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

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.

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Figure 1: HIF-1 antagonizes DNA-damage-induced apoptosis.
Figure 2: HIF-1 impedes DNA-damage-induced apoptosis by inhibiting CEP-1.
Figure 3: The antiapoptotic function of HIF-1 is mediated by a concerted action of TYR-2 and TYR-3.
Figure 4: HIF-1 drives tyr-2 expression in ASJ neurons.
Figure 5: TYR-2 is a l -dopachrome tautomerase secreted by the ASJ neurons to inhibit apoptosis.

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Acknowledgements

We thank Y. Lazebnik, A. Gartner, A. Hajnal, J. Jiricny, R. Wenger and C. Mosimann for critical reading of the manuscript. We are grateful to S. Schrimpf, L. Stergiou, E. Bogan, S. Egger, O. Georgiev, M. Moser and Hengartner, Hajnal and Lowe laboratory members for help and discussions. We thank Y. Auchli and P. Hunziker from the Functional Genomics Center Zurich for protein analysis. We are grateful to V. Hearing and J. Valencia for the TRP2 antibody and help. This work was supported by the Swiss National Science Foundation, the Kanton of Zurich and the Josef-Steiner Foundation. M.O.H. is Ernst Hadorn endowed Professor of Molecular Biology. A.S. was supported by Oncosuisse and the Swiss National Science Foundation. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR).

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A.S. designed experiments, performed most of the experiments and analysed data; I.K. generated opIs425 transgenic animals and performed experiments; C.F. established shRNA melanoma cell lines and helped to perform melanoma experiments; S.W.L. contributed to the design of melanoma experiments and analysed data; M.O.H. designed experiments and analysed the data. A.S. and M.O.H. wrote the paper.

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Correspondence to Michael O. Hengartner.

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Sendoel, A., Kohler, I., Fellmann, C. et al. HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature 465, 577–583 (2010). https://doi.org/10.1038/nature09141

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