Hypoxic inhibition of 3-methylcholanthrene-induced CYP1A1 expression is independent of HIF-1alpha.
Hypoxia-inducible factor-1alpha (HIF-1alpha) and aryl hydrocarbon receptor (AhR) both require dimerization with AhR nuclear translocator (ARNT) to initiate transcription of their respective target genes. It has been proposed that competition for ARNT results in decreased targeting of AhR to cytochrome P450 1A1 (CYP1A1) under hypoxia. We established primary cultures of HIF-1alpha null hepatocytes to examine the interaction between HIF-1alpha and AhR signaling. Gene expression of known HIF targets phosphoglycerate kinase (PGK), vascular endothelial growth factor (VEGF) and glucose transporter-1 (GLUT-1) increased under hypoxia, but was reduced in the HIF null cultures. Concomitant treatment of cultures with hypoxia (1% O2) and 3-methylcholanthrene (an AhR ligand) did not significantly alter HIF target gene expression. Furthermore, enzymatic activity and transcription of CYP1A1 was inhibited by hypoxia in HIF-1alpha null cultures, indicating that HIF-1alpha is not directly involved in negative regulation of AhR signaling.
Allen
Jared W
JW
Division of Biological Sciences, Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
Johnson
Randall S
RS
Bhatia
Sangeeta N
SN
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D015687:Cell Hypoxia / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051272:Glucose Transporter Type 1; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D018336:Receptors, Aryl Hydrocarbon; C495678:Slc2a1 protein, mouse; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1