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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-36729

Sendoel, A; Kohler, I; Fellmann, C; Lowe, S W; Hengartner, M O (2010). HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature, 465(7298):577-583.

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Abstract

Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration. HIFalpha 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.

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
DDC:570 Life sciences; biology
Language:English
Date:2010
Deposited On:09 Nov 2010 16:53
Last Modified:01 Dec 2013 01:45
Publisher:Nature Publishing Group
ISSN:0028-0836
Publisher DOI:10.1038/nature09141
PubMed ID:20520707
Citations:Web of Science®. Times Cited: 66
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Scopus®. Citation Count: 70

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