HIF-1: master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs.
The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O2 concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O2 homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. We will introduce the different actors involved in HIF-1 regulation, and their mechanisms of action via invalidation by siRNAs and discuss therapies targeting HIF-1, to selectively kill tumor cells that adapt to low O2 concentrations.
Institute of Signaling, Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France.
Nathalie M
NM
Mazure
M Christiane
MC
Brahimi-Horn
Mélanie A
MA
Berta
Emmanuel
E
Benizri
Rebecca L
RL
Bilton
Frédéric
F
Dayan
Amandine
A
Ginouvès
Edurne
E
Berra
Jacques
J
Pouysségur
D000818:Animals; D015687:Cell Hypoxia; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*; D015398:Signal Transduction; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C080681:TRIM23 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D009569:Nitric Oxide; D011393:Procollagen-Proline Dioxygenase; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019204:GTP-Binding Proteins; C497446:VHL protein, human; D010100:Oxygen