Fig. 4. The complex regulation of HIF-1. HIF-1 is activated by growth factors and cytokines through two main signalling pathways: PI3K/Akt (orange) and MAPK (blue). Nonetheless, in normoxic tissues, successive hydroxylations lead to (i) HIF-1 degradation by the 26S proteasome or to (ii) the inhibition of its transcriptional activity (blue arrows). Otherwise, interaction with the chaperone protein Hsp90 (for its dimerization) and co-factors such as p300/CEB (for the activation of its transcriptional activity) are also required.