P53 Is Cleaved by Caspases Generating Fragments Localizing to Mitochondria

Berna S Sayan,A Emre Sayan,Richard A Knight,Gerry Melino,Gerald M Cohen

doi:10.1074/jbc.m512467200

Abstract

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.

Highlights

Due to its multifunctional nature and central role in many cellular events, p53 is a target of many post-translational regulations, such as phosphorylation, ubiquitylation, and acetylation (9)
Since we observed low molecular weight p53-derived proteins following induction of apoptosis, we asked whether p53 could be processed by caspases and whether any of these cleavage products could have an effect on mitochondria
The high molecular weight p53 protein forms have been identified as ubiquitylated forms of full-length p53, whereas some of the low molecular

Summary

Introduction

Due to its multifunctional nature and central role in many cellular events, p53 is a target of many post-translational regulations, such as phosphorylation, ubiquitylation, and acetylation (9). Since we observed low molecular weight p53-derived proteins following induction of apoptosis, we asked whether p53 could be processed by caspases and whether any of these cleavage products could have an effect on mitochondria. With the N-terminal-specific DO1 antibody, we detected two cleavage products (fragments 2 and 3, Fig. 1D).

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Results

Conclusion