Acts as a transcriptional regulator in adaptive response to low oxygen tension. Attenuates the ability of transcription factor HIF1A, EPAS1 and the HIF1A-ARNT complex to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis. May act as a tumor suppressor. Interacts with ARNT, BAD, BCL2L2, EPAS1, HIF1A, MCL1 and VHL. In the nuclei of all periportal and perivenous hepatocytes. In the distal perivenous zone, detected in the cytoplasm of the hepatocytes (PubMed:11237857). Localized in the cytoplasm and nuclei under normoxia, but increased in the nucleus under hypoxic conditions. Colocalized with HIF1A in kidney tumors. Colocalizes with BAD in the cytoplasm. Colocalizes with EPAS1 and HIF1A in the nucleus and speckles. Shuttles between the nucleus and the cytoplasm in a CRM1-dependent manner. Expressed in the perivenous zone of the liver (PubMed:11237857). Expressed in all tissues examined during normoxia (PubMed:12824304). Expressed in brain and lung. Expressed in periportal and perivenous hepatocytes and in endothelial cells of the central vein (at protein level) (PubMed:11237857). Expressed in the perivenous zone of the liver (PubMed:11237857). Highest expression seen in the cerebral cortex, hippocampus, and lung. Low expression in myocardial tissue and liver (PubMed:12824304). Up-regulated by hypoxia. In normoxia, hydroxylated on Pro-487 in the oxygen-dependent degradation domain (ODD) by PHD. The hydroxylated proline promotes interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-dependent pathway and subsequently targeted for proteasomal degradation.