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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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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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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DOI: https://doi.org/10.1038/ng997
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