S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Physiology (생리학교실) Journal Papers (저널논문_생리학교실)
Differential responses of two degradation domains of HIF-1alpha to hypoxia and iron deficiency
- Lee, Kyoung-Hwa; Choi, Eunjoo; Chun, Yang-Sook; Kim, Myung-Suk; Park, Jong-Wan
- Issue Date
- Biochimie 88 (2006) 163-169
- 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
- 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.
- 0300-9084 (Print)
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