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

Abstract

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.

Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

“…ª 2020 The Authors EMBO Molecular Medicine 12: e10895 | 2020 transcriptome profile induced by FST317 overexpression was distinct from that induced by FST344 overexpression (Appendix Fig S5A, Table EV2). Specifically, the differentially expressed gene RAS oncogene family like 6 (RABL6, also known as RBEL1 and C9orf86) (Hagen et al, 2014), CD93 (Iwasaki et al, 2015), and Zinc Finger Protein 709 (ZNF709) (Yan et al, 2016) have been implicated in cancers and leukemia. Upregulation of PRTFDC1 and PODXL2 expression was correlated with poor survival of AML, whereas downregulation of CCNL1 and RP11-762I7.5 was correlated with poor survival of AML (Appendix Fig S5B).…”

Comparison of quantitative faecal immunochemical tests for haemoglobin (FIT) for asymptomatic population screening

“…Interestingly, our laboratory recently demonstrated that PCBP4, a KH domain containing RBP and target of p53 (44), indirectly regulates p53 protein levels by modulating the mRNA stability of ZNF709. Knockout of PCBP4 led to increased ZNF709 protein expression ultimately leading to decreased p53 via a proteasome-dependent degradation pathway (45). These lines of evidence further solidify the overwhelming complexity of p53 regulation and open up the possibility for potential therapeutic intervention by modulating the regulation of p53 by RBP's.…”

TAp63γ and ΔNp63γ are regulated by RBM38 via mRNA stability and have an opposing function in growth suppression

“…The p21 3’UTR, known to contain an RBM38-binding site, was used as positive control (Figure 3B , lanes 11-12) [ 19 , 22 ]. The ZFP871 3’UTR [ 28 ] without an RBM38-binding site was used as negative control (Figure 3C ). Furthermore, we found that the probe E-protein complex was super-shifted with anti-RBM38 (Figure 3D ) or inhibited by an excess amount of cold p21 probe (Figure 3E ).…”

“…p63γ 3’UTRs were PCR-amplified using forward primers containing T7 promoter sequence and reverse primers as listed in Table 1 . The p21 [ 19 ] and ZFP871 [ 28 ] probes were generated as previously described and used as positive and negative control, respectively. RNA probes were made from in vitro transcription with T7 RNA polymerase in the presence of α- 32 P-UTP.…”