title: Role of protein phosphatases 2C on tolerance to lithium toxicity in the yeast Saccharomyces cerevisiae.
abstract: Protein phosphatases 2C are a family of conserved enzymes involved in many aspects of the cell biology. We reported that, in the yeast Saccharomyces cerevisiae, overexpression of the Ptc3p isoform resulted in increased lithium tolerance in the hypersensitive hal3 background. We have found that the tolerance induced by PTC3 overexpression is also observed in wild-type cells and that this is most probably the result of increased expression of the ENA1 Na(+)-ATPase mediated by the Hog1 MAP kinase pathway. This effect does not require a catalytically active protein. Surprisingly, deletion of PTC3 (similarly to that of PTC2, PTC4 or PTC5) does not confer a lithium-sensitive phenotype, but mutation of PTC1 does. Lack of PTC1 in an ena1-4 background did not result in additive lithium sensitivity and the ptc1 mutant showed a decreased expression of the ENA1 gene in cells stressed with LiCl. In agreement, under these conditions, the ptc1 mutant was less effective in extruding Li(+) and accumulated higher concentrations of this cation. Deletion of PTC1 in a hal3 background did not exacerbate the halosensitive phenotype of the hal3 strain. In addition, induction from the ENA1 promoter under LiCl stress decreased similarly (50%) in hal3, ptc1 and ptc1 hal3 mutants. Finally, mutation of PTC1 virtually abolishes the increased tolerance to toxic cations provided by overexpression of Hal3p. These results indicate that Ptc1p modulates the function of Ena1p by regulating the Hal3/Ppz1,2 pathway. In conclusion, overexpression of PTC3 and lack of PTC1 affect lithium tolerance in yeast, although through different mechanisms.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat Autónoma de Barcelona, Bellaterra 08193, Barcelona, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Ruiz
authors.forename: Asier
authors.initials: A
authors.lastname: González
authors.forename: Raúl
authors.initials: R
authors.lastname: García-Salcedo
authors.forename: José
authors.initials: J
authors.lastname: Ramos
authors.forename: Joaquín
authors.initials: J
authors.lastname: Ariño
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects / Q000235:genetics; D018021:Lithium Chloride / Q000633:toxicity*; D009154:Mutation / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000071636:Protein Phosphatase 2C; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000633:toxicity; D000254:Sodium-Potassium-Exchanging ATPase
chemical_list: D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; C086375:ENA1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D012964:Sodium; C000607464:PTC3 protein, S cerevisiae; C000607465:PTC4 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D000251:Adenosine Triphosphatases; D000254:Sodium-Potassium-Exchanging ATPase; D018021:Lithium Chloride