Hypoxia-dependent regulation of PHD1: cloning and characterization of the human PHD1/EGLN2 gene promoter.
The recent identification of hypoxia-inducible-factor (HIF) prolyl hydroxylases (PHD1, 2, and 3), which modify HIF-1 alpha in an oxygen-dependent manner, provided an important link between oxygen availability and hypoxia-induced gene expression. However, little is known about the regulation of the PHDs. To investigate the transcriptional regulation of PHD1, we cloned the PHD1 gene promoter. Here, we report that the expression of PHD1 is reduced under hypoxic conditions. Furthermore, we identified binding sites for aryl hydrocarbon nuclear translocator (ARNT/HIF-1 beta) within the PHD1 promoter, and showed that ARNT is associated in vivo with the PHD1 promoter following hypoxia, which implies a role for ARNT in the hypoxia-dependent regulation of PHD1. Taken together, our findings suggest a hypoxia-induced regulatory loop of PHD1 expression, mediated by ARNT.
Erez
Neta
N
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Stambolsky
Perry
P
Shats
Igor
I
Milyavsky
Michael
M
Kachko
Tami
T
Rotter
Varda
V
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001483:Base Sequence; D001665:Binding Sites; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D003676:Deferoxamine / Q000494:pharmacology; D049308:Dioxygenases; D005786:Gene Expression Regulation; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000166:cytology; D009687:Nuclear Proteins / Q000235:genetics*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014162:Transfection
C497396:ARNT protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D049308:Dioxygenases; D011393:Procollagen-Proline Dioxygenase; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D003676:Deferoxamine