Published online January 21, 2008
doi:10.1083/jcb.200708096
The Journal of Cell Biology, Vol. 180, No. 2, 341-355
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Lee et al.
A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation
Erinna F. Lee1,
Peter E. Czabotar1,
Mark F. van Delft1,
Ewa M. Michalak1,
Michelle J. Boyle1,2,
Simon N. Willis1,
Hamsa Puthalakath1,
Philippe Bouillet1,
Peter M. Colman1,
David C.S. Huang1, and
W. Douglas Fairlie1
1 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia
2 Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Correspondence to W. Douglas Fairlie: fairlie{at}wehi.edu.au
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, BimS2A, which is highly selective for Mcl-1. Unlike Noxa, BimS2A is unable to trigger Mcl-1 degradation, yet, like Noxa, BimS2A promotes cell killing only when Bcl-xL 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.
H. Puthalakath's present address is Department of Biochemistry, La Trobe University, Melbourne, Victoria 3086, Australia.
Abbreviations used in this paper: BH3, Bcl-2 homology 3; IRES, internal ribosome entry site; ITC, isothermal titration calorimetry; MEF, mouse embryonic fibroblast; shRNA, short hairpin RNA.
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