Figure 1
From: Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule
Regulation of the HIF pathway by oxygen dependant and independent mechanisms (a) Under normoxia, prolyl hydroxylase domain proteins use oxygen and α-ketoglutarate as substrates to hydroxylate conserved proline residues on HIF-α subunits. This allows binding of the VHL protein which recruits an ubiquitin ligase complex via Elongin C, leading to HIF-α ubiquitination and proteosomal degradation8. Oxygen-independent control of HIF is mediated by RACK1 which also recruits Elongin C and directs the HIF-α subunits to the proteasome. PI3K/AKT/mTOR and MAPK pathways can increase translation of HIF-α mRNA in an oxygen-independent manner11. In hypoxia, stabilised HIF-α subunits dimerise with HIF-β subunits enabling interaction with HREs in a wide range of gene promoters in the nucleus. The resulting pattern of transcription drives cellular responses to hypoxia such as angiogenesis and metabolic reprogramming and can up-regulate the expression of multiple genes that contribute to cancer progression through survival, metastasis and invasion13. (b) Structure of CL67.
