n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems
n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems
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DOI：
10.1042/bj20070824
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发表时间：
2008-04-01
影响因子：
4.1
通讯作者：
Hirota, Kiichi
中科院分区：
文献类型：
--
作者：
Kimura, Motohide;Takabuchi, Satoshi;Hirota, Kiichi
缺氧诱导因子-1(HIF-1)是细胞对低氧适应性反应的主要调节因子。HIF-1α亚基的表达和转录活性受细胞内氧分压的严格控制，这些氧分压是通过脯氨酸基和天冬酰胺基羟基酶的作用实现的。在本研究中，我们证明了PG(没食子酸正丙酯)在常氧条件下激活HIF-1及其下游靶基因在培养细胞和小鼠中的表达。PG可提高HIF-1α的稳定性和转录活性。PG抑制HIF-1α与VHL(von Hippel-Lindau Protein)之间的相互作用，促进HIF-1α与p300之间的相互作用，表明PG同时抑制Pro和天冬酰胺基HIF-1α羟基酶的活性。我们认为PG通过直接影响体内和体外的细胞内氧感应系统来激活HIF-1并增强其基因表达，PG是开发无毒的HIF-1激活剂的先导化合物。
HIF-1 (hypoxia-inducible factor 1) is a master regulator of cellular adaptive responses to hypoxia. The expression and transcriptional activity of the HIF-1 alpha subunit is stringently controlled by intracellular oxygen tension through the action of prolyl and asparaginyl hydroxylases. In the present study we demonstrate that PG (n-propyl gallate) activates HIF-1 and expression of its downstream target genes under normoxic conditions in cultured cells and in mice. The stability and transcriptional activity of HIF-1 alpha are increased by PG. PG treatment inhibits the interaction between HIF-1 alpha and VHL (von Hippel-Lindau protein) and promotes the interaction between HIF-1 alpha and p300, indicating that PG inhibits the activity of both prolyl and asparaginyl HIF-1 alpha hydroxylases. We conclude that PG activates HIF-1 and enhances the resultant gene expression by directly affecting the intracellular oxygen sensing system in vitro and in vivo and that PG represents a lead compound for the development of a non-toxic activator of HIF-1.