Abstract
Survivin is an inhibitor of apoptosis protein, which is over-expressed in most tumors. Aberrant expression of survivin and loss of wild-type p53 in many tumors prompted us to investigate a possible link between these two events. Here we show that wild-type p53 represses survivin expression at both mRNA and protein levels. Transient transfection analyses revealed that the expression of wild-type p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The over-expression of exogenous survivin protein rescues cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least, in part the p53-dependent apoptotic pathway. In spite of the presence of two putative p53-binding sites in the survivin promoter, deletion and mutation analyses suggested that neither site is required for transcriptional repression of survivin expression. This was confirmed by chromatin immunoprecipitation assays. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.
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Abbreviations
- IAP:
-
inhibitor of apoptosis protein
- rAd-p53:
-
recombinant adenovirus encoding wild-type p53
- rAd-control:
-
recombinant adenovirus containing empty vector
- HDAC:
-
histone deacetylase complex
- ChIP:
-
chromatin immunoprecipitation
- PCNA:
-
proliferating cell nuclear antigen
- TSA:
-
trichostatin A
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Acknowledgements
We thank Dr Bruno Amati in DNAX Research Institute for helpful discussion, the critical reading of the manuscript, Dr Beth Hutchins in Canji Inc. for providing us rAd-p53 and rAd-control, Jeremy Shinoda in Canji Inc. for technical support, and Dr Maureen Murphy in Fox Chase Cancer Center for providing survivin expression plasmid and exchanging data prior to publication.
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Mirza, A., McGuirk, M., Hockenberry, T. et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 21, 2613–2622 (2002). https://doi.org/10.1038/sj.onc.1205353
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DOI: https://doi.org/10.1038/sj.onc.1205353
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