title: Time-dependent quantitative multicomponent control of the G₁-S network by the stress-activated protein kinase Hog1 upon osmostress.
abstract: Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. Exposure of yeast to hyperosmotic stress activates the SAPK Hog1, which delays cell cycle progression through G₁ by direct phosphorylation of the cyclin-dependent kinase (CDK) inhibitor Sic1 and by inhibition of the transcription of the genes encoding the G₁ cyclins Cln1 and 2. Additional targets of Hog1 may also play a role in this response. We used mathematical modeling and quantitative in vivo experiments to define the contributions of individual components of the G₁-S network downstream of Hog1 to this stress-induced delay in the cell cycle. The length of the arrest depended on the degree of stress and the temporal proximity of the onset of the stress to the commitment to cell division, called "Start." Hog1-induced inhibition of the transcription of the gene encoding cyclin Clb5, rather than that of the gene encoding Cln2, prevented entry into S phase upon osmostress. By controlling the accumulation of specific cyclins, Hog1 delayed bud morphogenesis (through Clns) and delayed DNA replication (through Clb5). Hog1-mediated phosphorylation and degradation of Sic1 at Start prevented residual activity of the cyclin/CDK complex Clb5/Cdc28 from initiating DNA replication before adaptation to the stress. Thus, our work defines distinct temporal roles for the actions of Hog1 on Sic1 and cyclins in mediating G₁ arrest upon hyperosmotic stress.
authors.affiliation: Cell Signaling Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, E-08003 Barcelona, Spain.
authors.forename: Miquel Àngel
authors.initials: MÀ
authors.lastname: Adrover
authors.forename: Zhike
authors.initials: Z
authors.lastname: Zi
authors.forename: Alba
authors.initials: A
authors.lastname: Duch
authors.forename: Jörg
authors.initials: J
authors.lastname: Schaber
authors.forename: Alberto
authors.initials: A
authors.lastname: González-Novo
authors.forename: Javier
authors.initials: J
authors.lastname: Jimenez
authors.forename: Mariona
authors.initials: M
authors.lastname: Nadal-Ribelles
authors.forename: Josep
authors.initials: J
authors.lastname: Clotet
authors.forename: Edda
authors.initials: E
authors.lastname: Klipp
authors.forename: Francesc
authors.initials: F
authors.lastname: Posas
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000502:physiology; D015966:Gene Expression Regulation, Fungal / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009997:Osmotic Pressure / Q000502:physiology; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: C082719:CLN1 protein, S cerevisiae; C082721:CLN2 protein, S cerevisiae; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; C086926:SIC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C088589:HOG1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases