RNA-binding Protein PCBP2 Regulates p73 Expression and p73-dependent Antioxidant Defense
Open accessAbstract
TAp73, a member of the p53 family tumor suppressors, plays a critical rule in tumor suppression and neuronal development. However, how p73 activity is controlled at the posttranscriptional level is not well understood. Here, we showed that TAp73 activity is regulated by RNA-binding protein PCBP2. Specifically, we found that knockdown or knock-out of PCBP2 reduces, whereas ectopic expression of PCBP2 increases, TAp73 expression. We also showed that PCBP2 is necessary for p73 mRNA stability via the CU-rich elements in p73 3'-UTR. To uncover the biological relevance of PCBP2-regulated TAp73 expression, we showed that ectopic expression of PCBP2 inhibits, whereas knockdown or knock-out of PCBP2 increases, the production of reactive oxygen species (ROS) in a TAp73-dependent manner. Additionally, we found that glutaminase 2 (GLS2), a modulator of p73-dependent antioxidant defense, is also involved in PCBP2-regulated ROS production. Moreover, we generated PCBP2-deficient mice and primary mouse embryonic fibroblasts (MEFs) and showed that loss of PCBP2 leads to decreased p73 expression and, subsequently, increased ROS production and accelerated cellular senescence. Together, our data suggest that PCBP2 regulates p73 expression via mRNA stability and p73-dependent biological function in ROS production and cellular senescence.
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The direction of the influence of an RBP on the stability and translation efficiency of RNA can depend on the cell type and on the target RNA, as exemplified by PCBP2.
“Nevertheless, it should be noted that the direction of the influence of an RBP on the stability and translation efficiency of RNA can depend on the cell type and on the target RNA, as exemplified by PCBP2: it can stabilize some mRNAs but promotes the degradation of other mRNAs [25,26,27].”
From Untranslated Region Sequences and the Efficacy of mRNA Vaccines against Tuberculosis (2024) · cites this paper as [27]
The Results section reports that loss of PCBP2 shortens p73 mRNA half-life in HCT116 and H1299 cells, supporting PCBP2 as an example of an RBP that stabilizes a target RNA. The paper also describes PCBP2 as regulating the stability and translation of several RNAs, but it does not show PCBP2 promoting degradation of another mRNA or reversing the direction of its effect by cell type. (LLM, conf=0.86)
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- Tissir, F., Ravni, A., Achouri, Y., Riethmacher, D., Meyer, G., and Goffinet, A. M. (2009) ⌬Np73 regulates neuronal survival in vivo. Proc. Natl. Acad. Sci. U.S.A. 106, 16871-16876
- Frey, A. G., Nandal, A., Park, J. H., Smith, P. M., Yabe, T., Ryu, M. S., Ghosh, M. C., Lee, J., Rouault, T. A., Park, M. H., and Philpott, C. C. (2014) Iron chaperones PCBP1 and PCBP2 mediate the metallation of the di- nuclear iron enzyme deoxyhypusine hydroxylase. Proc. Natl. Acad. Sci.
- Ghosh, D., Srivastava, G. P., Xu, D., Schulz, L. C., and Roberts, R. M. (2008) A link between SIN1 (MAPKAP1) and poly(rC) binding protein 2 (PCBP2) in counteracting environmental stress. Proc. Natl. Acad. Sci. U.S.A. 105, 11673-11678
- Suzuki, S., Tanaka, T., Poyurovsky, M. V., Nagano, H., Mayama, T., Oh- kubo, S., Lokshin, M., Hosokawa, H., Nakayama, T., Suzuki, Y., Sugano, S., Sato, E., Nagao, T., Yokote, K., Tatsuno, I., and Prives, C. (2010) Phos- phate-activated glutaminase (GLS2), a p53-inducible regulator of gluta- mine metabolism and reactive oxygen species. Proc. Natl. Acad. Sci. U.S.A. 107, 7461-7466
- Agostini, M., Tucci, P., Killick, R., Candi, E., Sayan, B. S., Rivetti di Val Cervo, P., Nicotera, P., McKeon, F., Knight, R. A., Mak, T. W., and Melino, G. (2011) Neuronal differentiation by TAp73 is mediated by microRNA- 34a regulation of synaptic protein targets. Proc. Natl. Acad. Sci. U.S.A. 108, 21093-21098
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Kirshina, A., Vasileva, O., Kunyk, D., Seregina, K., Muslimov, A., Ivanov, R., & Reshetnikov, V. (2023) · Biomolecules · doi:10.3390/biom13111677 · Cited by 26 · see citing works
- Authors
- Ren, C., Zhang, J., Yan, W., Zhang, Y., & Chen, X.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Zhang, Jin
- Chen, Xinbin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 291
- Issue
- 18
- Pages
- 9629-9637
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4850300
- OpenAlex
- W2279444834
- Cited by
- 29
- References
- 0
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 1 · 2016: 2
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (CA081237, CA123227, CA121137)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- PCBP2, TAp73, p73, RNA-binding proteins, mRNA stability, 3' untranslated region, reactive oxygen species, antioxidant defense, GLS2, cellular senescence, post-transcriptional regulation
- MeSH terms
- Tumor Protein p73, Transaminases, Animals, Antioxidants, DNA-Binding Proteins, Embryo, Mammalian, Fibroblasts, Gene Expression Regulation, Nuclear Proteins, RNA-Binding Proteins, Cellular Senescence, Reactive Oxygen Species, Mice, Knockout, 3' Untranslated Regions, RNA Stability, Tumor Suppressor Proteins, Mice
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