n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems.
HIF-1 (hypoxia-inducible factor 1) is a master regulator of cellular adaptive responses to hypoxia. The expression and transcriptional activity of the HIF-1alpha 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-1alpha are increased by PG. PG treatment inhibits the interaction between HIF-1alpha and VHL (von Hippel-Lindau protein) and promotes the interaction between HIF-1alpha and p300, indicating that PG inhibits the activity of both prolyl and asparaginyl HIF-1alpha 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.
Kimura
Motohide
M
Department of Surgery, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.
Takabuchi
Satoshi
S
Tanaka
Tomoharu
T
Murata
Miyahiko
M
Nishi
Kenichiro
K
Oda
Seiko
S
Oda
Tomoyuki
T
Kanai
Michiyuki
M
Fukuda
Kazuhiko
K
Kizaka-Kondoh
Shinae
S
Adachi
Takehiko
T
Takabayashi
Arimichi
A
Semenza
Gregg L
GL
Hirota
Kiichi
K
D000818:Animals; D002460:Cell Line; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D011435:Propyl Gallate / Q000494:pharmacology*; D014162:Transfection; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D011435:Propyl Gallate; D050880:p300-CBP Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D010100:Oxygen