title: PPM1D phosphatase, a target of p53 and RBM38 RNA-binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38.
abstract: 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.
authors.affiliation: Comparative Oncology Laboratory, Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Comparative Oncology Laboratory, Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Xu
authors.affiliation: Comparative Oncology Laboratory, Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Comparative Oncology Laboratory, Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C515435:RBM38 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
references.citation: Cell Death Differ. 2006 Jul;13(7):1170-80
references.pmid: 16311512
references.citation: Genes Dev. 2005 May 15;19(10):1162-74
references.pmid: 15870257
references.citation: Mol Cell. 2006 Sep 1;23(5):757-64
references.pmid: 16949371
references.citation: Genes Dev. 2006 Nov 1;20(21):2961-72
references.pmid: 17050675
references.citation: Nat Protoc. 2006;1(2):577-80
references.pmid: 17406284
references.citation: Mol Cell Biol. 2007 May;27(10):3868-80
references.pmid: 17353261
references.citation: Cancer Cell. 2007 Oct;12(4):342-54
references.pmid: 17936559
references.citation: Oncogene. 2008 Feb 14;27(8):1036-44
references.pmid: 17700519
references.citation: Nat Genet. 2002 Jun;31(2):133-4
references.pmid: 12021784
references.citation: Cancer Res. 1994 Aug 15;54(16):4448-53
references.pmid: 8044794
references.citation: Curr Protoc Protein Sci. 2001 May;Chapter 3:Unit 3.7
references.pmid: 18429172
references.citation: Oncogene. 2013 Oct;32(40):4737-47
references.pmid: 23146903
references.citation: Genes Dev. 2013 Oct 15;27(20):2246-58
references.pmid: 24142875
references.citation: Nat Protoc. 2013 Nov;8(11):2281-308
references.pmid: 24157548
references.citation: PLoS One. 2013;8(10):e78031
references.pmid: 24250749
references.citation: Nat Chem Biol. 2014 Mar;10(3):181-7
references.pmid: 24390428
references.citation: Braz J Med Biol Res. 2014 Dec;47(12):1044-9
references.pmid: 25387670
references.citation: Cancer Genet Cytogenet. 2008 Apr 1;182(1):33-9
references.pmid: 18328948
references.citation: EMBO J. 2000 Dec 1;19(23):6517-26
references.pmid: 11101524
references.citation: Mol Cell. 2009 Mar 13;33(5):591-601
references.pmid: 19285943
references.citation: Clin Cancer Res. 2009 Apr 1;15(7):2269-80
references.pmid: 19293255
references.citation: Clin Cancer Res. 2009 Apr 15;15(8):2711-22
references.pmid: 19318498
references.citation: Nucleic Acids Res. 2010 Apr;38(7):2256-67
references.pmid: 20064878
references.citation: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9614-9
references.pmid: 20457941
references.citation: Genes Dev. 2011 Jul 15;25(14):1528-43
references.pmid: 21764855
references.citation: Nat Commun. 2011;2:513
references.pmid: 22027593
references.citation: J Biol Chem. 2012 Apr 27;287(18):14535-44
references.pmid: 22371495
references.citation: Mol Cell Biol. 2012 Jul;32(13):2336-48
references.pmid: 22508983
references.citation: Mol Cancer Res. 2012 Sep;10(9):1169-77
references.pmid: 22798430
references.citation: Nature. 2013 Jan 17;493(7432):406-10
references.pmid: 23242139
references.citation: Oncogene. 2013 Apr 25;32(17):2169-78
references.pmid: 22710720
references.citation: J Cell Biol. 2013 May 13;201(4):511-21
references.pmid: 23649806
references.citation: J Biol Chem. 2013 Aug 16;288(33):23680-6
references.pmid: 23836903
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6048-53
references.pmid: 9177166
references.citation: Mol Carcinog. 2006 Aug;45(8):594-604
references.pmid: 16652371