Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress

Lee, I. H., Kawai, Y., Fergusson, M. M., Rovira, II, Bishop, A. J., Motoyama, N., Cao, L., Finkel, T. Science 336, 225. 2012

Speaker: Wan-Ting Kuo (郭琬婷)                                 Time: 15:00-16:00. May.1, 2013

Commentator: Dr. Chih-Peng Chang (張志鵬老師)    Location: Room 601

Abstract:

Atg7 is an essential gene of autophagy and has E1-like enzymatic activity. Along with prolonged nutrient deprivation, cell death and autophagy are simultaneously activated. However, how autophagy interacts with cell cycle progression or apoptotic cell death remains unclear. In this study, the authors demonstrated that Atg7 modulate p53 to trigger cell cycle arrest in the cell. Moreover, cell lacking Atg7 displayed increased p53-mediated cell death. To clarify the relationship between cell cycle progression and autophagy, the authors investigated the S-phase of cell cycle under nutrient withdrawal conditions between wild-type Atg7 (+/+) and Atg7 (-/-) mouse embryonic fibroblasts. They found that Atg7-p53 complex regulated p21 promoter activity to trigger cell cycle arrest. The authors confirmed that Atg7 is specific for cell cycle arrest and p21 but not for other autophagy related genes such as Beclin-1 and Atg5. The authors analyzed the interaction between Atg7 and p53, and showed that the TET domain of p53 mediates the interaction of Atg7. The ability of Atg7 binding p53 to regulate transcription of p21 is E1-like enzymatic function independent. In addition, when withdrawal of nutrients, cells lacking Atg7 increased phosphorylation of p53 at Ser²⁰ and activated DNA damage response pathway. According to previous study, Beclin1 and Atg5 deficiency exhibited increased DNA damage and reactive oxygen species (ROS). In this study, MEF-Atg7 (-/-) showed high level of ROS under basal and starved conditions. Thus, the treatment of wild-type-Atg7 (+/+) and Atg7 (-/-)-MEF with N-acetyl cysteine (NAC) to reduce ROS produced. The authors found that NAC inhibited ROS and resulted in phosphorylated p53 and decrease of DNA damage. Taken together, ROS triggers p53-mediated cell death pathways in MEF-Atg7 (-/-). After γ irradiation induced DNA damage, a protein kinase Chk2 is activated and directly phosphorylates p53 on serine 20 for increased stability of p53 (1). The authors revealed the increase of pro-apoptotic gene expression in Atg7-deficient cells. In conclusion, p53 and Atg7 directly bind to each other to regulate p21 expression, which triggers cell cycle arrest after withdrawal of nutrients.

Reference:

1.      Hirao, A., Kong, Y. Y., Matsuoka, S et al., (2000). DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science, 287, 1824-1827.