title: Whi2p links nutritional sensing to actin-dependent Ras-cAMP-PKA regulation and apoptosis in yeast.
abstract: Elucidating the mechanisms by which eukaryotic cells coordinate environmental signals with intracellular ;fate' decisions, such as apoptosis, remains one of the important challenges facing cell biologists. It has recently emerged that the dynamic nature of the actin cytoskeleton is an important factor in the linkage of sensation of extracellular stimuli to signalling mechanisms that regulate programmed cell death. In yeast, actin has been shown to play a role in the regulation of apoptosis as cells prepare themselves for quiescence in the face of nutritional exhaustion, by facilitating the shutdown of Ras-cAMP-PKA pathway activity. Here, we demonstrate that the loss of Whi2p function, a protein known to influence cell cycle exit under conditions of nutritional stress, leads to cell death in yeast that displays the hallmarks of actin-mediated apoptosis. We show that actin-mediated apoptosis occurs as a result of inappropriate Ras-cAMP-PKA activity in Deltawhi2 cells. Cells lacking Whi2p function exhibit an aberrant accumulation of activated Ras2 at the mitochondria in response to nutritional depletion. This study provides evidence that the shutdown of cAMP-PKA signalling activity in wild-type cells involves Whi2p-dependent targeting of Ras2p to the vacuole for proteolysis. We also demonstrate for the first time that Whi2p-dependent regulation of cAMP-PKA signalling plays a physiological role in the differentiation of yeast colonies by facilitating elaboration of distinct zones of cell death.
authors.affiliation: Department of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Leadsham
authors.forename: Katherine
authors.initials: K
authors.lastname: Miller
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Ayscough
authors.forename: Sonia
authors.initials: S
authors.lastname: Colombo
authors.forename: Enzo
authors.initials: E
authors.lastname: Martegani
authors.forename: Pete
authors.initials: P
authors.lastname: Sudbery
authors.forename: Campbell W
authors.initials: CW
authors.lastname: Gourlay
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; C470937:Whi2 protein, S cerevisiae; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D018631:ras Proteins