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.