| 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. |
| Keywords: |
controlled study; protein expression; unclassified drug; human cell; nonhuman; animal cell; mouse; animals; mice; mice, knockout; cells, cultured; proteasome; ubiquitin protein ligase; embryo; protein degradation; protein targeting; animal model; rna interference; hemoglobin; transcription, genetic; hela cells; mice, inbred c57bl; animalia; transcription factors; nuclear proteins; hypoxia; gene expression regulation; blotting, western; regulatory mechanism; reverse transcriptase polymerase chain reaction; fibroblast; fibroblasts; cell hypoxia; hypoxia inducible factor 1alpha; ubiquitin-protein ligases; hypoxia-inducible factor 1, alpha subunit; spectrometry, mass, matrix-assisted laser desorption-ionization; degradation; null cell; procollagen proline 2 oxoglutarate 4 dioxygenase; precipitin tests; humans; human; male; female; priority journal; article; ubiquitin protein ligase siah 1a; ubiquitin protein ligase siah 2; hyperpnea; procollagen-proline dioxygenase
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