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

Area of Science:

• Molecular Biology
• Cell Cycle Regulation
• Apoptosis

Background:

• Survivin is an apoptosis inhibitor and mitotic spindle checkpoint protein.
• p53 (tumor suppressor) negatively regulates genes in the G(2)/M cell cycle transition.
• Few anti-apoptotic genes regulated by p53 repression have been identified.

Purpose of the Study:

• To identify the anti-apoptotic survivin gene as a p53-repressed gene.
• To investigate the mechanism of survivin repression by p53.
• To understand the role of survivin repression in p53-dependent apoptosis.

Main Methods:

• Chromatin immunoprecipitation to detect p53 binding to the survivin promoter in vivo.
• Immunobinding studies to analyze p53 and E2F transcription factor binding sites.
• Site-directed mutagenesis to alter the p53 binding site on the survivin promoter.
• Overexpression studies to assess survivin's effect on UV-induced apoptosis.

Main Results:

• Survivin is identified as a p53-repressed gene, independent of p53-mediated growth arrest.
• p53 binds to the survivin promoter in vivo, overlapping with an E2F binding site.
• A 3-nucleotide spacer in the p53 binding site is crucial for repression; its deletion enables transactivation.
• Survivin overexpression inhibits UV-induced apoptosis in p53-sensitive cells.

Conclusions:

• Transcriptional repression of survivin by p53 is a novel mechanism contributing to p53-dependent apoptosis.
• The specific binding interaction between p53 and the survivin promoter provides insight into cell death regulation.
• Targeting survivin repression could be a strategy in cancer therapy.