title: The Hippo pathway promotes cell survival in response to chemical stress.
abstract: Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress.
authors.affiliation: Department of Cell Biology, Medical Sciences Building, Faculty of Medicine & Dentistry, University of Alberta, Edmonton T6G 2H7, Alberta, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Di Cara
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Maile
authors.affiliation: Department of Medical Microbiology and Immunology, 6-020 Katz Group Centre, University of Alberta, Edmonton AB T6G 2E1, Alberta, Canada.
authors.forename: B D
authors.initials: BD
authors.lastname: Parsons
authors.affiliation: Department of Pediatrics, Faculty of Medicine & Dentistry, Katz Group Centre, University of Alberta, Edmonton T6G 2H7, Alberta, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Magico
authors.affiliation: Centre for Molecular Oncology, Institute of Cancer, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: S
authors.initials: S
authors.lastname: Basu
authors.affiliation: Apoptosis and Proliferation Control Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: N
authors.initials: N
authors.lastname: Tapon
authors.affiliation: Department of Biological Sciences, University of Alberta, G-504 Biological Sciences Bldg, Edmonton T6G 2E9, Alberta, Canada.
authors.forename: K
authors.initials: K
authors.lastname: King-Jones
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002110:Caffeine / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D000099317:Hippo Kinases
chemical_list: D002110:Caffeine; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases