TY - JOUR T1 - Mammalian-unique eIF4E2 maintains GSK3β proline kinase activity to resist senescence against hypoxia JF - bioRxiv DO - 10.1101/2020.10.20.346569 SP - 2020.10.20.346569 AU - Min zhang AU - Lei Sun AU - Dong He AU - Jian Chen AU - Zhiqiang Dong AU - Huiting Liang AU - Yu Cao AU - Bingcheng Cai AU - He Yang Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/21/2020.10.20.346569.abstract N2 - Cellular senescence is a stable state of cell cycle arrest elicited by various stresses. Hypoxia modulates senescence, but its consequences and implications in living organisms remains unknown. Here we identified the eIF4E2-GSK3β pathway regulated by hypoxia to maintain p53 proline-directed phosphorylation (S/T-P) to prevent senescence. We previously knew that GSK3β activates p53 translation through phosphorylation of RBM38 Ser195 (-Pro196). Unexpectedly, eIF4E2 directly binds to GSK3β via a conserved motif, mediating Ser195 phosphorylation. Phosphoproteomics revealed that eIF4E2-GSK3β specifically regulates proline-directed phosphorylation. Peptide e2-I or G3-I that disrupts this pathway dephosphorylates p53 at multiple S/T-P, which accelerate senescence by transcriptional suppressing TOPBP1 and TRX1. Consistently, peptides induce liver senescence that is rescued by TOPBP1 expression, and mediate senescence-dependent tumor regression. Furthermore, hypoxia inhibits eIF4E2-GSK3β. Inspiringly, eIF4E2-GSK3β is unique to mammals, which maintains mice viability and prevents liver senescence against physiological hypoxia. Interestingly, this mammalian eIF4E2 protects heart of zebrafish against hypoxia. Together, we identified a mammalian -unique eIF4E2-GSK3β pathway preventing senescence and guarding against hypoxia in vivo. ER -