Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim
Details
Publication Year 2003-12-15,Volume 22,Issue #24,Page 6653-6664
Journal Title
EMBO JOURNAL
Publication Type
Journal Article
Abstract
Osteoclasts (OCs) undergo rapid apoptosis without trophic factors, such as macrophage colony-stimulating factor (M-CSF). Their apoptosis was associated with a rapid and sustained increase in the pro-apoptotic BH3-only Bcl-2 family member Bim. This was caused by the reduced ubiquitylation and proteasomal degradation of Bim that is mediated by c-Cbl. Although the number of OCs was increased in the skeletal tissues of bim-/- mice, the mice exhibited mild osteosclerosis due to reduced bone resorption. OCs differentiated from bone marrow cells of bim-/- animals showed a marked prolongation of survival in the absence of M-CSF, compared with bim+/+ OCs, but the bone-resorbing activity of bim-/- OCs was significantly reduced. Overexpression of a degradation-resistant lysine-free Bim mutant in bim-/- cells abrogated the anti-apoptotic effect of M-CSF, while wild-type Bim did not. These results demonstrate that ubiquitylation-dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.
Publisher
OXFORD UNIV PRESS
Keywords
CELL-DEATH; BONE-RESORPTION; PROTEIN BIM; C-CBL; DEPENDENT DEGRADATION; SIGNALING PATHWAY; LIGASE ACTIVITY; X-L; SURVIVAL; UBIQUITIN
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Creation Date: 2003-12-15 12:00:00
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