title: Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas.
abstract: The p53 pathway is critical for tumor suppression, as the majority of human cancer has a faulty p53. Here, we identified RNPC1, a p53 target and a RNA-binding protein, as a critical regulator of p53 translation. We showed that ectopic expression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 translation under normal and stress conditions. We also showed that RNPC1 prevented cap-binding protein eIF4E from binding p53 mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53 mRNA. Consistent with this, we found that RNPC1 directly binds to p53 5' and 3'untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 5' or 3' UTR. Moreover, we showed that loss of RNPC1 in mouse embryonic fibroblasts increased the level of p53 protein, leading to enhanced premature senescence in a p53-dependent manner. Finally, to explore the clinical relevance of our finding, we showed that RNPC1 was frequently overexpressed in dog lymphomas, most of which were accompanied by decreased expression of wild-type p53. Together, we identified a novel p53-RNPC1 autoregulatory loop, and our findings suggest that RNPC1 plays a role in tumorigenesis by repressing p53 translation.
authors.affiliation: Comparative Cancer Center, Schools of Medicine and Veterinary Medicine, University of California at Davis, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Cho
authors.forename: Limin
authors.initials: L
authors.lastname: Shu
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yan
authors.forename: Teri
authors.initials: T
authors.lastname: Guerrero
authors.forename: Michael
authors.initials: M
authors.lastname: Kent
authors.forename: Katherine
authors.initials: K
authors.lastname: Skorupski
authors.forename: Hongwu
authors.initials: H
authors.lastname: Chen
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004285:Dogs; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008223:Lymphoma / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D011072:Poly U / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions; C515435:RBM38 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C547649:Rbm38 protein, mouse; D016159:Tumor Suppressor Protein p53; D011072:Poly U