The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
Differentiating the functional role of hypoxia‐inducible factor (HIF)‐1α and HIF‐2α (EPAS‐1) by the use of RNA interference: erythropoietin is a HIF‐2α target gene in Hep3B and Kelly cells
Abstract
Activation of the hypoxia‐inducible factor α‐subunits, HIF‐1α and HIF‐2α, seems to be subject to similar regulatory mechanisms, and transgene approaches suggested partial functional redundancy. Here, we used RNA interference to determine the contribution of HIF‐1α vs. HIF‐2α to the hypoxic gene induction. Surprisingly, most genes tested were responsive only to the HIF‐1α siRNA, showing no effect by HIF‐2α knock‐down. The same was found for the activation of reporter genes driven by hypoxia‐responsive elements (HREs) from the erythropoietin (EPO), vascular endothelial growth factor, or phosphoglycerate kinase gene. Interestingly, EPO was the only gene investigated that showed responsiveness only to HIF‐2α knock‐down, as observed in Hep3B and Kelly cells. In contrast to the EPO‐HRE reporter, the complete EPO enhancer displayed dependency on HIF‐2α regulation, indicating that additional cis ‐acting elements confer HIF‐2α specificity within this region. In 786‐0 cells lacking HIF‐1α protein, the identified HIF‐1α target genes were regulated by HIF‐2α. Overexpression of the HIFα subunits in different cell lines also led to a loss of target gene specificity. In conclusion, we found a remarkably restricted target gene specificity of the HIFα subunits, which can be overcome in cells with perturbations in the pVHL/HIF system and under forced expression.
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Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
Self-citationHIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · cited 1×
“Both HIFα subunits are predominantly regulated at the protein level by oxygen-dependent prolyl hydroxylation, which leads to rapid pVHL (von Hippel-Lindau protein)-mediated ubiquitination and proteasomal degradation in normoxia (20, 21).”
BackgroundCellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558
Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (2002) · Genes & Development · doi:10.1101/gad.991402 · Cited by 1,550
Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9361-9374.2003 · Cited by 1,386
Mahon, P. C., Hirota, K., & Semenza, G. L. (2001) · Genes & Development · doi:10.1101/gad.924501 · Cited by 1,385
Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D., & Pouysségur, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg392 · Cited by 1,348
Wenger, R. H. (2002) · The FASEB Journal · doi:10.1096/fj.01-0944rev · Cited by 1,135
Cited by
Integration of Oxygen Signaling at the Consensus HRE
Wenger, R. H., Stiehl, D. P., & Camenisch, G. (2005) · Science's STKE · doi:10.1126/stke.3062005re12 · Cited by 1,032
Raval, R. R., Lau, K. W., Tran, M. G. B., Sowter, H. M., Mandriota, S. J., Li, J.-L., Pugh, C. W., Maxwell, P. H., Harris, A. L., & Ratcliffe, P. J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.13.5675-5686.2005 · Cited by 940
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787
Holmquist-Mengelbier, L., Fredlund, E., Löfstedt, T., Noguera, R., Navarro, S., Nilsson, H., Pietras, A., Vallon-Christersson, J., Borg, Å., Gradin, K., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.026 · Cited by 735
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641
Metadata
- Authors
- Warnecke, C., Zaborowska, Z., Kurreck, J., Erdmann, V. A., Frei, U., Wiesener, M., & Eckardt, K.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2004-07
- Volume
- 18
- Issue
- 12
- Pages
- 1462-1464
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2153771223
- Cited by
- 398
- References
- 14
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- closed
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- Warnecke, C., Zaborowska, Z., Kurreck, J., Erdmann, V. A., Frei, U., Wiesener, M., & Eckardt, K. (2004). Differentiating the functional role of hypoxia‐inducible factor (HIF)‐1α and HIF‐2α (EPAS‐1) by the use of RNA interference: erythropoietin is a HIF‐2α target gene in Hep3B and Kelly cells. The FASEB Journal. https://doi.org/10.1096/fj.04-1640fje
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