Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor

• Mircea Ivan

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• Thomas Haberberger

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• David C. Gervasi

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• Kristen S. Michelson

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• Volkmar Günzler

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• Keiichi Kondo

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• Haifeng Yang

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• Irina Sorokina

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• Ronald C. Conaway

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• Joan W. Conaway

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

• William G. Kaelin

  Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; FibroGen, Inc., South San Francisco, CA 94080; Stowers Research Institute, Kansas City, MO 64110; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

抄録

The product of the von Hippel–Lindau gene, pVHL, targets the α subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitination in the presence of oxygen. The binding of pVHL to HIF is governed by the enzymatic hydroxylation of conserved prolyl residues within peptidic motifs present in the HIFα family members. By using a biochemical purification strategy, we have identified a human homolog of Caenorhabditis elegans Egl9 as a HIF prolyl hydroxylase. In addition, we studied the activity of a structurally diverse collection of low molecular weight inhibitors of procollagen prolyl 4-hydroxylase as potential inhibitors of the HIF hydroxylase. A model compound of this series stabilized HIF in a variety of cells, leading to the increased production of its downstream target, vascular endothelial growth factor.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 99 (21), 13459-13464, 2002-09-26

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361418520459325568
• NII論文ID: 80015599730
• DOI: 10.1073/pnas.192342099
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.192342099
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