| RRC ID |
81411
|
| Author |
Suzuki N, Johmura Y, Wang TW, Migita T, Wu W, Noguchi R, Yamaguchi K, Furukawa Y, Nakamura S, Miyoshi I, Yoshimori T, Ohta T, Nakanishi M.
|
| Title |
TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis.
|
| Journal |
Autophagy
|
| Abstract |
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.Abbreviations: BBC3/PUMA: BCL2 binding component 3; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; ChIP-seq: chromatin immunoprecipitation followed by sequencing; DDB2: damage specific DNA binding protein 2; DRAM: DNA damage regulated autophagy modulator; ESR/ER: estrogen receptor 1; FMD: fasting mimicking diet; HCQ: hydroxychloroquine; KDM4B: lysine-specific demethylase 4B; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; NCOR1: nuclear receptor corepressor 1; SCF: SKP1-CUL-F-box protein; SQSTM1: sequestosome 1; TFEB: transcription factor EB.
|
| Volume |
17(11)
|
| Pages |
3776-3793
|
| Published |
2021-11-1
|
| DOI |
10.1080/15548627.2021.1897961
|
| PMID |
33706682
|
| PMC |
PMC8632335
|
| MeSH |
Animals
Autophagy*
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology
Cells, Cultured
F-Box Proteins / metabolism*
F-Box Proteins / physiology
Female
Fibroblasts / metabolism
Hormesis*
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, Cytoplasmic and Nuclear / metabolism*
Receptors, Cytoplasmic and Nuclear / physiology
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Protein p53 / physiology
Ubiquitination
|
| IF |
9.77
|
| Resource |
| DNA material |
CS-RfA-ETBsd (RDB07917)
CSII-CMV-MCS (RDB04377)
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394) |
