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.
MeSH terms
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Adenoviridae
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis*
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Base Sequence
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Chromosomal Proteins, Non-Histone / genetics*
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Chromosomal Proteins, Non-Histone / metabolism
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Cysteine Proteinase Inhibitors / genetics*
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Cysteine Proteinase Inhibitors / metabolism
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DNA Primers / chemistry
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Doxorubicin / pharmacology
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Inhibitor of Apoptosis Proteins
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Luciferases / metabolism
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Microtubule-Associated Proteins*
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Molecular Sequence Data
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Neoplasm Proteins
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Precipitin Tests
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Proliferating Cell Nuclear Antigen / genetics
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Proliferating Cell Nuclear Antigen / metabolism
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Promoter Regions, Genetic
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RNA, Messenger / metabolism
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RNA, Neoplasm / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Survivin
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Transcription, Genetic
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antibiotics, Antineoplastic
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BIRC5 protein, human
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Chromosomal Proteins, Non-Histone
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Cysteine Proteinase Inhibitors
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DNA Primers
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Proliferating Cell Nuclear Antigen
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RNA, Messenger
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RNA, Neoplasm
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Survivin
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Tumor Suppressor Protein p53
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Doxorubicin
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Luciferases