TY - JOUR
T1 - Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1
AU - Zhang, Min
AU - Zhang, Jin
AU - Chen, Xiangling
AU - Cho, Seong Jun
AU - Chen, Xinbin
PY - 2013/10/15
Y1 - 2013/10/15
N2 - 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.
AB - 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.
KW - eIF4E
KW - eIF4G
KW - GSK3
KW - p53
KW - Rbm38
KW - RNPC1
UR - http://www.scopus.com/inward/record.url?scp=84885900730&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885900730&partnerID=8YFLogxK
U2 - 10.1101/gad.221739.113
DO - 10.1101/gad.221739.113
M3 - Article
C2 - 24142875
AN - SCOPUS:84885900730
VL - 27
SP - 2246
EP - 2258
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 20
ER -