Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 699, Issue 1-3, Pages 124-131Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2012.12.008
Keywords
Hypoxia inducible factor-1; HIF-prolyl hydroxylase; Piceatannol; Colitis; Structural analysis
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Funding
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [2009-0071594]
- National Research Foundation of Korea [2009-0071594] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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To investigate the mechanisms underlying the biological activity of piceatannol (PCT), a hydroxystilbene natural product that has anti-colitic properties, we examined whether PCT could modulate hypoxia-inducible factor (HIF)-1 activity in human colon carcinoma cells. PCT induced HIF-1 alpha protein, leading to induction of its target gene products, vascular endothelial growth factor and heme oxygenase-1, which are involved in amelioration of colitis. PCT induction of HIF-1 alpha resulted from HIF-1 alpha protein stabilization, which occurred through inhibition of HIF-prolyl hydroxylase-2 (HPH-2). PCT inhibition of HPH-2 was reversed by addition of ascorbate, a cofactor of HPH-2, but not the cosubstrate, 2-ketoglutarate, to the reaction mixture of an in vitro von Hippel-Lindau (VHL) capture assay, and pretreatment with ascorbate abrogated PCT induction of cellular HIF-1 alpha. Moreover, PCT prevented hydroxylation of cellular HIF-1 alpha and attenuated coimmunoprecipitation of Flag-VHL protein and HA-HIF-1 alpha over-expressed in human embryonic kidney 293 cells. Structural analysis using derivatives of PCT revealed that the catechol moiety in PCT was required for the stabilization of HIF-1 alpha protein. Taken together, PCT activation of HIF-1 resulting from inhibition of HPH-2 may be a molecular mechanism for an anti-colitic effect of the natural product. (C) 2012 Elsevier B.V. All rights reserved.
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