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.
- inhibitor of apoptosis
- glyceraldehyde-3-phosphate dehydrogenase
- cell cycle-dependent elements
- histone deacetylase
- poly(ADP) ribose polymerase
- Received July 16, 2001.
- Revision received November 6, 2001.