p53 Is Cleaved by Caspases Generating Fragments Localizing to Mitochondria

The p53 tumor suppressor protein exerts most of its anti-tumorigenic activity by transcriptionally activating several pro-apoptotic genes. Accumulating evidence also suggests a transcription-independent function of p53 during apoptosis. It has recently been shown that, when activated, a fraction of...

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Bibliographic Details
Published in:The Journal of biological chemistry 2006-05, Vol.281 (19), p.13566-13573
Main Authors: Sayan, Berna S., Sayan, A. Emre, Knight, Richard A., Melino, Gerry, Cohen, Gerald M.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Apoptosis
Caspases - metabolism
Cell Line
Cytosol
Humans
Mitochondria - metabolism
Mitochondrial Membranes
Mutation
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Protein Transport
Transcription, Genetic
Tumor Suppressor Protein p53 - chemistry
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:The p53 tumor suppressor protein exerts most of its anti-tumorigenic activity by transcriptionally activating several pro-apoptotic genes. Accumulating evidence also suggests a transcription-independent function of p53 during apoptosis. It has recently been shown that, when activated, a fraction of p53 translocates to mitochondria, causing cytochrome c release. We now demonstrate a caspase-dependent cleavage of p53 resulting in the generation of four fragments, two of which lack a nuclear localization signal and consequently localize to cytosol. Moreover, these two fragments translocate to mitochondria and induce mitochondrial membrane depolarization in the absence of transcriptional activity. This novel feature of p53 supports the model whereby cytosolic p53 exerts major functions in apoptosis and also suggests the presence of a positive feedback loop in which activated caspases cleave p53 to augment mitochondrial membrane depolarization.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M512467200