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SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitination

Nature Cell Biology volume 8, pages 1424–1431 (2006)Cite this article

Abstract

The p53 tumour suppressor has a key role in the control of cell growth and differentiation, and in the maintenance of genome integrity1,2. p53 is kept labile under normal conditions, but in response to stresses, such as DNA damage, it accumulates in the nucleus for induction of cell-cycle arrest, DNA repair or apoptosis. Mdm2 is an ubiquitin ligase that promotes p53 ubiquitination and degradation3,4,5. Mdm2 is also self-ubiquitinated and degraded. Here, we identified a novel cascade for the increase in p53 level in response to DNA damage. A new SUMO-specific protease, SUSP4, removed SUMO-1 from Mdm2 and this desumoylation led to promotion of Mdm2 self-ubiquitination, resulting in p53 stabilization. Moreover, SUSP4 competed with p53 for binding to Mdm2, also resulting in p53 stabilization. Overexpression of SUSP4 inhibited cell growth, whereas knockdown of susp4 by RNA interference (RNAi) promoted of cell growth. UV damage induced SUSP4 expression, leading to an increase in p53 levels in parallel with a decrease in Mdm2 levels. These findings establish a new mechanism for the elevation of cellular p53 levels in response to UV damage.

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Figure 1: Interaction of SUSP4 with p53 and Mdm2 and their colocalization.
Figure 2: Desumoylation of p53 and Mdm2 by SUSP4.
Figure 3: Effect of SUSP4 on ubiquitination and stability of Mdm2 and p53.
Figure 4: SUSP4-mediated inhibition of cell growth.
Figure 5: Induction of SUSP4 expression by UV.

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References

  1. Ko, L. J. & Prives, C. p53: puzzle and paradigm. Genes Dev. 10, 1054–1072 (1996).

    Article  CAS  Google Scholar 

  2. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).

    Article  CAS  Google Scholar 

  3. Haupt, Y., Maya, R., Kazaz, A. & Oren, M. Mdm2 promotes the rapid degradation of p53. Nature 387, 296–299 (1997).

    Article  CAS  Google Scholar 

  4. Kubbutat, M. H., Jones, S. N. & Vousden, K. H. Regulation of p53 stability by Mdm2. Nature 387, 299–303 (1997).

    Article  CAS  Google Scholar 

  5. Li, M. et al. Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302, 1972–1975 (2003).

    Article  CAS  Google Scholar 

  6. Melchior, F. SUMO — nonclassical ubiquitin. Annu. Rev. Cell Dev. Biol. 16, 591–626 (2000).

    Article  CAS  Google Scholar 

  7. Muller, S., Hoege, C., Pyrowolakis, G. & Jentsch, S. SUMO, ubiquitin's mysterious cousin. Nature Rev. Mol. Cell Biol. 2, 202–210 (2001).

    Article  CAS  Google Scholar 

  8. Pichler, A., Gast, A., Seeler, J. S., Dejean, A. & Melchior, F. The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108, 109–120 (2002).

    Article  CAS  Google Scholar 

  9. Kagey, M. H., Melhuish, T. A. & Wotton, D. The polycomb protein Pc2 is a SUMO E3. Cell 113, 127–137 (2003).

    Article  CAS  Google Scholar 

  10. Kahyo, T., Nishida, T. & Yasuda, H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol. Cell 8, 713–718 (2001).

    Article  CAS  Google Scholar 

  11. Sachdev, S. et al. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15, 3088–3103 (2001).

    Article  CAS  Google Scholar 

  12. Kim, K. I. et al. A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J. Biol. Chem. 275, 14102–14106 (2000).

    Article  CAS  Google Scholar 

  13. Melchior, F., Schergaut, M. & Pichler, A. SUMO: ligases, isopeptidases and nuclear pores. Trends Biochem. Sci. 28, 612–618 (2003).

    Article  CAS  Google Scholar 

  14. Hay, R. T. SUMO: a history of modification. Mol. Cell 18, 1–12 (2005).

    Article  CAS  Google Scholar 

  15. Li, S. J. & Hochstrasser, M. A new protease required for cell-cycle progression in yeast. Nature 398, 246–251 (1999).

    Article  CAS  Google Scholar 

  16. Li, S. J. & Hochstrasser, M. The yeast ULP2 (SMT4) gene encodes a novel protease specific for the ubiquitin-like Smt3 protein. Mol. Cell Biol. 20, 2367–2377 (2000).

    Article  CAS  Google Scholar 

  17. Yeh, E. T., Gong, L. & Kamitani, T. Ubiquitin-like proteins: new wines in new bottles. Gene 248, 1–14 (2000).

    Article  CAS  Google Scholar 

  18. Gong, L. & Yeh, E. T. Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J. Biol. Chem. 281, 15869–15877 (2006).

    Article  CAS  Google Scholar 

  19. Gostissa, M. et al. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J. 18, 6462–6471 (1999).

    Article  CAS  Google Scholar 

  20. Rodriguez, M. S. et al. SUMO-1 modification activates the transcriptional response of p53. EMBO J. 18, 6455–5461 (1999).

    Article  CAS  Google Scholar 

  21. Muller, S. et al. c-Jun and p53 activity is modulated by SUMO-1 modification. J. Biol. Chem. 275, 13321–13329 (2000).

    Article  CAS  Google Scholar 

  22. Kwek, S. S., Derry, J., Tyner, A. L., Shen, Z. & Gudkov, A. V. Functional analysis and intracellular localization of p53 modified by SUMO-1. Oncogene 20, 2587–2599 (2001).

    Article  CAS  Google Scholar 

  23. Schmidt, D. & Muller, S. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc. Natl Acad. Sci. USA 99, 2872–2877 (2002).

    Article  CAS  Google Scholar 

  24. Xirodimas, D. P., Chisholm, J., Desterro, J. M., Lane, D. P. & Hay, R. T. P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2. FEBS Lett. 528, 207–211 (2002).

    Article  CAS  Google Scholar 

  25. Chen, L. & Chen, J. MDM2–ARF complex regulates p53 sumoylation. Oncogene 22, 5348–5357 (2003).

    Article  CAS  Google Scholar 

  26. Boggio, R., Colombo, R., Hay, R. T., Draetta, G. F. & Chiocca, S. A mechanism for inhibiting the SUMO pathway. Mol. Cell 16, 549–561 (2004).

    Article  CAS  Google Scholar 

  27. Tago, K., Chiocca, S. & Sherr, C. J. Sumoylation induced by the Arf tumor suppressor: a p53-independent function. Proc. Natl Acad. Sci. USA 102, 7689–7694 (2005).

    Article  CAS  Google Scholar 

  28. Best, J. L. et al. SUMO-1 protease-1 regulates gene transcription through PML. Mol. Cell 10, 843–855 (2002).

    Article  CAS  Google Scholar 

  29. Chen, J., Marechal, V. & Levine, A. J. Mapping of the p53 and mdm-2 interaction domains. Mol. Cell Biol. 13, 4107–4114 (1993).

    Article  CAS  Google Scholar 

  30. Tang, J. et al. Critical role for Daxx in regulating Mdm2. Nature Cell Biol. 8, 855–862 (2006).

    Article  CAS  Google Scholar 

  31. Goodson, M. L. et al. Sumo-1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor. J. Biol. Chem. 276, 18513–18518 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank G. Lozano and H. Kim for providing p53−/−mdm2−/− and p53−/− MEF cells. We also thank R. Hay for providing pGEX–Sae1–Sae2. This work was supported by grants from the Korea Science and Engineering Foundation (M10533010001-05N3301-00100) and the Korea Research Foundation (KRF-2003-070-C00033 and KRF-2005-084-C00025).

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Authors and Affiliations

  1. NRL of Protein Biochemistry, School of Biological Sciences, Seoul National University, Seoul, 151-742, Korea

    Moon Hee Lee, Sung Won Lee, Eun Joo Lee, Soo Joon Choi, Sung Soo Chung, Jae Hong Seol, Sung Hee Baek, Ok Sun Bang & Chin Ha Chung

  2. Crystalgenomics Inc., Seoul, 138-736, Korea

    Jae Il Lee & Joong Myung Cho

  3. Department of Biological Sciences, Sookmyung Woman's University, Seoul, 140-742, Korea

    Keun Il Kim

  4. Tokyo Metropolitan Institute of Medical Sciences, Tokyo, 113, Japan

    Tomoki Chiba & Keiji Tanaka

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Correspondence to Ok Sun Bang or Chin Ha Chung.

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Supplementary figures S1, S2, S3, S4 and S5 (PDF 262 kb)

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Lee, M., Lee, S., Lee, E. et al. SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitination. Nat Cell Biol 8, 1424–1431 (2006). https://doi.org/10.1038/ncb1512

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