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Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis

Oncogene volume 23, pages 7863–7873 (2004)Cite this article

Abstract

Mcl-1 is an antiapoptotic member of the Bcl-2 family that can promote cell viability. We report here that Mcl-1 is a new substrate for caspases during induction of apoptosis. Mcl-1 cleavage occurs after Asp127 and Asp157 and generates four fragments of 24, 19, 17 and 12 kDa in both intact cells and in vitro, an effect prevented by selective caspase inhibitors. As a consequence, the resulting protein that lacks the first 127 or 157 amino acids contains only the BH1–BH3 domains of Bcl-2 family members. Mutation of Asp127 and Asp157 abolishes the generation of the 24 and 12 kDa fragments and that of the 19 and 17 kDa fragments, respectively. Interestingly, when expressed in HeLa cells Mcl-1 wt and Mcl-1 Δ127 showed a markedly different intracellular distribution. Mcl-1 wt colocalized with α-Tubulin near the internal face of the plasma membrane, while Mcl-1 Δ127 coassociated with Bim-EL at the mitochondrial level. Coimmunoprecipitation experiments also demonstrated that Mcl1 Δ127 exhibited increased binding to Bim when compared to Mcl-1 wt. Finally, Mcl-1 wt unlike Mcl-1 Δ127 inhibited Bim-EL-induced caspase activation. Altogether, our findings demonstrate that cleavage of Mcl-1 by caspases modifies its subcellular localization, increases its association with Bim and inhibits its antiapoptotic function.

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Acknowledgements

We thank Pr E Solary for the kind gift of the Mcl-1 cDNA. We are indebted to Dr B Mari for critical review of the manuscript. This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Ligue Nationale Contre le Cancer (LNC, Equipe labellisée). Dr S Marchetti and Dr F Luciano are recipients of a LNC fellowship. Imatinib mesylate is a kind gift from Novartis Pharma.

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  1. INSERM U526, Physiopathologie de la Survie et de la Mort Cellulaires et Infections Virales, Equipe Labellisée par la Ligue Nationale contre le Cancer, IFR50, Faculté de Médecine, Avenue de Valombrose, Nice, Cedex 2, 06107, France

    Magali Herrant, Arnaud Jacquel, Sandrine Marchetti, Nathalie Belhacène, Pascal Colosetti & Patrick Auberger

  2. The Burnham Institute, 10901 Torrey Pines Rd, La Jolla, 92037, CA, USA

    Frédéric Luciano

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  1. Magali Herrant
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Correspondence to Patrick Auberger.

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Herrant, M., Jacquel, A., Marchetti, S. et al. Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis. Oncogene 23, 7863–7873 (2004). https://doi.org/10.1038/sj.onc.1208069

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