Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1).
The hypoxia-inducible factor 1 (HIF-1) plays a critical role in cellular responses to hypoxia. The aim of the present study was to evaluate which genes are induced by hypoxia, and whether this induction is mediated by HIF-1, by expression microarray analysis of wt and HIF-1alpha null mouse fibroblasts. Forty-five genes were up-regulated by hypoxia and 40 (89%) of these were regulated by HIF-1. Of the 114 genes down-regulated by hypoxia, 19 (17%) were HIF-1-dependent. All glycolytic enzymes were strongly up-regulated by hypoxia in a HIF-1-dependent manner. Genes already known to be related to hypoxia, such as glucose transporter 1, BNIP3, and hypoxia-induced gene 1, were induced. In addition, multiple new HIF-1-regulated genes were identified, including genes involved in metabolism (adenylate kinase 4, galactokinase), apoptosis (galectin-3 and gelsolin), and invasion (RhoA). Genes down-regulated by hypoxia were involved in cytoskeleton maintenance (Rho kinase), mRNA processing (heterogeneous nuclear ribonucleoprotein H1 and splicing factor), and DNA repair (REV3). Furthermore, seven cDNAs from genes with unknown function or expressed sequence tags (ESTs) were up-regulated and 27 such cDNAs were down-regulated. In conclusion, hypoxia causes down- rather than up-regulation of gene expression and HIF-1 seems to play a major role in the regulation of hypoxia-induced genes.
Greijer
A E
AE
Department of Pathology, VUMC, Amsterdam, The Netherlands. ae.greijer@vumc.nl
van der Groep
P
P
Kemming
D
D
Shvarts
A
A
Semenza
G L
GL
Meijer
G A
GA
van de Wiel
M A
MA
Belien
J A M
JA
van Diest
P J
PJ
van der Wall
E
E
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D003599:Cytoskeleton / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000502:physiology*; D005686:Galactokinase / Q000235:genetics; D037502:Galectin 3 / Q000235:genetics; D018260:Gelsolin / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D051272:Glucose Transporter Type 1; D006019:Glycolysis / Q000235:genetics; D000860:Hypoxia / Q000235:genetics*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000235:genetics
D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D005686:Galactokinase; D037502:Galectin 3; D018260:Gelsolin; D051272:Glucose Transporter Type 1; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D020742:rhoA GTP-Binding Protein; C090121:BNIP3 protein, human; C497443:Hif1a protein, mouse; C495678:Slc2a1 protein, mouse; C486862:REV3L protein, mouse