A novel pathway determining multidrug sensitivity in Schizosaccharomyces pombe.
In this study, we show that a mutation isolated during a screen for determinants of chemosensitivity in S. pombe results in loss of function of a previously uncharacterized protein kinase now named Hal4. Hal4 shares sequence homology to Hal4 and Hal5 in S. cerevisiae, and previous evidence indicates that these kinases positively regulate the major potassium transporter Trk1,2 and thereby maintain the plasma membrane potential. Disruption of this ion homeostasis pathway results in a hyperpolarized membrane and a concomitant increased sensitivity to cations. We demonstrate that a mutation in hal4+ results in hyperpolarization of the plasma membrane. In addition to the original selection agent, the hal4-1 mutant is sensitive to a variety of chemotherapeutic agents and stress-inducing compounds. Furthermore, this wider chemosensitive phenotype is also displayed by corresponding mutants in S. cerevisiae, and in a trk1deltatrk2delta double deletion mutant in S. pombe. We propose that this pathway and its role in regulating the plasma membrane potential may act as a pleiotropic determinant of sensitivity to chemotherapeutic agents.
Thornton
Gemma
G
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK.
Wilkinson
Caroline R M
CR
Toone
W Mark
WM
Jones
Nic
N
D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002412:Cations / Q000378:metabolism / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D008564:Membrane Potentials; D009154:Mutation / Q000502:physiology; D011189:Potassium Chloride / Q000378:metabolism / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism / Q000494:pharmacology; D017385:Sequence Homology
D027682:Cation Transport Proteins; D002412:Cations; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; C085258:TRK2 protein, S cerevisiae; C068664:TRK1 protein, S cerevisiae; D011189:Potassium Chloride; D011494:Protein Kinases; C501076:Hal4 protein, S pombe; D017346:Protein Serine-Threonine Kinases