Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression (PubMed:9840812, PubMed:11734856, PubMed:21546903). Plays a role in the development of the cardiorespiratory system (PubMed:18070924). Acts as positive regulator of hypoxia-inducible gene expression. Associates to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters in a ARNT-dependent manner, and hence also participates in the transcriptional activation of reporter genes driven by HRE (PubMed:9840812). 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. May act as a tumor suppressor (PubMed:11734856). May also be involved in apoptosis (PubMed:21546903). 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 (PubMed:18070924). Also plays a role in the development of the lung and heart during embryonic and neonatal stages (PubMed:18070924). Isoform 1 interacts with ARNT (PubMed:9840812). Isoform 2 interacts with HIF1A (PubMed:11734856, PubMed:21546903). Isoform 2 interacts EPAS1 (PubMed:21546903). Isoform 2 interacts (via C-terminus domain) with BAD; the interaction reduces the binding between BAD and BAX (PubMed:21546903). Isoform 2 (via C-terminus domain) interacts with BCL2L2 and MCL1 (PubMed:21546903). Interacts with VHL (By similarity). In the nuclei of all periportal and perivenous hepatocytes. In the distal perivenous zone, detected in the cytoplasm of the hepatocytes. 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 (PubMed:21546903). Colocalizes with EPAS1 and HIF1A in the nucleus and speckles (PubMed:21546903). Shuttles between the nucleus and the cytoplasm in a CRM1-dependent manner (PubMed:24092767). Isoform 3 is expressed in endothelial cells of vessels and capillaries in alveoli of the neonatal lung (at protein level) (PubMed:18070924). Expressed in lung, brain, heart and kidney (PubMed:9840812). Isoform 2 is expressed in heart and lung (PubMed:12119283). Isoform 2 is highly expressed in the epithelial cell layer of the cornea with lower expression in the layers of ganglion cells, inner nuclear cells, and rods and cones of the retina (PubMed:11734856). Isoform 2 is expressed in the cerebellum only in the Purkinje cell layer (PubMed:11734856). Isoform 3 is expressed in brain, heart, lung, liver and kidney at 15.5 dpc. Isoform 3 is expressed in heart, lung, liver and kidney at 18.5 dpc. Isoform 2 is up-regulated in corneal epithelium cells under hypoxia (at protein level) (PubMed:11734856). Isoform 2 is up-regulated by hypoxia in a HIF1A-dependent manner (PubMed:12119283, PubMed:17355974). Isoform 3 is up-regulated by hypoxia (PubMed:18070924). Contains a nuclear localization signal between amino acid positions 75 and 98. Contains a nuclear export signal between amino acid positions 228 and 272. 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 (By similarity). Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-dependent pathway and subsequently targeted for proteasomal degradation. Mice appeared outwardly normal and are viable and fertile. Show hypertrophy of the right atrium and ventricle, disarrangement of striated muscle fibers in the heart, and pulmonary hyperplasia (PubMed:18070924). Mutagenesis of Lys-75, Arg-76, Arg-97 and Arg-98 increase strongly cytoplasmic localization. Mutagenesis of Pro-228, Pro-229, Leu-271 and Leu-272 increase strongly nuclear localization.