HIF3

Hypoxia-inducible factor 3 (HIF-3) refers to the third member of the hypoxia-inducible factor family of transcription factors. The HIF3A gene encodes the HIF-3 alpha subunit, which can dimerize with ARNT (HIF-1β) to form HIF-3 complexes that bind hypoxia response elements in DNA. Multiple isoforms arise from alternative splicing and promoter usage; some isoforms retain the DNA-binding and dimerization domains but lack the C-terminal transactivation domain, and some may function as dominant-negative regulators of HIF-1 and HIF-2 by competing for ARNT and DNA binding.

Functionally, HIF-3 is thought to modulate the cellular response to hypoxia rather than acting as a primary activator. In hypoxic conditions, HIF-1 and HIF-2 are typically activated to drive target genes; HIF-3 can influence this pathway by repressing or selectively regulating gene expression under certain contexts and tissues. The full spectrum of HIF-3 target genes remains an area of active research.

Expression patterns show HIF3A transcripts in a range of human tissues, including the placenta, brain, lung, and adipose tissue, with levels influenced by developmental stage and physiological conditions. In disease settings, alterations in HIF3A expression have been reported in some cancers and metabolic disorders, but the precise implications are not yet settled.

See also: Hypoxia-inducible factor, HIF-1, HIF-2, ARNT.