Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax.
Proc Natl Acad Sci U S A
; 105(47): 18081-7, 2008 Nov 25.
Article
em En
| MEDLINE
| ID: mdl-18981409
ABSTRACT
A central issue in the control of apoptosis is whether its essential mediators Bax and Bak must be restrained by Bcl-2-like prosurvival relatives to prevent their damaging mitochondria and unleashing apoptosis. The issue is particularly vexed for Bax, which is largely a cytosolic monomer in unstressed cells. To determine whether Bax regulation requires its binding by prosurvival relatives, we replaced a conserved aspartate in its BH3 interaction domain with arginine. Bax D68R functioned and behaved like wild-type Bax in localization and activation but had greatly impaired binding to the prosurvival family members. Nevertheless, Bcl-x(L) remained able to block apoptosis induced by Bax D68R. Whereas cells with sufficient Bcl-x(L) tolerated expression of Bax D68R, it provoked apoptosis when Bcl-x(L) was absent, downregulated, or inactivated. Moreover, Bax D68R rendered membrane bound by a C-terminal anchor mutation overwhelmed endogenous Bcl-x(L) and killed cells. These unexpected results suggest that engagement of Bax by its prosurvival relatives is a major barrier to its full activation. We propose that the Bcl-2-like proteins must capture the small proportion of Bax molecules with an exposed BH3 domain, probably on the mitochondrial membrane, to prevent Bax-imposed cell death, but that Bcl-x(L) also controls Bax by other mechanisms.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sobrevivência Celular
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Apoptose
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Proteínas Proto-Oncogênicas c-bcl-2
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Proteína X Associada a bcl-2
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Austrália