PPM1D phosphatase, a target of p53 and RBM38 RNA-binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

Gene Expression Regulation, Neoplastic*; Breast Neoplasms/*metabolism ; Colonic Neoplasms/*metabolism ; Phosphoprotein Phosphatases/*metabolism ; RNA, Messenger/*metabolism ; RNA-Binding Proteins/*metabolism ; Tumor Suppressor Protein p53/*metabolism; 3' Untranslated Regions/genetics ; Blotting, Western ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Female ; Flow Cytometry ; Humans ; Immunoenzyme Techniques ; Immunoprecipitation ; Phosphoprotein Phosphatases/antagonists & inhibitors ; Phosphoprotein Phosphatases/genetics ; Phosphorylation ; Protein Phosphatase 2C ; RNA Processing, Post-Transcriptional ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; RNA-Binding Proteins/antagonists & inhibitors ; RNA-Binding Proteins/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/antagonists & inhibitors ; Tumor Suppressor Protein p53/genetics

PPM1D phosphatase, also called wild-type p53-induced phosphatase 1, promotes tumor development by inactivating the p53 tumor suppressor pathway. RBM38 RNA-binding protein, also called RNPC1 and a target of p53, inhibits p53 messenger RNA (mRNA) translation, which can be reversed by GSK3 protein kinase via phosphorylation of RBM38 at serine 195. Here we showed that ectopic expression of RBM38 increases, whereas knockdown of RBM38 inhibits, PPM1D mRNA translation. Consistent with this, we found that RBM38 directly binds to PPM1D 3'-untranslated region (3'-UTR) and promotes expression of a heterologous reporter gene that carries PPM1D 3'-UTR in a dose-dependent manner. Interestingly, we showed that PPM1D directly interacts with and dephosphorylates RBM38 at serine 195. Furthermore, we showed that PPM1D modulates p53 mRNA translation and p53-dependent growth suppression through dephosphorylation of RBM38. These findings provide evidence that the crosstalk between PPM1D and RBM38, both of which are targets and modulators of p53, has a critical role in p53 expression and activity.

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R01 CA121137 United States CA NCI NIH HHS; CA076069 United States CA NCI NIH HHS; R01 CA081237 United States CA NCI NIH HHS; CA121137 United States CA NCI NIH HHS; R01 CA076069 United States CA NCI NIH HHS; R29 CA076069 United States CA NCI NIH HHS; CA081237 United States CA NCI NIH HHS

0 (3' Untranslated Regions)
0 (RBM38 protein, human)
0 (RNA, Messenger)
0 (RNA, Small Interfering)
0 (RNA-Binding Proteins)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
EC 3.1.3.16 (PPM1D protein, human)
EC 3.1.3.16 (Phosphoprotein Phosphatases)
EC 3.1.3.16 (Protein Phosphatase 2C)

Date Created: 20150331 Date Completed: 20160308 Latest Revision: 20181113

20221213

PMC4589422

10.1038/onc.2015.31

25823026