論文 - 詳細
| RRC ID | 81411 |
|---|---|
| 著者 | 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. |
| タイトル | TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis. |
| ジャーナル | 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. |
| 巻・号 | 17(11) |
| ページ | 3776-3793 |
| 公開日 | 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | CS-RfA-ETBsd (RDB07917) CSII-CMV-MCS (RDB04377) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) |