PUBLICATION
Mammalian eIF4E2-GSK3β maintains basal phosphorylation of p53 to resist senescence under hypoxia
- Authors
- Sun, L., Yang, H., He, D., Chen, J., Dong, Z., Luo, S., Liang, H., Cao, Y., Cai, B., Zhang, M.
- ID
- ZDB-PUB-220516-2
- Date
- 2022
- Source
- Cell Death & Disease 13: 459 (Journal)
- Registered Authors
- Dong, Zhiqiang
- Keywords
- none
- MeSH Terms
-
- Animals
- Eukaryotic Initiation Factor-4E*/genetics
- Eukaryotic Initiation Factor-4E*/metabolism
- Glycogen Synthase Kinase 3 beta/genetics
- Glycogen Synthase Kinase 3 beta/metabolism
- Hypoxia
- Mammals
- Phosphorylation
- Tumor Suppressor Protein p53*/genetics
- Tumor Suppressor Protein p53*/metabolism
- Zebrafish/metabolism
- PubMed
- 35568694 Full text @ Cell Death Dis.
Citation
Sun, L., Yang, H., He, D., Chen, J., Dong, Z., Luo, S., Liang, H., Cao, Y., Cai, B., Zhang, M. (2022) Mammalian eIF4E2-GSK3β maintains basal phosphorylation of p53 to resist senescence under hypoxia. Cell Death & Disease. 13:459.
Abstract
Hypoxia modulates senescence, but their physiological link remains unclear. Here, we found that eIF4E2, a hypoxia-activated translation initiation factor, interacted with GSK3β to maintain phosphorylation of p53, thus resisting senescence under hypoxia. RNA-binding protein RBM38 interacted with eIF4E to inhibit the translation of p53, but GSK3β-mediated Ser195 phosphorylation disrupted the RBM38-eIF4E interaction. Through investigation of RBM38 phosphorylation, we found that the eIF4E2-GSK3β pathway specifically regulated proline-directed serine/threonine phosphorylation (S/T-P). Importantly, peptides e2-I or G3-I that blocking eIF4E2-GSK3β interaction can inhibit the basal S/T-P phosphorylation of p53 at multiple sites, therby inducing senescence through transcriptional inhibition. Additionally, a nanobody was screened via the domain where eIF4E2 bound to GSK3β, and this nanobody inhibited S/T-P phosphorylation to promote senescence. Furthermore, hypoxia inhibited eIF4E2-GSK3β pathway by mediating S-Nitrosylation of GSK3β. Blocking eIF4E2-GSK3β interaction promoted liver senescence under hypoxia, thus leading to liver fibrosis, eventually accelerating N, N-diethylnitrosamine (DEN)-induced tumorigenesis. Interestingly, eIF4E2 isoforms with GSK3β-binding motif exclusively exist in mammals, which protect zebrafish heart against hypoxia. Together, this study reveals a mammalian eIF4E2-GSK3β pathway that prevents senescence by maintaining basal S/T-P phosphorylation of p53, which underlies hypoxia adaptation of tissues.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping