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 59 and 39untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 59 or 39 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.

p73 Expression Is Regulated by RNPC1, a Target of the p53 Family, via mRNA Stability

“…While p73 transcription and protein stability have been extensively investigated, little is known about whether p73 is regulated by posttranscriptional mechanisms, such as mRNA stability. Previously, we showed that RNPC1 is a target of members of the p53 family, including p73 (31,44,45). In this study, we further found that ectopic expression of TAp73␣ or TAp73␤ increased the expression of RNPC1 in SW480 and p53 Ϫ/Ϫ HCT116 cells ( Fig.…”

“…Previously, we showed that RNPC1 is a target of the p53 family, including p73, and in turn, RNPC1 posttranscriptionally regulates the p53 family, including p53 and p63 (31,44,45). Here we further found that ectopic expression of p73 increases RNPC1 expression whereas knockdown of p73 decreases it (Fig.…”

“…RNA-binding proteins generally contain one or more RNA-binding domains along with auxiliary domains for protein-protein interaction and subcellular targeting (43). Previously, we showed that RNPC1, an RNA-binding protein and a target of the p53 family, is capable of posttranscriptionally regulating members of the p53 family, including p53 and p63 (44,45). In addition, RNPC1 is able to stabilize p21 transcripts and, consequently, to suppress cell growth (5,19,24,31).…”

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

“…The other possibility is that Ninj1-mediated signals may modulate the assembly of translation initiation complex such as eIF4F complex (4E+4G+4A), eIF4B, and poly(A)-binding protein (33). For example, RNPC1, also called Rbm38, is a p53 target, which, in turn, represses p53 mRNA translation by preventing eIF4E from binding to p53 mRNA (22).…”

Serine 123 Phosphorylation Modulates p21 Protein Stability and Activity by Suppressing Ubiquitin-independent Proteasomal Degradation

“…Cell Line Generation-Cf2Th cells that can inducibly express HA-tagged wild-type dog p21, dog p21(S123A), and dog p21(S123D), were generated by using a Tet-on inducible system as described previously (33,34). Briefly, pcDNA4 vectors containing HA-tagged wild-type dog p21, dog p21(S123A), or dog p21(S123D) were transfected into Cf2Th cells expressing a tetracycline repressor (pcDNA6).…”