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. 2016 Feb 20;7(14):17591–17607. doi: 10.18632/oncotarget.7540

Figure 1. The major pathways involved in the activation of autophagy under hypoxic stress.

Figure 1

Under hypoxia, the stabilization of HIF-1α leads to its translocation to the nucleus and a rapid induction of the BH3-only proteins (BNIP3 and BNIP3L) through its binding to the hypoxia response element in the promoter of BNIP3. The induction of BNIP3 and BNIP3L displaces Beclin1 from Bcl-2, leading to the induction of autophagy (1). The activation of autophagy by UPR involves PERK which detects unfolded protein. The activation of PERK induces ATF4 via phospho-EIF2α and regulates the expression of LC3 and ATG5, two essential components of the autophagy machinery (2). Autophagy can also be induced during hypoxia following an increase in the intracellular ADP/ATP ratio. This leads to the activation of AMPK which subsequently activates autophagy directly or indirectly through the inhibition of mTOR (3).