A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation
Details
Publication Year 2008-01-28, Volume 180, Issue #2, Page 341-355
Journal Title
JOURNAL OF CELL BIOLOGY
Publication Type
Journal Article
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(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.
Publisher
ROCKEFELLER UNIV PRESS
Keywords
BCL-2 FAMILY-MEMBERS; CHRONIC LYMPHOCYTIC-LEUKEMIA; DEPENDENT KINASE INHIBITOR; DOWN-REGULATION; BH3-ONLY PROTEINS; MULTIPLE-MYELOMA; PROSURVIVAL BCL-2; BINDING PEPTIDES; INDUCE APOPTOSIS; MIMETIC ABT-737
Rights Notice
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Creation Date: 2008-01-28 12:00:00
Last Modified: 0001-01-01 12:00:00
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