title: Identification of mitogen-activated protein kinase signaling pathways that confer resistance to endoplasmic reticulum stress in Saccharomyces cerevisiae.
abstract: Hypoxia activates all components of the unfolded protein response (UPR), a stress response initiated by the accumulation of unfolded proteins within the endoplasmic reticulum (ER). Our group and others have shown previously that the UPR, a hypoxia-inducible factor-independent signaling pathway, mediates cell survival during hypoxia and is required for tumor growth. Identifying new genes and pathways that are important for survival during ER stress may lead to the discovery of new targets in cancer therapy. Using the set of 4,728 homozygous diploid deletion mutants in budding yeast, Saccharomyces cerevisiae, we did a functional screen for genes that conferred resistance to ER stress-inducing agents. Deletion mutants in 56 genes showed increased sensitivity under ER stress conditions. Besides the classic UPR pathway and genes related to calcium homeostasis, we report that two additional pathways, including the SLT2 mitogen-activated protein kinase (MAPK) pathway and the osmosensing MAPK pathway, were also required for survival during ER stress. We further show that the SLT2 MAPK pathway was activated during ER stress, was responsible for increased resistance to ER stress, and functioned independently of the classic IRE1/HAC1 pathway. We propose that the SLT2 MAPK pathway is an important cell survival signaling pathway during ER stress. This study shows the feasibility of using the yeast deletion pool to identify relevant mammalian orthologues of the UPR.
authors.affiliation: Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University Medical Center, Stanford, CA 94305, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Chen
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Feldman
authors.forename: Changchun
authors.initials: C
authors.lastname: Deng
authors.forename: James A
authors.initials: JA
authors.lastname: Brown
authors.forename: Anthony F
authors.initials: AF
authors.lastname: De Giacomo
authors.forename: Allison F
authors.initials: AF
authors.lastname: Gaw
authors.forename: Gongyi
authors.initials: G
authors.lastname: Shi
authors.forename: Quynh T
authors.initials: QT
authors.lastname: Le
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002470:Cell Survival; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008623:Mercaptoethanol / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D016366:Open Reading Frames; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C091341:HAC1 protein, S cerevisiae; D008562:Membrane Glycoproteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014415:Tunicamycin; D008623:Mercaptoethanol; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C072724:SLT2 protein, S cerevisiae; D004229:Dithiothreitol