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NO donor, SNAP activates HIF‐1α in prolyl‐ and asparaginyl‐hydroxylation‐independent mechanism
Author(s) -
Lee Hoyoul,
Oh Myoungsuk,
Park YoungKwon,
Lee Taekyoung,
Park Hyunsung
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb82-d
By using molecular oxygen, proline (402 and 564 th ) residues and asparagine (803 rd ) residue of HIF‐1α are hydroxylated by Proline Hydroxylase Domain 2 (PHD2) and Factor‐Inhibiting HIF‐1α (FIH‐1), respectively. The proline hydroxylation of HIF‐1α leads to the interaction with VHL E3 ligase, while asparagine hydroxylation inhibits the interaction with its coactivator CBP/p300. Therefore HIF‐1α can be activated when both hydroxylases are inhibited. We found that NO donor, (±)‐S‐nitroso‐N‐acetylpenicillamine (SNAP) stabilizes HIF‐1α and activates its target genes, vascular endothelial growth factor and carbonic anhydrase 9 in cGMP‐independent pathway. We found that in the presence of SNAP, HIF‐1α is not ubiquitinated and able to interact with CBP. The presence of SNAP fails to inhibit the hydroxylation activities of both purified PHD2 and purified FIH‐1 in vitro, suggesting that SNAP activates HIF‐1α not by directly inhibiting both PHD2 and FIH‐1. [This study was supported by a grant (2004‐01967) from the Molecular and Cellular BioDiscovery Research Program and a grant (2004‐01969) from the Neurobiology Research Program]