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- Title
A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation.
- Authors
Lee, Erinna F.; Czabotar, Peter E.; van Delft, Mark F.; Michalak, Ewa M.; Boyle, Michelle J.; Willis, Simon N.; Puthalakath, Hamsa; Bouillet, Philippe; Colman, Peter M.; Huang, David C. S.; Fairlie, W. Douglas
- Abstract
Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2-like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)--only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, Bim[sub s]2A, which is highly selective for Mcl-1. Unlike Noxa, Bim[sub s]2A is unable to trigger Mcl-1 degradation, yet, like Noxa, Bim[sub s]2A promotes cell killing only when Bcl-x[sub L] is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1.
- Subjects
LIGANDS (Biochemistry); CELL death; BINDING sites; CELL growth; CYTOLOGY
- Publication
Journal of Cell Biology, 2008, Vol 180, Issue 2, p341
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.200708096