NDLI: A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation

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A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation

Content Provider	Scilit
Author	Lee, Erinna Czabotar, Peter van Delft, Mark Michalak, Ewa Boyle, Michelle Willis, Simon N. Puthalakath, Hamsa Bouillet, Philippe Colman, Peter M. Huang, David Fairlie, W. Douglas
Copyright Year	2008
Description	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.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213596/pdf
Ending Page	355
Page Count	15
Starting Page	341
DOI	10.1083/jcb.200708096
Journal	Journal of Cell Biology
Issue Number	2
Volume Number	180
Language	English
Publisher	Rockefeller University Press
Publisher Date	2008-01-21
Access Restriction	Open
Subject Keyword	Biochemistry and Molecular Biology Apoptosis Survival Proteins Functional Mcl Structural Bcl Noxa Bh3 Bims2a Journal: Journal of Cell Biology (Vol- 180, Issue- 2)
Content Type	Text

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