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

The Journal of Cell Biology
Erinna F LeeWalter D Fairlie

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.

References

Jan 1, 1991·Methods in Enzymology·T A KunkelJ McClary
Aug 1, 1996·Human Gene Therapy·T M Kinsella, G P Nolan
Feb 28, 1998·The EMBO Journal·L O'ConnorD C Huang
Aug 18, 1999·Proceedings of the National Academy of Sciences of the United States of America·K MoriishiJ M Adams
Nov 15, 2000·Methods in Enzymology·S S SidhuJ A Wells
Feb 24, 2001·Protein Science : a Publication of the Protein Society·A M PetrosS W Fesik
Sep 22, 2001·Acta Crystallographica. Section D, Biological Crystallography·R J Read
Nov 25, 2003·Genes & Development·Andrea CuconatiEileen White
Nov 25, 2003·Oncogene·Suzanne CoryJerry M Adams
Dec 12, 2003·Nature·Joseph T OpfermanStanley J Korsmeyer
Mar 3, 2004·Acta Crystallographica. Section D, Biological Crystallography·Laurent C StoroniRandy J Read
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Feb 19, 2005·Science·Joseph T OpfermanStanley J Korsmeyer
Apr 5, 2005·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoyRandy J Read
May 20, 2005·Nature·Tilman OltersdorfSaul H Rosenberg
Oct 22, 2005·Nature Reviews. Cancer·Stephen W Fesik
Oct 26, 2005·Current Opinion in Cell Biology·Simon N Willis, Jerry M Adams
Nov 18, 2005·Journal of Hepatology·Wolfgang SieghartVolker Wacheck
Feb 4, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kirsten Canté-BarrettGerald R Crabtree
Apr 29, 2006·Cell Death and Differentiation·D ZhaiJ C Reed
May 20, 2006·Cell Death and Differentiation·J T Opferman
Oct 5, 2006·Cancer Research·Jian-Zhong QinBrian J Nickoloff

❮ Previous
Next ❯

Citations

Nov 24, 2017·Cell Adhesion & Migration·Adelaide Ij YoungSamantha R Oakes
Apr 23, 2013·Nature Chemical Biology·Guillaume LesseneKeith G Watson
Jul 12, 2011·Chembiochem : a European Journal of Chemical Biology·Erinna F LeeW Douglas Fairlie
Dec 24, 2018·The EMBO Journal·Jonathan P BernardiniGrant Dewson
Feb 21, 2018·Cell Death and Differentiation·Colin HockingsRuth M Kluck
Nov 7, 2019·Acta Crystallographica. Section D, Structural Biology·Jakub LuptakDavid Hargreaves
Jun 5, 2019·Nature Communications·Richard W BirkinshawPeter E Czabotar
Dec 2, 2008·Nature Reviews. Drug Discovery·Guillaume LessenePeter M Colman
Dec 2, 2009·The Journal of Cell Biology·Joslyn K BrunelleAnthony Letai
Dec 17, 2010·Journal of Virology·Logan BanadygaMichele Barry
Mar 30, 2011·Proceedings of the National Academy of Sciences of the United States of America·Erinna F LeeW Douglas Fairlie
Dec 4, 2013·Leukemia & Lymphoma·Shadia ZamanVarsha Gandhi
Nov 10, 2009·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Fabio GhiottoSilvia Bruno
Feb 17, 2010·Cellular and Molecular Life Sciences : CMLS·Gabriela BrumattiPaul G Ekert
Jul 2, 2011·Proteins·Stéphane AcocaEnrico O Purisima
Jun 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Lisa M LindqvistDavid L Vaux
Aug 10, 2013·Chembiochem : a European Journal of Chemical Biology·Brian J SmithW Douglas Fairlie
Dec 21, 2013·Nature Reviews. Molecular Cell Biology·Peter E CzabotarJerry M Adams
Jul 31, 2014·Proceedings of the National Academy of Sciences of the United States of America·Liang ZhaoPeter Koopman
Sep 26, 2015·Oncotarget·Ronit Vogt SionovZvi Granot
Oct 28, 2016·Nature·András KotschyOlivier Geneste
Sep 12, 2020·Cell Death & Disease·Ming-Jie LuoJia-Nan Gong
Mar 11, 2010·Apoptosis : an International Journal on Programmed Cell Death·Lubomir ProchazkaJiri Neuzil
Aug 3, 2013·Investigational New Drugs·Kumudha Balakrishnan, Varsha Gandhi
Feb 18, 2017·Nature Reviews. Drug Discovery·Avi AshkenaziAndrew J Souers

❮ Previous
Next ❯

Datasets Mentioned

BETA
ABT-737

Methods Mentioned

BETA
xenograft
phage display
biosensor
isothermal titration calorimetry
ELISAs
immunoprecipitation
ELISA
coimmunoprecipitation
transfection

Software Mentioned

PHASER
HKL2000
COOT

Related Concepts

Related Feeds

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis