Figure 2: The intracellular HIF-1α regulation pathway in normoxia and hypoxia. Under normoxia, HIF-1α will be constituently ubiquitinated and subsequently degraded via proteasomal pathway after recruitment of von Hippel-Lindau protein (pVHL), which depends on the hydroxylation of proline residues on 564 and 402. However, under hypoxia, the praline hydroxylation of HIF-1α will be inhibited, HIF-1α will be translocated into the nucleus and combine with HIF-1β, then activate the transcription of a series of downstream genes including LDH-A, PDK1, GLUT-1, and VEGF. The levels of HIF-1α were also influenced by the PI3K/AKT pathway after stimulation of growth factors such as EGF and IGF.