Binding and regulation of hypoxia-inducible factor-1 by the inhibitory PAS proteins.
Hypoxia-inducible factor-1 (HIF-1), which consists of oxygen-sensitive HIF-1alpha and constitutively expressed HIF-1beta subunits, activates transcription of genes encoding proteins that mediate adaptive responses to reduced oxygen availability. The mouse inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) functions as a negative regulator in HIF-mediated gene expression. In this report, we cloned the human orthologs of the mouse IPAS gene, IPASH1 and IPASH2, to further study the regulatory mechanism of HIF-1 by the IPAS proteins. The human IPAS proteins inhibited the transactivation function of HIF-1alpha under hypoxic conditions. In addition, human IPAS proteins blocked the hypoxia-induced VEGF expression and inhibited cell migration and tube formation of human umbilical vein endothelial cells. Interestingly, both HIF-1alpha and HIF-1beta interacted with the IPAS proteins. Collectively, these results suggest that human IPAS proteins inhibit angiogenesis by binding to and inhibiting HIF-1alpha and HIF-1beta.
Jang
Mi Sun
MS
Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 305-333, Republic of Korea.
Park
Jae Eun
JE
Lee
Jung A
JA
Park
Sung Goo
SG
Myung
Pyung Keun
PK
Lee
Do Hee
DH
Park
Byoung Chul
BC
Cho
Sayeon
S
D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D015687:Cell Hypoxia; D002460:Cell Line; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D051017:Apoptosis Regulatory Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C497396:ARNT protein, human; C497397:Arnt protein, mouse; C497442:HIF1A protein, human; C116973:HIF3A protein, human; C444643:Hif3a protein, mouse