FIGURE 3.

HIF-1α regulation under normoxia and hypoxia. I. Normoxia represents pO₂ > 40 mm Hg. (A) Under normal oxygen tension, PHD2 (prolylhydroxylase-2) hydroxylates HIF-1α at proline residues P402 and P564 and Factor Inhibiting HIF-1α hydroxylates HIF-1α at asparagine residue N803. in presence of O2 as substrate, Oxoglutarate as co-substrate and Fe as cofactor. (B) Prolyl Hydroxylation of HIF-1α allows for binding of pVHL to NTAD ( N-terminal transactivation domain) of HIF-1α. Binding of pVHL recruits ubiquitinin by activation of E3- ubiquitinin ligase which marks HIF-1α for proteasomal degradation. (C) HIF-1α is degraded by 26S proteasome thus preventing stabilization and accumulation of HIF-1α. Asparginyl hydroxylation of HIF-1α at CTAD (C-terminal transactivation domain) prevents binding of CBP/P300 to the CTAD (CH- 1 domain) and thereby inhibiting downstream mechanism involved in HIF-1α transactivation. II. Hypoxia represents pO₂ < 40 mmHg. (A) Under hypoxia HIF-1α escapes degradation and gets stabilized since PHD2 enzymes which are responsible for its proteasomal degradation are inhibited. (B) Stabilized HIF-1α gets accumulated in the cytosol till the oxygen tension reaches the level (pO₂> 10 mmHg) that it becomes limiting for FIH-1, such that CBP/P300 proteins are able to bind to CTAD. (C) HIF-1α translocate into the nucleus to bind with β-subunit that is constitutively expressed in the nucleus. HIF-1α further binds with hypoxia response element on targeted gene and trigger gene transcription.