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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)-1_α_ downregulation in renal cell carcinoma (RCC)4 cells during normoxia, suggesting that

this domain is not an absolute requirement for the ubiquitination of HIF-1_α_. 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-1_α_ ubiquitination, which is shown to be due to a loss in high-affinity binding to the target substrate. When VHL

regulation of both HIF-1_α_ 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-1_α_ were observed in

comparison with full-length VHL, with a shift in the maximal induction of HIF-1_α_ 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-1_α_. Access through your

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BEING VIEWED BY OTHERS LUBAC PROMOTES ANGIOGENESIS AND LUNG TUMORIGENESIS BY UBIQUITINATING AND ANTAGONIZING AUTOPHAGIC DEGRADATION OF HIF1Α Article Open access 25 January 2024 THE E3

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DEPENDENT MANNER Article Open access 18 February 2021 ABBREVIATIONS * VHL: von Hippel–Lindau * HIF: hypoxia-inducible factor * HLF: HIF-like factors * Cul-2: Cullin-2 * VEGF: vascular

endothelial growth factor * GLUT1: glucose transporter 1 * E3: ubiquitin protein isopeptide ligase * aa: amino acids * TIMP: tissue inhibitors of metalloproteinases * MCS: multiple cloning

site * DMSO: dimethyl sulphoxide * RCC: renal cell carcinoma * HRE: HIF response element * EF-IRES: elongation factor promoter-internal ribosome entry site * NES: nuclear export signal *

NLS: nuclear localization signal * DRB: 5,6-dichlorobenzimidazole ribososide * DMEM: Dulbecco's modified Eagle's medium * FCS: foetal calf serum REFERENCES * Clifford SC and Maher

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This work was supported in part by the National Health and Medical Research Council of Australia, Project Grant: 10365, awarded to BJ Roberts. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

School of Pharmaceutical, Molecular and Biomedical Sciences, Reid Building, University of South Australia, Frome Rd., Adelaide, 5000, Australia Martin D Lewis & Ben J Roberts Authors *

Martin D Lewis View author publications You can also search for this author inPubMed Google Scholar * Ben J Roberts View author publications You can also search for this author inPubMed 

Google Scholar CORRESPONDING AUTHOR Correspondence to Ben J Roberts. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lewis, M., Roberts, B. Role of the

C-terminal _α_-helical domain of the von Hippel–Lindau protein in its E3 ubiquitin ligase activity. _Oncogene_ 23, 2315–2323 (2004). https://doi.org/10.1038/sj.onc.1207384 Download citation

* Received: 14 April 2003 * Revised: 23 October 2003 * Accepted: 20 November 2003 * Published: 22 December 2003 * Issue Date: 25 March 2004 * DOI: https://doi.org/10.1038/sj.onc.1207384

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clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * VHL * HIF * ubiquitin * cancer