Figure 1.

Autophagy regulation. Growth factor signaling activates the PI3K/AKT/mTOR axis resulting in autophagy inhibition. In contrast, class III PI3K activates autophagy. Low cellular energy levels with increased AMP/ATP ratio activate the LKB1-AMPK-mTOR pathway to also upregulate autophagy. Furthermore, increased calcium ion levels induce autophagy by two mechanisms, i.e., the Ca²⁺-CaMKKβ-AMPK pathway and direct Ca²⁺-induced ER stress. p53 exhibits complex autophagy regulation, as nuclear p53 activated by genotoxic or oncogenic stress positively regulates autophagy by inhibiting mTOR in an activated AMPK- and TSC1/TSC2-dependent manner, whereas cytoplasmic p53 can suppress autophagy.