The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Hypoxia-Associated Factor, a Novel E3-Ubiquitin Ligase, Binds and Ubiquitinates Hypoxia-Inducible Factor 1α, Leading to Its Oxygen-Independent Degradation
Open accessAbstract
The hypoxia-inducible factor 1alpha (HIF-1alpha) is the master regulator of the cellular response to hypoxia. A key regulator of HIF-1alpha is von Hippel-Lindau protein (pVHL), which mediates the oxygen-dependent, proteasomal degradation of HIF-1alpha in normoxia. Here, we describe a new regulator of HIF-1alpha, the hypoxia-associated factor (HAF), a novel E3-ubiquitin ligase that binds HIF-1alpha leading to its proteasome-dependent degradation irrespective of cellular oxygen tension. HAF, a protein expressed in proliferating cells, binds and ubiquitinates HIF-1alpha in vitro, and both binding and E3 ligase activity are mediated by HAF amino acids 654 to 800. Furthermore, HAF overexpression decreases HIF-1alpha levels in normoxia and hypoxia in both pVHL-competent and -deficient cells, whereas HAF knockdown increases HIF-1alpha levels in normoxia, hypoxia, and under epidermal growth factor stimulation. In contrast, HIF-2alpha is not regulated by HAF. In vivo, tumor xenografts from cells overexpressing HAF show decreased levels of HIF-1alpha accompanied by decreased tumor growth and angiogenesis. Therefore, HAF is the key mediator of a new HIF-1alpha-specific degradation pathway that degrades HIF-1alpha through a new, oxygen-independent mechanism.
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Citations
Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
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
HIFα 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×
“HIF-1 produced in Escherichia coli is unhydroxylated as bacterial cells lack this capability ( 22 ).”
BackgroundOhh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T.-Y., Huang, L. E., Pavletich, N., Chau, V., & Kaelin, W. G. (2000) · Nature Cell Biology · doi:10.1038/35017054 · Cited by 1,577
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
Ravi, R., Mookerjee, B., Bhujwalla, Z. M., Sutter, C. H., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000) · Genes & Development · doi:10.1101/gad.14.1.34 · Cited by 967
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
Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway
Isaacs, J. S., Jung, Y.-J., Mimnaugh, E. G., Martinez, A., Cuttitta, F., & Neckers, L. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204733200 · Cited by 663
SUMO-Specific Protease 1 Is Essential for Stabilization of HIF1α during Hypoxia
Cheng, J., Kang, X., Zhang, S., & Yeh, E. T. H. (2007) · Cell · doi:10.1016/j.cell.2007.08.045 · Cited by 624
The hypoxic response of tumors is dependent on their microenvironment
Blouw, B., Song, H., Tihan, T., Bosze, J., Ferrara, N., Gerber, H.-P., Johnson, R. S., & Bergers, G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00194-6 · Cited by 408
Paull, T. T., Cortez, D., Bowers, B., Elledge, S. J., & Gellert, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111125998 · Cited by 282
Cited by
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693
Passing the baton: the HIF switch
Koh, M. Y., & Powis, G. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.06.004 · Cited by 589
Self-citationHIF-1 and HIF-2 Transcription Factors - Similar but Not Identical
Loboda, A., Jozkowicz, A., & Dulak, J. (2010) · Molecules and Cells · doi:10.1007/s10059-010-0067-2 · Cited by 477
Koh, M. Y., Lemos, R., Liu, X., & Powis, G. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-4142 · Cited by 350
Self-citationLuo, W., Zhong, J., Chang, R., Hu, H., Pandey, A., & Semenza, G. L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.068577 · Cited by 232
Metadata
- Authors
- Koh, M. Y., Darnay, B. G., & Powis, G.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-12
- Volume
- 28
- Issue
- 23
- Pages
- 7081-7095
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2114920820
- Cited by
- 182
- References
- 10
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- green
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