Integration of oxygen signaling at the consensus HRE.
The hypoxia-inducible factor 1 (HIF-1) was initially identified as a transcription factor that regulated erythropoietin gene expression in response to a decrease in oxygen availability in kidney tissue. Subsequently, a family of oxygen-dependent protein hydroxylases was found to regulate the abundance and activity of three oxygen-sensitive HIFalpha subunits, which, as part of the HIF heterodimer, regulated the transcription of at least 70 different effector genes. In addition to responding to a decrease in tissue oxygenation, HIF is proactively induced, even under normoxic conditions, in response to stimuli that lead to cell growth, ultimately leading to higher oxygen consumption. The growing cell thus profits from an anticipatory increase in HIF-dependent target gene expression. Growth stimuli-activated signaling pathways that influence the abundance and activity of HIFs include pathways in which kinases are activated and pathways in which reactive oxygen species are liberated. These pathways signal to the HIF protein hydroxylases, as well as to HIF itself, by means of covalent or redox modifications and protein-protein interactions. The final point of integration of all of these pathways is the hypoxia-response element (HRE) of effector genes. Here, we provide comprehensive compilations of the known growth stimuli that promote increases in HIF abundance, of protein-protein interactions involving HIF, and of the known HIF effector genes. The consensus HRE derived from a comparison of the HREs of these HIF effectors will be useful for identification of novel HIF target genes, design of oxygen-regulated gene therapy, and prediction of effects of future drugs targeting the HIF system.
Wenger
Roland H
RH
Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, CH-8057 Zürich, Switzerland. roland.wenger@access.unizh.ch
Stiehl
Daniel P
DP
Camenisch
Gieri
G
D000818:Animals; D002455:Cell Division; D015687:Cell Hypoxia / Q000502:physiology*; D016384:Consensus Sequence; D004249:DNA Damage; D015195:Drug Design; D044127:Epigenesis, Genetic; D005544:Forecasting; D005786:Gene Expression Regulation / Q000502:physiology*; D015316:Genetic Therapy; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006899:Mixed Function Oxygenases; D008954:Models, Biological; D010100:Oxygen / Q000502:physiology*; D011393:Procollagen-Proline Dioxygenase / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D021122:Protein Subunits; D017382:Reactive Oxygen Species / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
D051793:Hypoxia-Inducible Factor 1; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014157:Transcription Factors; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D011393:Procollagen-Proline Dioxygenase; D011494:Protein Kinases; D010100:Oxygen