Mice deficient in poly(C)-binding protein 4 are susceptible to spontaneous tumors through increased expression of ZFP871 that targets p53 for degradation

Poly(C)-binding protein 4 (PCBP4), also called MCG10 and a target of p53, plays a role in the cell cycle and is implicated in lung tumor suppression. Here, we found that PCBP4-deficient mice are prone to lung adenocarcinoma, lymphoma, and kidney tumor and that PCBP4-deficient mouse embryo fibroblasts (MEFs) exhibit enhanced cell proliferation but decreased cellular senescence. We also found that p53 expression is markedly reduced in PCBP4-deficient MEFs and mouse tissues, suggesting that PCBP4 in turn regulates p53 expression. To determine how PCBP4 regulates p53 expression, PCBP4 targets were identified by RNA immunoprecipitation followed by RNA sequencing (RNA-seq). We found that the transcript encoding ZFP871 (zinc finger protein 871; also called ZNF709 in humans) interacts with and is regulated by PCBP4 via mRNA stability. Additionally, we found that ZFP871 physically interacts with p53 and MDM2 proteins. Consistently, ectopic expression of ZFP871 decreases—whereas knockdown of ZFP871 increases—p53 protein stability through a proteasome-dependent degradation pathway. Moreover, loss of ZFP871 reverses the reduction of p53 expression by lack of PCBP4, and thus increased expression of ZFP871 is responsible for decreased expression of p53 in the PCBP4-deficient MEFs and mouse tissues. Interestingly, we found that, like PCBP4, ZFP871 is also regulated by DNA damage and p53. Finally, we showed that knockdown of ZFP871 markedly enhances p53 expression, leading to growth suppression and apoptosis in a p53-dependent manner. Thus, the p53–PCBP4–ZFP871 axis represents a novel feedback loop in the p53 pathway. Together, we hypothesize that PCBP4 is a potential tissue-specific tumor suppressor and that ZFP871 is part of MDM2 and possibly other ubiquitin E3 ligases that target p53 for degradation.