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 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.
Medical Research Council (MRC) Toxicology Unit, Leicester LE1 9HN, United Kingdom.
Berna S
BS
Sayan
Medical Research Council (MRC) Toxicology Unit, Leicester LE1 9HN, United Kingdom.
A Emre
AE
Sayan
Medical Research Council (MRC) Toxicology Unit, Leicester LE1 9HN, United Kingdom.
Richard A
RA
Knight
Medical Research Council (MRC) Toxicology Unit, Leicester LE1 9HN, United Kingdom. Electronic address: gm89@leicester.ac.uk.
Gerry
G
Melino
Medical Research Council (MRC) Toxicology Unit, Leicester LE1 9HN, United Kingdom.
Gerald M
GM
Cohen
D000595:Amino Acid Sequence; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D020169:Caspases