HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase.
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.
Sendoel
Ataman
A
Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Kohler
Ines
I
Fellmann
Christof
C
Lowe
Scott W
SW
Hengartner
Michael O
MO
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015687:Cell Hypoxia; D004249:DNA Damage; D005854:Germ Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D014442:Monophenol Monooxygenase / Q000172:deficiency / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000201:enzymology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D051793:Hypoxia-Inducible Factor 1; D016159:Tumor Suppressor Protein p53; D014442:Monophenol Monooxygenase; C550749:TYRosinase family member 2, C elegans; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase