A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation
AuthorLee, EF; Czabotar, PE; Van Delft, MF; Michalak, EM; Boyle, MJ; Willis, SN; Puthalakath, H; Bouillet, P; Colman, PM; Huang, DCS; ...
Source TitleThe Journal of Cell Biology
PublisherROCKEFELLER UNIV PRESS
University of Melbourne Author/sWillis, Simon; Huang, David; Michalak, Ewa; Czabotar, Peter; van Delft, Mark; Colman, Peter; LEE, ERINNA; Bouillet, Philippe; Puthalakath, Hamsa; BOYLE, MICHELLE
AffiliationMedical Biology (W.E.H.I.)
Sir Peter MacCallum Department of Oncology
Academic Services and Registrar
Document TypeJournal Article
CitationsLee, E. F., Czabotar, P. E., Van Delft, M. F., Michalak, E. M., Boyle, M. J., Willis, S. N., Puthalakath, H., Bouillet, P., Colman, P. M., Huang, D. C. S. & Fairlie, W. D. (2008). A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. JOURNAL OF CELL BIOLOGY, 180 (2), pp.341-355. https://doi.org/10.1083/jcb.200708096.
Access StatusOpen Access
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(S)2A, which is highly selective for Mcl-1. Unlike Noxa, Bim(S)2A is unable to trigger Mcl-1 degradation, yet, like Noxa, Bim(S)2A promotes cell killing only when Bcl-x(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.
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