Figure 3.

Different actors involved in the induction of autophagy by hypoxia. In normoxia, HIF1-α is hydroxylated and degraded by proteasome. As the presence of dioxygen is favorable to cellular proliferation, receptor tyrosine kinases that promote proliferation are activated, leading to mTOR activation and autophagy inhibition. However, in hypoxia, HIF1-α is stabilized and it associates with HIF1-β to form HIF1 that activates the transcription of several genes whose encoded proteins activate autophagy. For example, REDD1 activates the mTOR inhibitors, thus removing the autophagy inhibition. BNIP3 can also activate autophagy by decreasing the RHEB/GTP level. Moreover, BNIP3 is a HIF1 target, and it competes with Beclin1 for binding to Bcl-2 or Bcl-x_L, triggering the Beclin1 release and the induction of autophagy. BNIP3 can also be induced by AMPK that is activated in response to hypoxia. AMPK can also activate ULK1 and LC3, thus triggering autophagy. In hypoxic conditions, the unfolded protein response (UPR) activates the transcription factor, ATF4, which in turn activates Atg7 and LC3, two proteins involved in the autophagosome elongation