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Differential responses of two degradation domains of HIF-1alpha to hypoxia and iron deficiency
Cited 15 time in
Web of Science
Cited 16 time in Scopus
- Authors
- Issue Date
- 2006
- Publisher
- Elsevier
- Citation
- Biochimie 88 (2006) 163-169
- Keywords
- Anoxia/*metabolism ; Cell Line ; Deferoxamine/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Iron/*deficiency/metabolism ; Oxygen/*metabolism ; Point Mutation ; Protein Structure, Tertiary ; RNA, Small Interfering/genetics/metabolism ; RNA, Small Interfering/genetics/metabolism
- Abstract
- HIF-1alpha is a transcription factor involved in the cellular adaptation to either hypoxia or iron deficiency. In the presence of oxygen and iron, proline residues in two degradation domains are modified by HIF-1-prolyl hydroxylases (PHDs), resulting in ubiquitination and degradation of HIF-1alpha. Since both molecular oxygen and iron are elements required for this hydroxylation process, HIF-1alpha might be unmodified and stable in conditions lacking oxygen or iron. If so, two degradation domains may respond to hypoxia and iron-depletion in the same way. In this study, however, we found two degradation domains to differentially regulate the stability of HIF-1alpha. The C-terminal domain responded to both hypoxia and iron-depletion, but the N-terminal domain to only iron-depletion. The deletion or point-mutation of the C-terminal domain blunted the hypoxic induction of HIF-1alpha. However, PHD-silencing siRNAs revealed that two degradation domains were not regulated by different types of PHDs. Both domains were regulated mainly by PHD2. The further mutational analysis demonstrated that the ARD1-acetylated motif near the C-terminal degradation domain (CDD) modulates the oxygen-dependent regulation of HIF-1alpha. The oxygen-dependent HIF-1alpha regulation requiring both proline hydroxylation and lysine acetylation may be more complicated than the iron-dependent regulation requiring only proline hydroxylation.
- ISSN
- 0300-9084 (Print)
- Language
- English
- URI
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16139409
https://hdl.handle.net/10371/24799
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