Translational repression of p53 by RNPC1,a p53 target over expressed in lymphomas

Jin Zhang, Seong Jun Cho, Limin Shu, Wensheng Yan, Teri Guerrero, Michael S Kent, Katherine A Skorupski, Hongwu Chen, Xinbin Chen

Research output: Contribution to journalArticle

73 Scopus citations

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 p53mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53mRNA. 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' or3' UTR. Moreover, we showed that loss of RNPC1 in mouse embryonic fibroblasts increased the level of p53protein, 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 over expressed in dog lymphomas, most of which were accompanied by decreased expression of wild-type p53. Together, we identified a novel p53-RNPC1autoregulatory loop, and our findings suggest that RNPC1 plays a role in tumori genesis by repressing p53translation.

Original languageEnglish (US)
Pages (from-to)1528-1543
Number of pages16
JournalGenes and Development
Volume25
Issue number14
DOIs
StatePublished - Jul 15 2011

Keywords

  • eIF4E
  • P53
  • RBM38
  • RNA-binding protein
  • RNPC1
  • Translational control

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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