title: Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1.
abstract: The RNPC1 RNA-binding protein, also called Rbm38, is a target of p53 and a repressor of p53 mRNA translation. Thus, the p53-RNPC1 loop is critical for modulating p53 tumor suppression, but it is not clear how the loop is regulated. Here, we showed that RNPC1 is phosphorylated at Ser195 by glycogen synthase kinase 3 (GSK3). We also showed that GSK3 promotes p53 mRNA translation through phosphorylation of RNPC1. Interestingly, we found that the phosphor-mimetic mutant S195D and the deletion mutant Δ189-204, which lacks the GSK3 phosphorylation site, are unable to repress p53 mRNA translation due to loss of interaction with eukaryotic translation factor eIF4E on p53 mRNA. Additionally, we found that phosphorylated RNPC1, RNPC1-S195D, and RNPC1(Δ189-204) promote p53 mRNA translation through interaction with eukaryotic translation factor eIF4G, which then facilitates the assembly of the eIF4F complex on p53 mRNA. Furthermore, we showed that upon inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, GSK3 is activated, leading to increased RNPC1 phosphorylation and increased p53 expression in a RNPC1-dependent manner. Together, we postulate that the p53-RNPC1 loop can be explored to increase or decrease p53 activity for cancer therapy.
authors.affiliation: Comparative Oncology Laboratory, University of California at Davis, Davis, California 95616, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiangling
authors.initials: X
authors.lastname: Chen
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Cho
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C515435:RBM38 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: GSK3; RNPC1; Rbm38; eIF4E; eIF4G; p53