Mice Deficient in the RNA-Binding Protein Zfp871 Are Prone to Early Death and Steatohepatitis in Part through the p53-Mdm2 Axis.

Abstract

p53 transcription factor is activated upon exposure to various cellular stresses, leading to growth suppression. However, aberrant activation of p53 can lead to defects in embryonic development and other abnormalities. Here, we identified zinc finger protein Zfp871 as a p53 target gene. We showed that as an RNA-binding protein, Zfp871 binds to Mdm2 3'UTR and stabilizes Mdm2 mRNA, which in turn suppresses p53 expression through increased expression of Mdm2 E3 ubiquitin ligase. Consistently, Zfp871 deficiency increases p53 expression, leading to growth suppression in a p53-dependent manner. To determine the role of Zfp871 in the p53 pathway, we used Zfp871-deficient mouse model and found that Zfp871-null mice were prone to embryonic/pre-weaning lethality, which can be partially rescued by simultaneous deletion of Trp53. We also found that mice heterozygous for Zfp871 had a short lifespan and were susceptible to steatohepatitis but not to spontaneous tumors. To determine the underlying mechanism, RNA-seq analysis was performed and showed that an array of genes involved in development, lipid metabolism, and inflammation is regulated by Zfp871 in conjunction with p53. Taken together, we conclude that the Zfp871-Mdm2-p53 pathway plays a critical role in tumor-free survival and development. IMPLICATIONS: A fine equilibrium of p53 is required for preventing damaging effects of aberrant p53 expression. We identify the Zfp871-Mdm2-p53 pathway that plays a critical role in development of mice and steatohepatitis.

• Authors: Shakur Mohibi, Jin Zhang, Mingyi Chen, Xinbin Chen
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 19 Issue 10 Pg. 1751-1762 (10 2021) ISSN: 1557-3125 [Electronic] United States
• PMID: 34257081 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• 3' Untranslated Regions
• DNA-Binding Proteins
• RNA-Binding Proteins
• TP53 protein, human
• Trp53 protein, mouse
• Tumor Suppressor Protein p53
• ZFP871 protein, mouse
• MDM2 protein, human
• Mdm2 protein, mouse
• Proto-Oncogene Proteins c-mdm2
• Ubiquitin-Protein Ligases

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Cell Line, Tumor
• Cell Proliferation (genetics)
• DNA-Binding Proteins (genetics)
• Embryonic Development (genetics)
• Fatty Liver (genetics)
• HCT116 Cells
• Humans
• MCF-7 Cells
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins c-mdm2 (genetics)
• RNA-Binding Proteins (genetics)
• Signal Transduction (genetics)
• Tumor Suppressor Protein p53 (genetics)
• Ubiquitin-Protein Ligases (genetics)