JCB logo
PeproTech: Your source for Cell Biology Research Reagents
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
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.
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 3041K)
Right arrow PPT slides of all figures
Right arrow Supplemental Material Index
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, E. F.
Right arrow Articles by Fairlie, W. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, E. F.
Right arrow Articles by Fairlie, W. D.
Right arrowPubmed/NCBI databases
*Protein*Structure
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Article

 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.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents