A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo

Yoji Andrew Minamishima, Javid Moslehi, Robert F. Padera, Roderick T. Bronson, Ronglih Liao, William G. Kaelin

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Hypoxia-inducible factor (HIF), consisting of a labile α subunit and a stable β subunit, is a master regulator of hypoxia-responsive mRNAs. HIFα undergoes oxygen-dependent prolyl hydroxylation, which marks it for polyubiquitination by a complex containing the von Hippel-Lindau protein (pVHL). Among the three Phd family members, Phd2 appears to be the primary HIF prolyl hydroxylase. Phd3 is induced by HIF and, based on findings from in vitro studies, may participate in a HIF-regulatory feedback loop. Here, we report that Phd3 loss exacerbates the HIF activation, hepatic steatosis, dilated cardiomyopathy, and premature mortality observed in mice lacking Phd2 alone and produces a closer phenocopy of the changes seen in mice lacking pVHL than the loss of Phd2 alone. Importantly, the degree to which Phd3 can compensate for Phd2 loss and the degree to which the combined loss of Phd2 and Phd3 resembles pVHL loss appear to differ for different HIF-responsive genes and in different tissues. These findings highlight that the responses of different HIF target genes to changes in prolyl hydroxylase activity differ, quantitatively and qualitatively, in vivo and have implications for the development of paralog-specific prolyl hydroxylase inhibitors as therapeutic agents.

Original languageEnglish
Pages (from-to)5729-5741
Number of pages13
JournalMolecular and cellular biology
Volume29
Issue number21
DOIs
Publication statusPublished - 2009 Nov 1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Minamishima, Y. A., Moslehi, J., Padera, R. F., Bronson, R. T., Liao, R., & Kaelin, W. G. (2009). A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Molecular and cellular biology, 29(21), 5729-5741. https://doi.org/10.1128/MCB.00331-09