A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis
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- Melanie J. Percy
- Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Haematology, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Haematology, Queen's University, Belfast BT9 7AB, Northern Ireland, United Kingdom; and Renal Section, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom
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- Quan Zhao
- Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Haematology, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Haematology, Queen's University, Belfast BT9 7AB, Northern Ireland, United Kingdom; and Renal Section, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom
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- Adrian Flores
- Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Haematology, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Haematology, Queen's University, Belfast BT9 7AB, Northern Ireland, United Kingdom; and Renal Section, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom
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- Claire Harrison
- Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Haematology, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Haematology, Queen's University, Belfast BT9 7AB, Northern Ireland, United Kingdom; and Renal Section, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom
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- Terence R. J. Lappin
- Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Haematology, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Haematology, Queen's University, Belfast BT9 7AB, Northern Ireland, United Kingdom; and Renal Section, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom
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- Patrick H. Maxwell
- Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Haematology, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Haematology, Queen's University, Belfast BT9 7AB, Northern Ireland, United Kingdom; and Renal Section, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom
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- Mary Frances McMullin
- Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Haematology, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Haematology, Queen's University, Belfast BT9 7AB, Northern Ireland, United Kingdom; and Renal Section, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom
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- Frank S. Lee
- Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Haematology, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Haematology, Queen's University, Belfast BT9 7AB, Northern Ireland, United Kingdom; and Renal Section, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom
書誌事項
- 公開日
- 2006-01-09
- DOI
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- 10.1073/pnas.0508423103
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p>The number of red blood cells is normally tightly regulated by a classic homeostatic mechanism based on oxygen sensing in the kidney. Decreased oxygen delivery resulting from anemia induces the production of erythropoietin, which increases red cell production and hence oxygen delivery. Investigations of erythropoietin regulation identified the transcription factor hypoxia-inducible factor (HIF). HIF is now recognized as being a key regulator of genes that function in a comprehensive range of processes besides erythropoiesis, including energy metabolism and angiogenesis. HIF itself is regulated through the α-subunit, which is hydroxylated in the presence of oxygen by a family of three prolyl hydroxylase domain proteins (PHDs)/HIF prolyl hydroxylases/egg-laying-defective nine enzymes. Hydroxylation allows capture by the von Hippel–Lindau tumor suppressor gene product, ubiquitination, and destruction by the proteasome. Here we describe an inherited mutation in a mammalian PHD enzyme. We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis, identifying a previously unrecognized cause of this condition. Our findings indicate that PHD2 is critical for normal regulation of HIF in humans.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 103 (3), 654-659, 2006-01-09
Proceedings of the National Academy of Sciences
