Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression (PubMed:11573933, PubMed:16126907, PubMed:19694616, PubMed:20416395, PubMed:21069422). 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 (By similarity). Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Also inhibits hypoxia-inducible ARNT-mediated gene expression. Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Attenuates the ability of transcription factor HIF1A and EPAS1/HIF2A 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:16126907, PubMed:17998805, PubMed:19694616, PubMed:20416395). May act as a tumor suppressor and inhibits malignant cell transformation (PubMed:17998805). Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Isoform 2 interacts (via ODD domain) with VHL (via beta domain) (PubMed:12538644). Isoform 4 interacts with HIF1A; the interaction inhibits the binding of HIF1A to hypoxia-responsive element (HRE) and HIF1A/ARNT-dependent transcriptional activation (PubMed:16126907). Isoform 4 interacts with ARNT; the interaction occurs in a HIF1A- and DNA-binding-independent manner and does not induce HIF1A/ARNT-dependent transcriptional activation (PubMed:16126907). Isoform 4 interacts with EPAS1 (PubMed:17998805). Interacts with BAD, BCL2L2 and MCL1 (By similarity). In the nuclei of all periportal and perivenous hepatocytes. In the distal perivenous zone, detected in the cytoplasm of the hepatocytes. Shuttles between the nucleus and the cytoplasm in a CRM1-dependent manner. Colocalizes with BAD in the cytoplasm. Colocalizes with EPAS1 and HIF1A in the nucleus and speckles (By similarity). Localized in the cytoplasm and nuclei under normoxia, but increased in the nucleus under hypoxic conditions (PubMed:19694616). Colocalized with HIF1A in kidney tumors (PubMed:19694616). Additional isoforms seem to exist. Expressed in vascular cells (at protein level) (PubMed:21069422). Expressed in kidney (PubMed:11573933, PubMed:19694616). Expressed in lung epithelial cells (PubMed:16775626). Expressed in endothelial cells (venous and arterial cells from umbilical cord and aortic endothelial cells) and in vascular smooth muscle cells (aorta) (PubMed:21069422). Strongly expressed in the heart, placenta, and skeletal muscle, whereas a weak expression profile was found in the lung, liver, and kidney (PubMed:12538644). Expressed weakly in cell renal cell carcinoma (CC-RCC) compared to normal renal cells (PubMed:16126907). Expression is down-regulated in numerous kidney tumor cells compared to non tumor kidney tissues (PubMed:16126907). Isoform 2 is expressed in heart, placenta, lung, liver, skeletal muscle and pancreas and in numerous cancer cell lines (PubMed:20416395). Isoform 3 and isoform 4 are weakly expressed in heart, placenta, lung, liver, skeletal muscle and pancreas (PubMed:20416395). Isoform 4 is expressed in fetal tissues, such as heart, brain, thymus, lung, liver, skeletal kidney and spleen (PubMed:20416395). Isoform 3 is weakly expressed in fetal tissues, such as liver and kidney (PubMed:20416395). Up-regulated by hypoxia (at protein level) (PubMed:16775626). Induced by hypoxia (PubMed:16775626). Isoform 2, isoform 3, isoform 4 and isoform 5 are up-regulated by hypoxia in a HIF1A- and EPAS1/HIF2A-dependent manner (PubMed:19694616, PubMed:20416395, PubMed:21069422). Isoform 4 is down-regulated by hypoxia and up-regulated upon restoring normoxia in embryonic kidney cells (PubMed:16126907). In normoxia, hydroxylated on Pro-492 in the oxygen-dependent degradation domain (ODD) by prolyl hydroxylase(s) (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. Incomplete sequence. Incomplete sequence. Intron retention. Aberrant splicing site. Unlikely isoform. Aberrant splice sites. Intron retention. Intron retention. Intron retention. Hypoxia inducible factor entry