Journal article
Siah2 Regulates Stability of Prolyl-Hydroxylases, Controls HIF1α Abundance, and Modulates Physiological Responses to Hypoxia
Cell (Cambridge), Vol.117(7), pp.941-952
2004
DOI: 10.1016/j.cell.2004.06.001
PMID: 15210114
Abstract
Hypoxia-inducible factor-1α (HIF1α) is a central regulator of the cellular response to hypoxia. Prolyl-hydroxylation of HIF1α by PHD enzymes is prerequisite for HIF1α degradation. Here, we demonstrate that the abundance of PHD1 and PHD3 are regulated via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases Siah1a/2, under hypoxia conditions.
Siah2 null fibroblasts exhibit prolonged PHD3 half-life, resulting in lower levels of HIF1α expression during hypoxia. Significantly, hypoxia-induced HIF1α expression was completely inhibited in
Siah1a/2 null cells, yet could be rescued upon inhibition of PHD3 by RNAi. Siah2 targeting of PHD3 for degradation increases upon exposure to even mild hypoxic conditions, which coincides with increased
Siah2 transcription.
Siah2 null mice subjected to hypoxia displayed an impaired hyperpneic respiratory response and reduced levels of hemoglobin. Thus, the control of PHD1/3 by Siah1a/2 constitutes another level of complexity in the regulation of HIF1α during hypoxia.
Details
- Title: Subtitle
- Siah2 Regulates Stability of Prolyl-Hydroxylases, Controls HIF1α Abundance, and Modulates Physiological Responses to Hypoxia
- Creators
- Koh Nakayama - Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029 USAIan J Frew - Peter MacCallum Cancer Institute, Melbourne 3002, Victoria, AustraliaMette Hagensen - Department of Zoology, La Trobe University, Melbourne 3086, AustraliaMarianne Skals - Department of Zoology, La Trobe University, Melbourne 3086, AustraliaHasem Habelhah - Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029 USAAnindita Bhoumik - Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029 USATakayuki Kadoya - Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029 USAHediye Erdjument-Bromage - Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021 USAPaul Tempst - Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021 USAPeter B Frappell - Department of Zoology, La Trobe University, Melbourne 3086, AustraliaDavid D Bowtell - Peter MacCallum Cancer Institute, Melbourne 3002, Victoria, AustraliaZe'ev Ronai - Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029 USA
- Resource Type
- Journal article
- Publication Details
- Cell (Cambridge), Vol.117(7), pp.941-952
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.cell.2004.06.001
- PMID
- 15210114
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Language
- English
- Date published
- 2004
- Academic Unit
- Pathology
- Record Identifier
- 9984046806902771
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