期刊
AUTOPHAGY
卷 17, 期 11, 页码 3776-3793出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2021.1897961
关键词
AKT1; autophagy; FBXO22; hormesis; KDM4B; MYC; TP53; ubiquitination
类别
资金
- Japan Agency for Medical Research and Development [16ck0106085h0003, JP17gm5010001, JP17fk0310111, JP17cm0106122]
- Japan Society for the Promotion of Science [JP16K15239, 17K08676, JP26250027, JP22118003, JP24112005, 17H03585, JP16H06148, JP18H05026m, JP16K15238]
- Ono Medical Research Foundation
- RELAY FOR LIFE JAPAN CANCER SOCIETY
- Princess Takamatsu Cancer Research Fund
- Grants-in-Aid for Scientific Research [17H03585, 17K08676] Funding Source: KAKEN
The study demonstrates that TP53 upregulates basal autophagy through the FBXO22-TFEB axis, governing the hormetic effect in chemotherapy.
Preconditioning with a mild stressor such as fasting is a promising way to reduce severe side effects from subsequent chemo- or radiotherapy. However, the underlying mechanisms have been largely unexplored. Here, we demonstrate that the TP53/p53-FBXO22-TFEB (transcription factor EB) axis plays an essential role in this process through upregulating basal macroautophagy/autophagy. Mild stress-activated TP53 transcriptionally induced FBXO22, which in turn ubiquitinated KDM4B (lysine-specific demethylase 4B) complexed with MYC-NCOR1 suppressors for degradation, leading to transcriptional induction of TFEB. Upregulation of autophagy-related genes by increased TFEB dramatically enhanced autophagic activity and cell survival upon following a severe stressor. Mitogen-induced AKT1 activation counteracted this process through the phosphorylation of KDM4B, which inhibited FBXO22-mediated ubiquitination. Additionally, fbxo22(-/-) mice died within 10 h of birth, and their mouse embryonic fibroblasts (MEFs) showed a lowered basal autophagy, whereas FBXO22-overexpressing mice were resistant to chemotherapy. Taken together, these results suggest that TP53 upregulates basal autophagy through the FBXO22-TFEB axis, which governs the hormetic effect in chemotherapy.
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