.drug
Subjects
Details
- ISSN :
- 0026895X
- Volume :
- 61
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmacology
- Accession number :
- edsair.doi.dedup.....b5a7c24eed166531f110b08edcd90ba2
- Full Text :
- https://doi.org/10.1124/mol.61.3.659