Figure 2.

Transcriptional regulation of autophagy by p53. Under basal conditions p53 is degraded by mouse double minute 2 homolog (Mdm2)-mediated proteasomal degradation. In response to stress, p53 undergoes post-translational modifications leading to its stabilization and activation. Upon activation, p53 can induce transcription of autophagy-related genes (only a selection is represented here). Group 1: BH3-only proteins and death-associated protein kinase 1 (DAPK1), all stimulate autophagy by favoring Beclin 1 displacement from B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma extra large (Bcl-X_L). Beclin 1 can contribute to p53 stabilization by stabilizing the deubiquitinating enzymes ubiquitin-specific peptidase 10/13 (USP10/13). Group 2: AMP-activated protein kinase (AMPK) subunits β1 and β2, AMPK activators Sestrin 1/2, negative regulators of mammalian target of rapamycin (mTOR), tuberous sclerosis 2 (TSC2), and DNA damage-inducible transcript 4 (Ddit4), all promote autophagy induction. AMPK can in turn phosphorylate and activate p53. Group 3: unc-51-like autophagy-activating kinase 1 (ULK1), unc-51-like autophagy-activating kinase 2 (ULK2), and damage-regulated autophagy modulator. Target 4: F-box/LRR-repeat protein 20 (FBXL20) negatively regulates autophagy by promoting vacuolar protein sorting 34 (Vps34) degradation. Target 5: Key autophagy protein autophagy-related gene 7 (Atg7) cooperates with p53 for p21 induction.