The Hippo pathway promotes cell survival in response to chemical stress

F. Di Cara, T. M. Maile, B. D. Parsons, A. Magico, S. Basu, N. Tapon, K. King-Jones

Résultat de recherche: Articleexamen par les pairs

21 Citations (Scopus)

Résumé

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.

Langue d'origineEnglish
Pages (de-à)1526-1539
Nombre de pages14
JournalCell Death and Differentiation
Volume22
Numéro de publication9
DOI
Statut de publicationPublished - sept. 11 2015
Publié à l'externeOui

Note bibliographique

Funding Information:
Acknowledgements. We would like to thank the Bloomington Drosophila Stock Center at Indiana University for supplying fly stocks and the RNAi Screening facility at Li Ka-Shing Institute of Virology, University of Alberta. We also would like to thank Edan Foley for his help and advice he provided for the RNAi screening procedures. Finally, we wish to thank the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC) for supporting this work.

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

ASJC Scopus Subject Areas

  • Molecular Biology
  • Cell Biology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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