Cisplatin sensitivity in cAMP-dependent protein kinase mutants of Saccharomyces cerevisiae.
The emergence of cisplatin resistance poses a significant problem to the treatment of a variety of human malignancies. Therefore, understanding the molecular basis of cisplatin resistance could improve the clinical effectiveness of this anticancer agent. Recently, our laboratory has demonstrated that cAMP-dependent protein kinase (PKA) mutants of the Chinese hamster ovary (CHO) and the mouse adrenocortical carcinoma Y1 cells exhibited increased resistance to cisplatin as well as other DNA-damaging drugs. Further studies showed that either the functional inactivation of PKA or the mutation in the regulatory subunit gene may cause increased recognition of cisplatin-damaged DNA and enhanced DNA repair capacity. In this study, we evaluated the role of PKA in modulating cellular sensitivity to cisplatin in a series of PKA mutants of Saccharomyces cerevisiae. Mutants with decreased kinase activity resulting from a srv2 mutation showed no alterations in cisplatin sensitivity. Complementation of TPK1 in a yeast strain containing mutant tpk1 and also tpk2 and tpk3 deletions did not significantly alter its sensitivity to this DNA-damaging agent. Yeast transformants containing increased kinase activity resulting from overexpression of RAS2Val19 or TPK1 and yeast strains having increased kinase activities due to mutations in the BCY1 gene also did not show alterations in their sensitivity to cisplatin. Therefore, results from these studies unambiguously demonstrate that changes in PKA activity have no effect on cisplatin sensitivity in Saccharomyces cerevisiae.
Cvijic
M E
ME
Department of Medicine, Robert Wood Johnson Medical School, UMDNJ, New Brunswick 08901, USA.
Yang
W L
WL
Chin
K V
KV
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D004351:Drug Resistance; D017353:Gene Deletion; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology
D000970:Antineoplastic Agents; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D002945:Cisplatin