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Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim


Akiyama, T; Bouillet, P; Miyazaki, T; Kadono, Y; Chikuda, H; Chung, UG; Fukuda, A; Hikita, A; Seto, H; Okada, T; Inaba, T; Sanjay, A; Baron, R; Kawaguchi, H; Oda, H; Nakamura, K; Strasser, A; Tanaka, S
2003-12-15
EMBO JOURNAL
Journal Article
22
24
6653-6664
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.
OXFORD UNIV PRESS
CELL-DEATH; BONE-RESORPTION; PROTEIN BIM; C-CBL; DEPENDENT DEGRADATION; SIGNALING PATHWAY; LIGASE ACTIVITY; X-L; SURVIVAL; UBIQUITIN
10.1093/emboj/cdg635
Refer to copyright notice on published article.

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Creation Date 2003-12-15 12:00:00