Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, PubMed:20624928, PubMed:22009797, PubMed:30125331, PubMed:9887100). Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, PubMed:22009797, PubMed:30125331, PubMed:9887100). Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797).

Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 (PubMed:16543236, PubMed:9887100). Activity is enhanced by interaction with NCOA1 and/or NCOA2 (PubMed:10594042).

Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP (PubMed:10202154, PubMed:10594042). Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (PubMed:19528298)

Interacts with the ARNT; forms a heterodimer that binds core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (PubMed:10944113, PubMed:20699359). Interacts with COPS5; the interaction increases the transcriptional activity of HIF1A through increased stability (By similarity). Interacts with EP300 (via TAZ-type 1 domains); the interaction is stimulated in response to hypoxia and inhibited by CITED2 (PubMed:11959990, PubMed:12778114, PubMed:16543236, PubMed:16973622, PubMed:8917528, PubMed:9887100).

Interacts with CREBBP (via TAZ-type 1 domains) (PubMed:11959977, PubMed:8917528). Interacts with NCOA1, NCOA2, APEX1 and HSP90 (PubMed:10202154, PubMed:10594042). Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF1A proteasomal degradation (PubMed:14757845).

During hypoxia, sumoylated HIF1A also binds VHL; the interaction promotes the ubiquitination of HIF1A (PubMed:10944113, PubMed:11006129, PubMed:12004076, PubMed:12050673, PubMed:16862177). Interacts with SENP1; the interaction desumoylates HIF1A resulting in stabilization and activation of transcription (By similarity). Interacts (via the ODD domain) with NAA10; the interaction appears not to acetylate HIF1A nor have any affect on protein stability, during hypoxia (PubMed:12464182, PubMed:16288748).

Interacts with RWDD3; the interaction enhances HIF1A sumoylation (PubMed:17956732, PubMed:23469069). Interacts with TSGA10 (By similarity). Interacts with HIF3A (By similarity).

Interacts with RORA (via the DNA binding domain); the interaction enhances HIF1A transcription under hypoxia through increasing protein stability (PubMed:18658046). Interaction with PSMA7 inhibits the transactivation activity of HIF1A under both normoxic and hypoxia-mimicking conditions (PubMed:11389899). Interacts with USP20 (PubMed:15776016).

Interacts with RACK1; promotes HIF1A ubiquitination and proteasome-mediated degradation (PubMed:17244529). Interacts (via N-terminus) with USP19 (PubMed:22128162). Interacts with SIRT2 (PubMed:24681946).

Interacts (deacetylated form) with EGLN1 (PubMed:24681946). Interacts with CBFA2T3 (PubMed:25974097). Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842).

Interacts with DCUN1D1; this interaction increases the interaction between VHL and DCUN1D1 (PubMed:23401859). Interacts with HIF1AN (PubMed:12446723)

Expressed in most tissues with highest levels in kidney and heart. Overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. A higher level expression seen in pituitary tumors as compared to the pituitary gland

Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID)