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Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis

Abstract

The gene PTTG1 (encoding the pituitary tumor–transforming 1 protein) is overexpressed in several different tumor types, is tumorigenic in vivo and shows transcriptional activity1,2,3,4. The PTTG1 protein is cell-cycle regulated and was identified as the human securin (a category of proteins involved in the regulation of sister-chromatid separation) on the basis of biochemical similarities with the Pds1p protein of budding yeast and the Cut2p protein of fission yeast5,6. To unravel the function of human securin in oncogenesis, we carried out a phage-display screening to identify proteins that interact with securin. Notably, we isolated the p53 tumor suppressor. Pull-down and co-immunoprecipitation assays demonstrated that p53 interacts specifically with securin both in vitro and in vivo. This interaction blocks the specific binding of p53 to DNA and inhibits its transcriptional activity. Securin also inhibits the ability of p53 to induce cell death. Moreover, we observed that transfection of H1299 cells with securin induced an accumulation of G2 cells that compensated for the loss of G2 cells caused by transfection with p53. We demonstrated the physiological relevance of this interaction in PTTG1-deficient human tumor cells (PTTG1−/−): both apoptotic and transactivating functions of p53 were potentiated in these cells compared to parental cells. We propose that the oncogenic effect of increased expression of securin may result from modulation of p53 functions.

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Figure 1: In vitro and in vivo interaction of securin and p53.
Figure 2: Securin affected DNA-binding and transactivation activity of p53.
Figure 3: Securin inhibits p53-mediated cell death.
Figure 4: p53-mediated apoptosis was inhibited by securin; p53-dependent apoptosis was greater in the absence of securin.

References

  1. Domínguez, A. et al. hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms. Evidence for a transcriptional activation function of hPTTG. Oncogene 17, 2187–2193 (1998).

    Article  Google Scholar 

  2. Jallepalli, P.V. et al. Securin is required for chromosomal stability in human cells. Cell 105, 445–457 (2001).

    Article  CAS  Google Scholar 

  3. Saez, C. et al. hpttg is overexpressed in pituitary adenomas and other primary epithelial neoplasias. Oncogene 18, 5473–5476 (1999).

    Article  CAS  Google Scholar 

  4. Zhang, X. et al. Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol. Endocrinol. 13, 156–166 (1999).

    Article  CAS  Google Scholar 

  5. Zou, H., McGarry, T.J., Bernal, T. & Kirschner, M.W. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 285, 418–422 (1999).

    Article  CAS  Google Scholar 

  6. Ramos-Morales, F. et al. Cell cycle regulated expression and phosphorylation of hpttg proto-oncogene product. Oncogene 19, 403–409 (2000).

    Article  CAS  Google Scholar 

  7. Loeb, L.A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).

    CAS  PubMed  Google Scholar 

  8. Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  Google Scholar 

  9. Lengauer, C., Kinzler, K.W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  Google Scholar 

  10. Pei, L. Identification of c-myc as a down-stream target for pituitary tumor-transforming gene. J. Biol. Chem. 276, 8484–8491 (2000).

    Article  Google Scholar 

  11. Mei, J., Huang, H. & Zhang, P. Securin is not required for cellular viability, but is required for normal growth of mouse embryonic fibroblasts. Curr. Biol. 11, 1197–1201 (2001).

    Article  CAS  Google Scholar 

  12. Wang, Z., Yu, R. & Melmed, S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. Mol. Endocrinol. 15, 1870–1879 (2001).

    Article  CAS  Google Scholar 

  13. Romero, F. et al. Human securin/hPTTG is associated with the DNA-dependent protein kinase. Nucleic Acids Res. 29, 1300–1307 (2001).

    Article  CAS  Google Scholar 

  14. Hoogenboom, H.R. et al. Multi-subunit proteins on the surface of filamentous phage: methodologies for displaying antibody (Fab) heavy and light chains. Nucleic Acids Res. 19, 4133–4137 (1991).

    Article  CAS  Google Scholar 

  15. Bargonetti, J., Reynisdóttir, I., Friedman, P.N. & Prives, C. Site-specific binding of wild-type p53 to cellular DNA is inhibited by SV40 T antigen and mutant p53. Genes Dev. 6, 1886–1998 (1992).

    Article  CAS  Google Scholar 

  16. Green, D.R. & Reed, J.C. Mitochondria and apoptosis. Science 281, 1309–1312 (1998).

    Article  CAS  Google Scholar 

  17. Hermeking, H. et al. 14-3-3σ is a p53-regulated inhibitor of G2/M progression. Mol. Cell. 1, 3–11 (1997).

    Article  CAS  Google Scholar 

  18. El–Deiry, W.S. et al. WAF-1, a potential mediator of p53 tumor suppression. Cell 75, 817–925 (1993).

    Article  Google Scholar 

  19. Oliner, J.D. et al. Oncoprotein MDM2 conceals the activation domain of tumor suppressor p53. Nature 362, 857–860 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Bunz, F. et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J. Clin. Invest. 104, 263–269 (1999).

    Article  CAS  Google Scholar 

  22. Heaney, A.P. et al. Expression of pituitary-tumor transforming gene in colorectal tumors. Lancet North Am. Ed. 355, 716–719 (2000).

    Article  CAS  Google Scholar 

  23. Vousden, K.H. p53: death star. Cell 103, 691–694 (2000).

    Article  CAS  Google Scholar 

  24. Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  Google Scholar 

  25. Owen-Schaub, L.B. et al. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol. Cell. Biol. 15, 3032–3040 (1995).

    Article  CAS  Google Scholar 

  26. Schmitt, C.A. & Lowe, S.W. Apoptosis and therapy. J. Pathol. 187, 127–137 (1999).

    Article  CAS  Google Scholar 

  27. Soengas. M.S. et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409, 207–211 (2001).

    Article  CAS  Google Scholar 

  28. Raman, V. et al. Compromised HOXA5 function can limit p53 expression in human breast tumors. Nature 405, 974–978 (2001).

    Article  Google Scholar 

  29. O'Connor, D.J. et al. Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DP1. EMBO J. 14, 6184–6192 (1995).

    Article  CAS  Google Scholar 

  30. Zhu, L. et al. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. Genes Dev. 7, 1111–1125 (1993).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to R.M. Ríos for critical reading of the manuscript; M.M. Parra for technical assistance; P. Lastres for assistance with flow cytometry; M. Oren, B. Vogelstein, E. Harlow, A. Levine and W.S. El-Deiry for plasmids; and A. López-Rivas and B. Vogelstein for MCF7-E6 and PTTG1−/− HCT116 cells, respectively. This work was supported by grants from the Spanish Ministerio de Ciencia y Tecnologia and Dirección General de Universidades e Investigación of the Junta de Andalucía.

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Correspondence to José A. Pintor-Toro.

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Bernal, J., Luna, R., Espina, Á. et al. Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat Genet 32, 306–311 (2002). https://doi.org/10.1038/ng997

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