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https://hdl.handle.net/2440/45284
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Type: | Journal article |
Title: | Role of the C-terminal α-helical domain of the von Hippel–Lindau protein in its E3 ubiquitin ligase activity |
Other Titles: | Role of the C-terminal alpha-helical domain of the von Hippel-Lindau protein in its E3 ubiquitin ligase activity |
Author: | Lewis, M. Roberts, B. |
Citation: | Oncogene, 2004; 23(13):2315-2323 |
Publisher: | Nature Publishing Group |
Issue Date: | 2004 |
ISSN: | 0950-9232 1476-5594 |
Statement of Responsibility: | Martin D Lewis and Ben J Roberts |
Abstract: | In the present study, the role of the C-terminal α-helical domain (amino acid (aa) 195–208) of the von Hippel–Lindau (VHL) tumour suppressor was investigated. Deletions of the VHL C-terminus up to the naturally occurring 195-Gln-Term resulted in hypoxia-inducible factor (HIF)-1α downregulation in renal cell carcinoma (RCC)4 cells during normoxia, suggesting that this domain is not an absolute requirement for the ubiquitination of HIF-1α. However, detailed investigation of the ubiquitin protein isopeptide ligase ubiquitin ligase properties of VHL revealed C-terminal deletions to cause a significant impairment of HIF-1α ubiquitination, which is shown to be due to a loss in high-affinity binding to the target substrate. When VHL regulation of both HIF-1α N- and C-terminal oxygen-dependent degradation domains (HIF-ODDD) was investigated, it was found that only ubiquitination of the C-terminal HIF-ODDD was affected by the deletion of the VHL C-terminus. When RCC4 cells expressing C-terminal truncations of VHL were exposed to graded hypoxia, differences in the induction of HIF-1α were observed in comparison with full-length VHL, with a shift in the maximal induction of HIF-1α to a higher oxygen tension. These changes were accompanied by increased glucose transporter 1 expression, p300 CH1 domain binding and HIF-mediated reporter activity. We have thus defined a role for the C-terminal α-helical domain of VHL in the regulation of HIF-1α. |
Keywords: | VHL HIF ubiquitin cancer |
Rights: | © 2004 Nature Publishing Group. All rights reserved. |
DOI: | 10.1038/sj.onc.1207384 |
Published version: | http://dx.doi.org/10.1038/sj.onc.1207384 |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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