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The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins

Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct...

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Autores principales: Mérino, Delphine, Giam, Maybelline, Hughes, Peter D., Siggs, Owen M., Heger, Klaus, O'Reilly, Lorraine A., Adams, Jerry M., Strasser, Andreas, Lee, Erinna F., Fairlie, Walter D., Bouillet, Philippe
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728397/
https://www.ncbi.nlm.nih.gov/pubmed/19651893
http://dx.doi.org/10.1083/jcb.200905153
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author Mérino, Delphine
Giam, Maybelline
Hughes, Peter D.
Siggs, Owen M.
Heger, Klaus
O'Reilly, Lorraine A.
Adams, Jerry M.
Strasser, Andreas
Lee, Erinna F.
Fairlie, Walter D.
Bouillet, Philippe
author_facet Mérino, Delphine
Giam, Maybelline
Hughes, Peter D.
Siggs, Owen M.
Heger, Klaus
O'Reilly, Lorraine A.
Adams, Jerry M.
Strasser, Andreas
Lee, Erinna F.
Fairlie, Walter D.
Bouillet, Philippe
author_sort Mérino, Delphine
collection PubMed
description Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.
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spelling pubmed-27283972010-02-10 The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins Mérino, Delphine Giam, Maybelline Hughes, Peter D. Siggs, Owen M. Heger, Klaus O'Reilly, Lorraine A. Adams, Jerry M. Strasser, Andreas Lee, Erinna F. Fairlie, Walter D. Bouillet, Philippe J Cell Biol Research Articles Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models. The Rockefeller University Press 2009-08-10 /pmc/articles/PMC2728397/ /pubmed/19651893 http://dx.doi.org/10.1083/jcb.200905153 Text en © 2009 Mérino et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Mérino, Delphine
Giam, Maybelline
Hughes, Peter D.
Siggs, Owen M.
Heger, Klaus
O'Reilly, Lorraine A.
Adams, Jerry M.
Strasser, Andreas
Lee, Erinna F.
Fairlie, Walter D.
Bouillet, Philippe
The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins
title The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins
title_full The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins
title_fullStr The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins
title_full_unstemmed The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins
title_short The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins
title_sort role of bh3-only protein bim extends beyond inhibiting bcl-2–like prosurvival proteins
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728397/
https://www.ncbi.nlm.nih.gov/pubmed/19651893
http://dx.doi.org/10.1083/jcb.200905153
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