title: Genome-wide analysis of intracellular pH reveals quantitative control of cell division rate by pH(c) in Saccharomyces cerevisiae.
abstract: BACKGROUND
  Because protonation affects the properties of almost all molecules in cells, cytosolic pH (pH(c)) is usually assumed to be constant. In the model organism yeast, however, pH(c) changes in response to the presence of nutrients and varies during growth. Since small changes in pH(c) can lead to major changes in metabolism, signal transduction, and phenotype, we decided to analyze pH(c) control.
  
  
  RESULTS
  Introducing a pH-sensitive reporter protein into the yeast deletion collection allowed quantitative genome-wide analysis of pH(c) in live, growing yeast cultures. pH(c) is robust towards gene deletion; no single gene mutation led to a pH(c) of more than 0.3 units lower than that of wild type. Correct pH(c) control required not only vacuolar proton pumps, but also strongly relied on mitochondrial function. Additionally, we identified a striking relationship between pH(c) and growth rate. Careful dissection of cause and consequence revealed that pH(c) quantitatively controls growth rate. Detailed analysis of the genetic basis of this control revealed that the adequate signaling of pH(c) depended on inositol polyphosphates, a set of relatively unknown signaling molecules with exquisitely pH sensitive properties.
  
  
  CONCLUSIONS
  While pH(c) is a very dynamic parameter in the normal life of yeast, genetically it is a tightly controlled cellular parameter. The coupling of pH(c) to growth rate is even more robust to genetic alteration. Changes in pH(c) control cell division rate in yeast, possibly as a signal. Such a signaling role of pH(c) is probable, and may be central in development and tumorigenesis.
authors.affiliation: Molecular Biology and Microbial Food Safety, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, the Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Orij
authors.forename: Malene L
authors.initials: ML
authors.lastname: Urbanus
authors.forename: Franco J
authors.initials: FJ
authors.lastname: Vizeacoumar
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.forename: Stanley
authors.initials: S
authors.lastname: Brul
authors.forename: Gertien J
authors.initials: GJ
authors.lastname: Smits
mesh_terms: D002455:Cell Division; D003593:Cytoplasm / Q000378:metabolism; D016681:Genome, Fungal; D006863:Hydrogen-Ion Concentration; D007295:Inositol Phosphates / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D017494:Proton Pumps / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014617:Vacuoles / Q000378:metabolism
chemical_list: D007295:Inositol Phosphates; D017494:Proton Pumps