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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Epstein, A. C. et al. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001)
Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001)
Ivan, M. et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc. Natl Acad. Sci. USA 99, 13459–13464 (2002)
Yu, F., White, S. B., Zhao, Q. & Lee, F. S. HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc. Natl Acad. Sci. USA 98, 9630–9635 (2001)
Latif, F. et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260, 1317–1320 (1993)
Höckel, M. & Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl Cancer Inst. 93, 266–276 (2001)
Zhong, H. et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 59, 5830–5835 (1999)
Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003)
Johnstone, R. W., Ruefli, A. A. & Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002)
Jiang, H., Guo, R. & Powell-Coffman, J. A. The Caenorhabditis elegans hif-1 gene encodes a bHLH-PAS protein that is required for adaptation to hypoxia. Proc. Natl Acad. Sci. USA 98, 7916–7921 (2001)
Gumienny, T. L., Lambie, E., Hartwieg, E., Horvitz, H. R. & Hengartner, M. O. Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126, 1011–1022 (1999)
Gartner, A., Milstein, S., Ahmed, S., Hodgkin, J. & Hengartner, M. O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans . Mol. Cell 5, 435–443 (2000)
Derry, W. B., Putzke, A. P. & Rothman, J. H. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294, 591–595 (2001)
Horn, H. F. & Vousden, K. H. Coping with stress: multiple ways to activate p53. Oncogene 26, 1306–1316 (2007)
Quevedo, C., Kaplan, D. R. & Derry, W. B. AKT-1 regulates DNA-damage-induced germline apoptosis in C. elegans . Curr. Biol. 17, 286–292 (2007)
Bishop, T. et al. Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans . PLoS Biol. 2, e289 (2004)
Shen, C., Nettleton, D., Jiang, M., Kim, S. K. & Powell-Coffman, J. A. Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans . J. Biol. Chem. 280, 20580–20588 (2005)
Hedgecock, E. M., Culotti, J. G., Thomson, J. N. & Perkins, L. A. Axonal guidance mutants of Caenorhabditis elegans identified by filling sensory neurons with fluorescein dyes. Dev. Biol. 111, 158–170 (1985)
Wang, N. & Hebert, D. N. Tyrosinase maturation through the mammalian secretory pathway: bringing color to life. Pigment Cell Res. 19, 3–18 (2006)
Xu, Y., Setaluri, V., Takechi, Y. & Houghton, A. N. Sorting and secretion of a melanosome membrane protein, gp75/TRP1. J. Invest. Dermatol. 109, 788–795 (1997)
Grant, B. & Hirsh, D. Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte. Mol. Biol. Cell 10, 4311–4326 (1999)
del Marmol, V. & Beermann, F. Tyrosinase and related proteins in mammalian pigmentation. FEBS Lett. 381, 165–168 (1996)
Tsukamoto, K., Jackson, I. J., Urabe, K., Montague, P. M. & Hearing, V. J. A second tyrosinase-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrome tautomerase. EMBO J. 11, 519–526 (1992)
Gray, J. M. et al. Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue. Nature 430, 317–322 (2004)
Chang, A. J. & Bargmann, C. I. Hypoxia and the HIF-1 transcriptional pathway reorganize a neuronal circuit for oxygen-dependent behavior in Caenorhabditis elegans . Proc. Natl Acad. Sci. USA 105, 7321–7326 (2008)
Ward, A., Liu, J., Feng, Z. & Xu, X. Z. Light-sensitive neurons and channels mediate phototaxis in C. elegans . Nature Neurosci. 11, 916–922 (2008)
Bargmann, C. I. & Horvitz, H. R. Control of larval development by chemosensory neurons in Caenorhabditis elegans . Science 251, 1243–1246 (1991)
Ito, S., Kato, T., Shinpo, K. & Fujita, K. Oxidation of tyrosine residues in proteins by tyrosinase. Formation of protein-bonded 3,4-dihydroxyphenylalanine and 5-S-cysteinyl-3,4-dihydroxyphenylalanine. Biochem. J. 222, 407–411 (1984)
Freddi, G. et al. Tyrosinase-catalyzed modification of Bombyx mori silk fibroin: grafting of chitosan under heterogeneous reaction conditions. J. Biotechnol. 125, 281–294 (2006)
Chu, W. et al. Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications. Oncogene 19, 395–402 (2000)
Montano, X., Shamsher, M., Whitehead, P., Dawson, K. & Newton, J. Analysis of p53 in human cutaneous melanoma cell lines. Oncogene 9, 1455–1459 (1994)
Wellbrock, C. et al. Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS ONE 3, e2734 (2008)
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)
Bertolotto, C. et al. Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia. Mol. Cell. Biol. 18, 694–702 (1998)
Ying-Tao, Z., Yi-Ping, G., Lu-Sheng, S. & Yi-Li, W. Proteomic analysis of differentially expressed proteins between metastatic and non-metastatic human colorectal carcinoma cell lines. Eur. J. Gastroenterol. Hepatol. 17, 725–732 (2005)
Brenner, S. The genetics of Caenorhabditis elegans . Genetics 77, 71–94 (1974)
Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003)
Avery, L. & Horvitz, H. R. Pharyngeal pumping continues after laser killing of the pharyngeal nervous system of C. elegans . Neuron 3, 473–485 (1989)
Hofmann, E. R. et al. Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Curr. Biol. 12, 1908–1918 (2002)
Schumacher, B. et al. Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis. Cell 120, 357–368 (2005)
Palumbo, A., d’Ischia, M., Misuraca, G. & Prota, G. Effect of metal ions on the rearrangement of dopachrome. Biochim. Biophys. Acta 925, 203–209 (1987)
Edgar, R. C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004)
Dickins, R. A. et al. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nature Genet. 37, 1289–1295 (2005)
Silva, J. M. et al. Second-generation shRNA libraries covering the mouse and human genome. Nature Genet. 37, 1281–1288 (2005)
Serrano, M. et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)
Zuber, J. et al. Mouse models of human AML accurately predict chemotherapy response. Genes Dev. 23, 877–889 (2009)
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).
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
This file contains Supplementary Figures 1-21 with legends, Supplementary Tables 1-2 and References. (PDF 4900 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature09141
This article is cited by
-
Somatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy
Nature Communications (2022)
-
A practical spatial analysis method for elucidating the biological mechanisms of cancers with abdominal dissemination in vivo
Scientific Reports (2022)
-
Hypoxia-induced PVT1 promotes lung cancer chemoresistance to cisplatin by autophagy via PVT1/miR-140-3p/ATG5 axis
Cell Death Discovery (2022)
-
Identification of anti-tumoral feedback loop between VHLα and hnRNPA2B1 in renal cancer
Cell Death & Disease (2020)
-
Role of hypoxia in cancer therapy by regulating the tumor microenvironment
Molecular Cancer (2019)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.