TY - JOUR
T1 - The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins
AU - Mérino, Delphine
AU - Giam, Maybelline
AU - Hughes, Peter D.
AU - Siggs, Owen M.
AU - Heger, Klaus
AU - O'Reilly, Lorraine A.
AU - Adams, Jerry M.
AU - Strasser, Andreas
AU - Lee, Erinna F.
AU - Fairlie, Walter D.
AU - Bouillet, Philippe
N1 - 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/).
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=68549089038&partnerID=8YFLogxK
U2 - 10.1083/jcb.200905153
DO - 10.1083/jcb.200905153
M3 - Article
C2 - 19651893
AN - SCOPUS:68549089038
SN - 0021-9525
VL - 186
SP - 355
EP - 362
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 3
ER -