ER stress triggers apoptosis by activating BH3-only protein Bim
Details
Publication Year 2007-06-29, Volume 129, Issue #7, Page 1337-1349
Journal Title
CELL
Publication Type
Journal Article
Abstract
Endoplasmic reticulum ( ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-onlymember of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBP alpha-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.
Publisher
CELL PRESS
Keywords
ENDOPLASMIC-RETICULUM STRESS; FAMILY-MEMBER BIM; BCL-2 RELATIVE BIM; MOTOR COMPLEX; CELL-DEATH; PUMA; EXPRESSION; INHIBITOR; RESPONSES; PATHWAYS
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Creation Date: 2007-06-29 12:00:00
Last Modified: 0001-01-01 12:00:00
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