n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems

Motohide Kimura, Satoshi Takabuchi, Tomoharu Tanaka, Miyahiko Murata, Kenichiro Nishi, Seiko Oda, Tomoyuki Oda, Michiyuki Kanai, Kazuhiko Fukuda, Shinae Kizaka-Kondoh, Takehiko Adachi, Arimichi Takabayashi, Gregg L. Semenza, Kiichi Hirota

Research output: Contribution to journalArticle

Abstract

HIF-1 (hypoxia-inducible factor 1) is a master regulator of cellular adaptive responses to hypoxia. The expression and transcriptional activity of the HIF-1α 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-1α are increased by PG. PG treatment inhibits the interaction between HIF-1α and VHL (von Hippel-Lindau protein) and promotes the interaction between HIF-1α and p300, indicating that PG inhibits the activity of both prolyl and asparaginyl HIF-1α 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.

Original languageEnglish (US)
Pages (from-to)97-105
Number of pages9
JournalBiochemical Journal
Volume411
Issue number1
DOIs
StatePublished - Apr 1 2008

Keywords

  • Erythropoietin
  • Hypoxia-inducible factor 1α (HIF-1α) hydroxylase
  • Intestinal trefoil factor
  • Vascular endothelial growth factor (VEGF)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kimura, M., Takabuchi, S., Tanaka, T., Murata, M., Nishi, K., Oda, S., Oda, T., Kanai, M., Fukuda, K., Kizaka-Kondoh, S., Adachi, T., Takabayashi, A., Semenza, G. L., & Hirota, K. (2008). n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems. Biochemical Journal, 411(1), 97-105. https://doi.org/10.1042/BJ20070824