The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia.
The Hypoxia-Inducible Factor-1 (HIF-1) activates the transcription of many genes required for cellular and organismal responses to oxygen deprivation. The HIF-1 complex is composed of the ubiquitously expressed basic helix-loop-helix/PAS (bHLH/PAS) proteins HIF-1alpha and Arylhydrocarbon Receptor Nuclear Translocator (ARNT). ARNT2 is a conserved ARNT homolog that is highly expressed in neurons, suggesting that ARNT2/HIF-1alpha heterodimers mediate transcriptional responses to oxygen deprivation in the nervous system. We show here that ARNT2 forms functional HIF complexes in vivo, and that ARNT2 restores hypoxia-induced gene expression to ARNT-deficient ES cells and hepatocytes. Formation of neural ARNT2/HIF-1alpha complexes in Arnt(-/-) ES cell-derived teratocarcinomas may explain why these tumors express VEGF, vascularize and grow efficiently, in contrast to ARNT-deficient hepatomas. Interestingly, all neural cell types studied accumulate both ARNT- and ARNT2-containing HIF complexes. We conclude that ARNT2 forms functional HIF complexes in neurons and plays an integral role in hypoxic responses in the CNS.
Maltepe
E
E
Section of Hematology and Oncology, Pritzker School of Medicine, Chicago, Illinois 60637, USA.
Keith
B
B
Arsham
A M
AM
Brorson
J R
JR
Simon
M C
MC
D000818:Animals; D000918:Antibody Specificity; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon; D017386:Sequence Homology, Amino Acid; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D018243:Teratocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C497398:ARNT protein, rat; C497397:Arnt protein, mouse; C099817:Arnt2 protein, mouse; C490991:Arnt2 protein, rat; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat