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HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase

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  • Ataman Sendoel

    (Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    PhD program in Cancer Biology, University of Zurich, Winterthurerstrassse 190, CH-8057 Zurich, Switzerland
    MD-PhD program, University of Zurich)

  • Ines Kohler

    (Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    Present address: Institute of Medical Virology, University of Zurich, Winterthurerstrassse 190, CH-8057 Zurich, Switzerland.)

  • Christof Fellmann

    (Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
    PhD program in Molecular Life Sciences, University of Zurich, Winterthurerstrassse 190, CH-8057 Zurich, Switzerland)

  • Scott W. Lowe

    (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
    Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA)

  • Michael O. Hengartner

    (Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland)

Abstract

Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration. HIFα protein levels are increased in most solid tumours and correlate with patient prognosis. The link between HIF and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that Caenorhabditis elegans HIF-1 protects against DNA-damage-induced germ cell apoptosis by antagonizing the function of CEP-1, the homologue of the tumour suppressor p53. The antiapoptotic property of HIF-1 is mediated by means of transcriptional upregulation of the tyrosinase family member TYR-2 in the ASJ sensory neurons. TYR-2 is secreted by ASJ sensory neurons to antagonize CEP-1-dependent germline apoptosis. Knock down of the TYR-2 homologue TRP2 (also called DCT) in human melanoma cells similarly increases apoptosis, indicating an evolutionarily conserved function. Our findings identify a novel link between hypoxia and programmed cell death, and provide a paradigm for HIF-1 dictating apoptotic cell fate at a distance.

Suggested Citation

  • Ataman Sendoel & Ines Kohler & Christof Fellmann & Scott W. Lowe & Michael O. Hengartner, 2010. "HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase," Nature, Nature, vol. 465(7298), pages 577-583, June.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7298:d:10.1038_nature09141
    DOI: 10.1038/nature09141
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    Cited by:

    1. Najmeh Soltanmohammadi & Siyao Wang & Björn Schumacher, 2022. "Somatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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