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 Delta127 showed a markedly different intracellular distribution. Mcl-1 wt colocalized with alpha-Tubulin near the internal face of the plasma membrane, while Mcl-1 Delta127 coassociated with Bim-EL at the mitochondrial level. Coimmunoprecipitation experiments also demonstrated that Mcl1 Delta127 exhibited increased binding to Bim when compared to Mcl-1 wt. Finally, Mcl-1 wt unlike Mcl-1 Delta127 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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Herrant M,Jacquel A,Marchetti S,Belhacène N,Colosetti P,Luciano F,Auberger Pdoi
10.1038/sj.onc.1208069subject
Has Abstractpub_date
2004-10-14 00:00:00pages
7863-73issue
47eissn
0950-9232issn
1476-5594pii
1208069journal_volume
23pub_type
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