Transcriptional repression of the anti-apoptotic survivin gene by wild type p53.

Published on Feb 1, 2002in Journal of Biological Chemistry
· DOI :10.1074/jbc.M106643200
William H. Hoffman1
Estimated H-index: 1
(Fox Chase Cancer Center),
Siham Biade3
Estimated H-index: 3
(Fox Chase Cancer Center)
+ 2 AuthorsMaureen E. Murphy22
Estimated H-index: 22
(Fox Chase Cancer Center)
Abstract Survivin is a member of the inhibitor of apoptosis family. This apoptosis inhibitor also has an evolutionarily conserved role as a mitotic spindle checkpoint protein. Previous studies on p53-repressed genes have implicated several genes involved in the G2/M transition of the cell cycle as targets of negative regulation by p53. However, few targets of p53 repression that are anti-apoptotic have been identified. This study identifies the anti-apoptotic survivin gene as a p53-repressed gene. Notably, Survivin repression by p53 is shown to be distinct from p53-dependent growth arrest. Chromatin immunoprecipitations indicate that p53 binds the survivinpromoter in vivo; immunobinding studies indicate that this site overlaps with a binding site for E2F transcription factors and is subtly distinct from a canonical p53-transactivating element. Thesurvivin-binding site contains a 3-nucleotide spacer between the two decamer “half-sites” of the p53 consensus element; deletion of this spacer is sufficient to convert thesurvivin site into a transactivating element. Finally, we show that overexpression of Survivin in cells sensitive to p53-dependent cell death markedly inhibits apoptosis induced by ultraviolet light. The identification ofsurvivin as a p53 repressed gene should aid in the elucidation of the contribution of transcriptional repression to p53-dependent apoptosis.
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