Hypoxia-inducible factor 1-alpha C-terminal transactivation domain (HIF-1α C-TAD)

The Hypoxia-inducible factor 1-alpha C-terminal transactivation domain (HIF-1α C-TAD) is a specialized regulatory region (residues 786–826) of the HIF-1α protein that mediates the cellular transcriptional response to low oxygen levels [UniProt P41231]. Under hypoxic conditions, the C-TAD becomes available to bind the CH1 domain of the co-activators p300 and CREB-binding protein (CBP), a process regulated by the hydroxylation of Asparagine-803 by Factor Inhibiting HIF (FIH) [PubMed: 11836526]. This interaction is essential for the induction of over 100 genes involved in erythropoiesis, angiogenesis, and anaerobic metabolism, which are vital for cell survival in oxygen-deprived environments [PubMed: 11292088]. In many solid tumors, HIF-1α is overexpressed to facilitate adaptation to the hypoxic tumor microenvironment, driving metastasis and resistance to conventional therapies [PubMed: 12110602]. Consequently, the HIF-1α C-TAD/p300 interaction has emerged as a high-value therapeutic target. Small molecules like Chetomin and various peptidomimetics are being developed to disrupt this specific protein-protein interaction, thereby inhibiting tumor growth and vascularization [PubMed: 15314656].

Other names

HIF-1-alpha C-TADHIF1A C-TADC-terminal activation domain of HIF-1αHIF-1α CADHIF-1α C-terminal activation domain

Disruption of the protein-protein interaction between the HIF-1α C-TAD and the CH1 domain of transcriptional co-activators p300/CBP, thereby preventing the assembly of the functional transcriptional complex and inhibiting the expression of hypoxia-responsive genes.