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Survivin regulates the p53 tumor suppressor gene family

Oncogene volume 23, pages 8146–8153 (2004)Cite this article

Abstract

Survivin regulates cell division and inhibits apoptosis by blocking caspase activation. The tumor suppressor p53 inhibits cell cycle progression and induces apoptosis. Since Survivin overexpression and loss of wild-type p53 expression/function occur in most cancers, we investigated whether Survivin regulates p53. Stable overexpression of Survivin protects BaF3 cells from Adriamycin-induced apoptosis, while dominant-negative (T34A) and antisense (AS) Survivin accelerate apoptosis. In BaF3 cells and transiently transfected MCF7 breast cancer cells, elevation of total and phospho-Ser15-p53 in response to Adriamycin is blocked by Survivin and enhanced by Survivin disruption. Furthermore, in Adriamycin-treated MCF7 cells, ectopic Survivin decreased p53 mRNA and increased mRNA and protein of the p53 homologues ΔNp63 and TAp73 and mRNA for ΔNp73, suggesting that Survivin may differentially regulate p53 family transcription. Concomitant with decreasing p53 mRNA, Survivin decreased Mdm2 mRNA. Survivin disruption by T34A or AS Survivin resulted in reduced Mdm2 protein. The caspase inhibitor, Z-VAD-FMK, blocked the decrease in Mdm2 as well as the increase in p53 resulting from Survivin disruption, indicating that Survivin regulates Mdm2 at the post-translational level. Proteosome inhibition confirmed that reduced p53 protein observed in cells overexpressing Survivin is due to enhanced p53 degradation resulting from Survivin-mediated inhibition of Mdm2 cleavage by caspases. In summary, our results identify regulatory interactions between Survivin and p53 at the mRNA and protein levels, and suggest that the p53 homologues ΔNp63, TAp73 and ΔNp73 may also be regulated by Survivin.

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Acknowledgements

This work was supported by US Public Health Service grant HL079654 (to LMP) from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Microbiology and Immunology and The Walther Oncology Center, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, 46202, IN, USA

    Zhanxiang Wang, Seiji Fukuda & Louis M Pelus

  2. Walther Cancer Institute, 3202N Meridian Street, Indianapolis, 46202, IN, USA

    Zhanxiang Wang, Seiji Fukuda & Louis M Pelus

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  1. Zhanxiang Wang
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Correspondence to Louis M Pelus.

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Wang, Z., Fukuda, S. & Pelus, L. Survivin regulates the p53 tumor suppressor gene family. Oncogene 23, 8146–8153 (2004). https://doi.org/10.1038/sj.onc.1207992

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