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p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53

Abstract

p53 is one of the most important tumor suppressor genes, and the exploration of p53-target genes is important for elucidation of its functional mechanisms. In this study, we identified Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) as a direct target of p53 through ChIP-sequencing analysis. Activated p53 protein was found to bind to two distinct sites in the ARVCF gene, resulting in induction of ARVCF expression at both the mRNA and protein levels. We revealed that the knockdown of ARVCF inhibited p53-induced apoptosis. Interestingly, ARVCF interacted with hnRNPH2, which is involved in pre-mRNA splicing, and ARVCF knockdown induced dynamic changes in alternative splicing patterns. These results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Thus, we demonstrated that the induction of ARVCF expression contributed to the tumor suppressive function of p53. Recently, it has been reported that many tumors have thousands of alternative splicing events that are not detectable in normal samples. ARVCF may play a role in alternative splicing events in cancer and may provide clues to explore novel approaches for cancer diagnosis and therapy.

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Fig. 1: p53 response elements in the human ARVCF gene.
Fig. 2: ARVCF expression is induced by the p53 family.
Fig. 3: p53-induced apoptosis is suppressed by ARVCF knockdown.
Fig. 4: Modulation of alternative splicing patterns by ARVCF knockdown.
Fig. 5: Correlation between ARVCF expression and prognosis among cancer patients.

References

  1. 1.

    Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10.

    CAS  Article  Google Scholar 

  2. 2.

    Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9:701–13.

    CAS  Article  Google Scholar 

  3. 3.

    Idogawa M, Ohashi T, Sugisaka J, Sasaki Y, Suzuki H, Tokino T. Array-based genome-wide RNAi screening to identify shRNAs that enhance p53-related apoptosis in human cancer cells. Oncotarget. 2014;5:7540–8.

    Article  Google Scholar 

  4. 4.

    Ohashi T, Idogawa M, Sasaki Y, Tokino T. p53 mediates the suppression of cancer cell invasion by inducing LIMA1/EPLIN. Cancer Lett. 2017;390:58–66.

    CAS  Article  Google Scholar 

  5. 5.

    Ohashi T, Idogawa M, Sasaki Y, Suzuki H, Tokino T. AKR1B10, a transcriptional target of p53, is downregulated in colorectal cancers associated with poor prognosis. Mol Cancer Res. 2013;11:1554–63.

    CAS  Article  Google Scholar 

  6. 6.

    Idogawa M, Ohashi T, Sasaki Y, Maruyama R, Kashima L, Suzuki H, et al. Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites. Hum Mol Genet. 2014;23:2847–57.

    CAS  Article  Google Scholar 

  7. 7.

    Idogawa M, Ohashi T, Sasaki Y, Nakase H, Tokino T. Long non-coding RNA NEAT1 is a transcriptional target of p53 and modulates p53-induced transactivation and tumor-suppressor function. Int J Cancer. 2017;140:2785–91.

    CAS  Article  Google Scholar 

  8. 8.

    McCrea PD, Park JI. Developmental functions of the P120-catenin sub-family. Biochim Biophys Acta. 2007;1773:17–33.

    CAS  Article  Google Scholar 

  9. 9.

    Chang GS, Chen XA, Park B, Rhee HS, Li P, Han KH, et al. A comprehensive and high-resolution genome-wide response of p53 to stress. Cell Rep. 2014;8:514–27.

    CAS  Article  Google Scholar 

  10. 10.

    Wang B, Niu D, Lam TH, Xiao Z, Ren EC. Mapping the p53 transcriptome universe using p53 natural polymorphs. Cell Death Differ. 2014;21:521–32.

    CAS  Article  Google Scholar 

  11. 11.

    Rappe U, Schlechter T, Aschoff M, Hotz-Wagenblatt A, Hofmann I. Nuclear ARVCF protein binds splicing factors and contributes to the regulation of alternative splicing. J Biol Chem. 2014;289:12421–34.

    CAS  Article  Google Scholar 

  12. 12.

    Olsson A, Manzl C, Strasser A, Villunger A. How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression? Cell Death Differ. 2007;14:1561–75.

    CAS  Article  Google Scholar 

  13. 13.

    Katz Y, Wang ET, Airoldi EM, Burge CB. Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods. 2010;7:1009–15.

    CAS  Article  Google Scholar 

  14. 14.

    Zhang D, Tang N, Liu Y, Wang EH. ARVCF expression is significantly correlated with the malignant phenotype of non-small cell lung cancer. Mol Carcinog. 2015;54:E185–191.

    CAS  Article  Google Scholar 

  15. 15.

    Idogawa M, Nakase H, Sasaki Y, Tokino T. Prognostic effect of long noncoding RNA NEAT1 expression depends on p53 mutation status in cancer. J Oncol. 2019;2019:4368068.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Kahles A, Lehmann KV, Toussaint NC, Huser M, Stark SG, Sachsenberg T, et al. Comprehensive analysis of alternative splicing across tumors from 8705 patients. Cancer Cell. 2018;34:211–224 e216.

    CAS  Article  Google Scholar 

  17. 17.

    Idogawa M, Sasaki Y, Suzuki H, Mita H, Imai K, Shinomura Y, et al. A single recombinant adenovirus expressing p53 and p21-targeting artificial microRNAs efficiently induces apoptosis in human cancer cells. Clin Cancer Res. 2009;15:3725–32.

    CAS  Article  Google Scholar 

  18. 18.

    Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12:357–60.

    CAS  Article  Google Scholar 

  19. 19.

    Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28:511–5.

    CAS  Article  Google Scholar 

  20. 20.

    Fischer M. Census and evaluation of p53 target genes. Oncogene. 2017;36:3943–56.

    CAS  Article  Google Scholar 

  21. 21.

    Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.

    Article  Google Scholar 

Download references

Acknowledgements

The computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics.

Funding

This work was supported by JSPS KAKENHI (grant numbers: 19K08372, 19K07645, 16K09285, and 16K07122) and Takeda Science Foundation.

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Correspondence to Masashi Idogawa or Takashi Tokino.

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Suzuki, N., Idogawa, M., Tange, S. et al. p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53. Oncogene 39, 2202–2211 (2020). https://doi.org/10.1038/s41388-019-1133-7

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