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Molecular and Cellular Biology, November 2009, p. 5729-5741, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00331-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo{triangledown} ,{dagger}

Yoji Andrew Minamishima,1 Javid Moslehi,1,2 Robert F. Padera,3 Roderick T. Bronson,4 Ronglih Liao,2 and William G. Kaelin Jr.1,5*

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 Division of Cardiovascular Medicine, Department of Medicine,2 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,3 Rodent Histopathology Core, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,4 Howard Hughes Medical Institute, Chevy Chase, Maryland 208155

Received 14 March 2009/ Returned for modification 16 May 2009/ Accepted 22 August 2009

Hypoxia-inducible factor (HIF), consisting of a labile {alpha} subunit and a stable β subunit, is a master regulator of hypoxia-responsive mRNAs. HIF{alpha} 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.

* Corresponding author. Mailing address: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115. Phone: (617) 632-3975. Fax: (617) 632-4760. E-mail: william_kaelin{at}dfci.harvard.edu

{triangledown} Published ahead of print on 31 August 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2009, p. 5729-5741, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00331-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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