Identification of nonsense-mediated mRNA decay pathway as a critical regulator of p53 isoform ?.

ABSTRACT: Human TP53 gene encodes the tumor suppressor p53 and, via alternative splicing, the p53? and ? isoforms. Numerous studies have shown that p53?/? can modulate p53 functions and are critically involved in regulation of cellular response to stress conditions. However, it is not fully understood how the ? and ? isoforms are regulated following splicing. Using gene targeting and RNAi, we showed that depletion of the nonsense-mediated mRNA decay (NMD) factor SMG7 or UPF1 significantly induced p53? but had minimal effect on p53?. Sequence analysis reveals the presence of unique features - key hallmarks of NMD targets in the p53? transcript, which was further confirmed in NMD reporter gene assays. By manipulating splicing components, we found that NMD activities are crucial to control p53? levels under conditions that favor its splicing. Our data demonstrate that the NMD and alternative splicing pathways regulate p53? in a synergistic manner, and NMD plays a critical role in the determination of the p53? following its splicing. As aberrant p53? expression and dysfunctional NMD are both implicated in cancers, our studies may provide a novel insight into the regulation of p53? in tumorigenic settings.

SUBMITTER: Cowen LE 

PROVIDER: S-EPMC5727530 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature