Figure 3.

Pathways of autophagy induction by hypoxia and mutant RAS. (A) During hypoxia, autophagy is activated by sensors that detect low oxygen, unfolded proteins, and energy depletion. Low oxygen induces autophagy involving the HIF1α-mediated up-regulation of BNIP3 and BNIP3L. They compete with Bcl-2 for interaction with Beclin 1, and orient Beclin 1 to autophagosomes. AMPK is a major regulator of energy homeostasis. The kinase is sensitive to the AMP/ATP ratio: binding of AMP activates AMPK and induces phosphorylation by the tumor suppressor LKB1. Activation of AMPK inhibits mTOR-dependent signaling. Inhibition of mTOR induces autophagy. In addition, autophagy may be induced during hypoxia as a result of signals generated by the PERK-ATF4 mediated unfolded protein response in the endoplasmic reticulum. (B) The induction of autophagy by oncogenes such as mutant Ras is importance in tumorigenesis. Ras mutant activates the ROS-dependent JNK signaling pathway and upregulates the Atg5 gene to induce autophagy. Under certain circumstances, Ras mutant activates the MEK/ERK signaling pathway and upregulates the Beclin1 gene to induce autophagic cell death.