Regulation of Osteoclast Apoptosis by Ubiquitylation of Proapoptotic BH3-only Bcl-2 Family Member Bim

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2003 Dec 6

PMID 14657036

Citations 93

Authors

Toru Akiyama

Phillippe Bouillet

Tsuyoshi Miyazaki

Yuho Kadono

Hirotaka Chikuda

Ung-Il Chung

Akira Fukuda

Atsuhiko Hikita

Hiroaki Seto

Takashi Okada

Toshiya Inaba

Archana Sanjay

Roland Baron

Hiroshi Kawaguchi

Hiromi Oda

Kozo Nakamura

Andreas Strasser

Sakae Tanaka

Affiliations

Soon will be listed here.

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.

Citing Articles

Regulation of apoptosis by ubiquitination in liver cancer.

Li Y, Zhu J, Yu Z, Zhai F, Li H, Jin X Am J Cancer Res. 2023; 13(10):4832-4871.

PMID: 37970337 PMC: 10636691.

ECSIT is essential for RANKL-induced stimulation of mitochondria in osteoclasts and a target for the anti-osteoclastogenic effects of estrogens.

Marques-Carvalho A, Sardao V, Kim H, Almeida M Front Endocrinol (Lausanne). 2023; 14:1110369.

PMID: 37152948 PMC: 10157190. DOI: 10.3389/fendo.2023.1110369.

Identification of kukoamine a as an anti-osteoporosis drug target using network pharmacology and experiment verification.

Luo L, Guan Z, Jin X, Guan Z, Jiang Y Mol Med. 2023; 29(1):36.

PMID: 36941586 PMC: 10029210. DOI: 10.1186/s10020-023-00625-6.

Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer.

Nishihara S, Yamaoka T, Ishikawa F, Higuchi K, Hasebe Y, Manabe R Genes (Basel). 2022; 13(12).

PMID: 36553449 PMC: 9778480. DOI: 10.3390/genes13122183.

Protein ubiquitination in T cell development.

Zhong T, Lei K, Lin X, Xie Z, Luo S, Zhou Z Front Immunol. 2022; 13:941962.

PMID: 35990660 PMC: 9386135. DOI: 10.3389/fimmu.2022.941962.

References

Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H, Sawada Y, Yamamoto A . Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol. 2000; 148(2):333-42. PMC: 2174281. DOI: 10.1083/jcb.148.2.333. View

Wong B, Besser D, Kim N, Arron J, Vologodskaia M, Hanafusa H . TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell. 2000; 4(6):1041-9. DOI: 10.1016/s1097-2765(00)80232-4. View

Breitschopf K, Zeiher A, Dimmeler S . Ubiquitin-mediated degradation of the proapoptotic active form of bid. A functional consequence on apoptosis induction. J Biol Chem. 2000; 275(28):21648-52. DOI: 10.1074/jbc.M001083200. View

OReilly L, Cullen L, Visvader J, Lindeman G, Print C, Bath M . The proapoptotic BH3-only protein bim is expressed in hematopoietic, epithelial, neuronal, and germ cells. Am J Pathol. 2000; 157(2):449-61. PMC: 1850143. DOI: 10.1016/S0002-9440(10)64557-9. View

Strasser A, OConnor L, Dixit V . Apoptosis signaling. Annu Rev Biochem. 2000; 69:217-45. DOI: 10.1146/annurev.biochem.69.1.217. View

Joazeiro C, Weissman A . RING finger proteins: mediators of ubiquitin ligase activity. Cell. 2000; 102(5):549-52. DOI: 10.1016/s0092-8674(00)00077-5. View

Huang D, Strasser A . BH3-Only proteins-essential initiators of apoptotic cell death. Cell. 2001; 103(6):839-42. DOI: 10.1016/s0092-8674(00)00187-2. View

Shinjyo T, Kuribara R, Inukai T, Hosoi H, Kinoshita T, Miyajima A . Downregulation of Bim, a proapoptotic relative of Bcl-2, is a pivotal step in cytokine-initiated survival signaling in murine hematopoietic progenitors. Mol Cell Biol. 2001; 21(3):854-64. PMC: 86676. DOI: 10.1128/MCB.21.3.854-864.2001. View

Sanjay A, Houghton A, Neff L, DiDomenico E, Bardelay C, Antoine E . Cbl associates with Pyk2 and Src to regulate Src kinase activity, alpha(v)beta(3) integrin-mediated signaling, cell adhesion, and osteoclast motility. J Cell Biol. 2001; 152(1):181-95. PMC: 2193648. DOI: 10.1083/jcb.152.1.181. View

10.

Marshansky V, Wang X, Bertrand R, Luo H, Duguid W, Chinnadurai G . Proteasomes modulate balance among proapoptotic and antiapoptotic Bcl-2 family members and compromise functioning of the electron transport chain in leukemic cells. J Immunol. 2001; 166(5):3130-42. DOI: 10.4049/jimmunol.166.5.3130. View

11.

Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S . Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J. 2001; 20(6):1271-80. PMC: 145527. DOI: 10.1093/emboj/20.6.1271. View

12.

Putcha G, Moulder K, Golden J, Bouillet P, Adams J, Strasser A . Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron. 2001; 29(3):615-28. DOI: 10.1016/s0896-6273(01)00238-0. View

13.

Whitfield J, Neame S, Paquet L, Bernard O, Ham J . Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron. 2001; 29(3):629-43. DOI: 10.1016/s0896-6273(01)00239-2. View

14.

Zong W, LINDSTEN T, Ross A, Macgregor G, Thompson C . BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 2001; 15(12):1481-6. PMC: 312722. DOI: 10.1101/gad.897601. View

15.

Cheng E, Wei M, Weiler S, Flavell R, Mak T, LINDSTEN T . BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001; 8(3):705-11. DOI: 10.1016/s1097-2765(01)00320-3. View

16.

Mochizuki T, Asai A, Saito N, Tanaka S, Katagiri H, Asano T . Akt protein kinase inhibits non-apoptotic programmed cell death induced by ceramide. J Biol Chem. 2001; 277(4):2790-7. DOI: 10.1074/jbc.M106361200. View

17.

Dijkers P, Birkenkamp K, Lam E, Thomas N, Lammers J, Koenderman L . FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. J Cell Biol. 2002; 156(3):531-42. PMC: 2173339. DOI: 10.1083/jcb.200108084. View

18.

Jesenberger V, Jentsch S . Deadly encounter: ubiquitin meets apoptosis. Nat Rev Mol Cell Biol. 2002; 3(2):112-21. DOI: 10.1038/nrm731. View

19.

Bouillet P, Purton J, Godfrey D, Zhang L, Coultas L, Puthalakath H . BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature. 2002; 415(6874):922-6. DOI: 10.1038/415922a. View

20.

Glickman M, Ciechanover A . The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002; 82(2):373-428. DOI: 10.1152/physrev.00027.2001. View