Sendoel, A., Kohler, I., Fellmann, C., Lowe, S. W., Hengartner, M. O. (June 2010) HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature, 465 (7298). 577-U69. ISSN 0028-0836
Abstract
Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration. HIF alpha 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: | Paper |
|---|---|
| Uncontrolled Keywords: | HYPOXIA-INDUCIBLE FACTOR DAMAGE-INDUCED APOPTOSIS CAENORHABDITIS-ELEGANS C-ELEGANS CELL-LINES PROTEIN P53 PATHWAY CANCER GENE |
| Subjects: | organism description > animal > C elegans diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab |
| Depositing User: | CSHL Librarian |
| Date: | 3 June 2010 |
| Date Deposited: | 19 Oct 2011 16:28 |
| Last Modified: | 14 Mar 2018 14:25 |
| PMCID: | PMC3328299 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/15524 |
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