HIF pathway. In the presence of oxygen, PHDs catalyze the post-translational modification of HIF-1, causing the immediate binding of the von Hippel-Lindau tumor-suppressor protein (pVHL). pVHL binding, in turn, recruits binding of elongin-B, elongin-C, CUL-2,30 and RBX-1. Upon hydroxylation of Pro402 and Pro564 within the ODD of HIF-1, the VHL/elongin complex, in concert with ubiquitin-activating (E1) and ubiquitin-conjugating (E2) enzymes, mediates the ubiquitination of HIF-1, leading to subsequent degradation in the proteasome. Under hypoxia, the O2-requiring prolyl hydroxylases cannot modify HIF-1 and the protein remains stable. Stabilized HIF-1 translocates into the nucleus, where it dimerizes with HIF-1 and cofactors such as CBP/p300 and the DNA polymerase II complex to bind to HREs and activate gene transcription.
Additional keywords: hypoxia,normoxia,prolyl hydroxylase,HiF-1alpha