JNK Phosphorylation of Bim-related Members of the Bcl2 Family Induces Bax-dependent Apoptosis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Feb 20

PMID 12591950

Citations 399

Authors

Kui Lei

Roger J Davis

Affiliations

Soon will be listed here.

Abstract

The c-Jun NH(2)-terminal kinase (JNK) is activated when cells are exposed to environmental stress, including UV radiation. Gene disruption studies demonstrate that JNK is essential for UV-stimulated apoptosis mediated by the mitochondrial pathway by a Bax/Bak-dependent mechanism. Here, we demonstrate that JNK phosphorylates two members of the BH3-only subgroup of Bcl2-related proteins (Bim and Bmf) that are normally sequestered by binding to dynein and myosin V motor complexes. Phosphorylation by JNK causes release from the motor complexes. These proapoptotic BH3-only proteins therefore provide a molecular link between the JNK signal transduction pathway and the Bax/Bak-dependent mitochondrial apoptotic machinery.

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References

Bouillet P, Metcalf D, Huang D, Tarlinton D, Kay T, Kontgen F . Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science. 1999; 286(5445):1735-8. DOI: 10.1126/science.286.5445.1735. View

Stahl M, Dijkers P, Kops G, Lens S, Coffer P, Burgering B . The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol. 2002; 168(10):5024-31. DOI: 10.4049/jimmunol.168.10.5024. View

Tournier C, Hess P, Yang D, Xu J, Turner T, Nimnual A . Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science. 2000; 288(5467):870-4. DOI: 10.1126/science.288.5467.870. View

Marani M, Tenev T, Hancock D, Downward J, Lemoine N . Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol. 2002; 22(11):3577-89. PMC: 133811. DOI: 10.1128/MCB.22.11.3577-3589.2002. View

Liu J, Chandra D, Tang S, Chopra D, Tang D . Identification and characterization of Bimgamma, a novel proapoptotic BH3-only splice variant of Bim. Cancer Res. 2002; 62(10):2976-81. View

Lei K, Nimnual A, Zong W, Kennedy N, Flavell R, Thompson C . The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol. 2002; 22(13):4929-42. PMC: 133923. DOI: 10.1128/MCB.22.13.4929-4942.2002. View

Letai A, Bassik M, Walensky L, Sorcinelli M, Weiler S, Korsmeyer S . Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002; 2(3):183-92. DOI: 10.1016/s1535-6108(02)00127-7. View

Donovan N, Becker E, Konishi Y, Bonni A . JNK phosphorylation and activation of BAD couples the stress-activated signaling pathway to the cell death machinery. J Biol Chem. 2002; 277(43):40944-9. DOI: 10.1074/jbc.M206113200. View

Inoshita S, Takeda K, Hatai T, Terada Y, Sano M, Hata J . Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress. J Biol Chem. 2002; 277(46):43730-4. DOI: 10.1074/jbc.M207951200. View

10.

Derijard B, Hibi M, Wu I, Barrett T, Su B, Deng T . JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994; 76(6):1025-37. DOI: 10.1016/0092-8674(94)90380-8. View

11.

Raingeaud J, Gupta S, Rogers J, Dickens M, Han J, Ulevitch R . Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995; 270(13):7420-6. DOI: 10.1074/jbc.270.13.7420. View

12.

Xia Z, Dickens M, Raingeaud J, Davis R, Greenberg M . Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995; 270(5240):1326-31. DOI: 10.1126/science.270.5240.1326. View

13.

Raingeaud J, Whitmarsh A, Barrett T, Derijard B, Davis R . MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996; 16(3):1247-55. PMC: 231107. DOI: 10.1128/MCB.16.3.1247. View

14.

Park D, Stefanis L, Yan C, Farinelli S, Greene L . Ordering the cell death pathway. Differential effects of BCL2, an interleukin-1-converting enzyme family protease inhibitor, and other survival agents on JNK activation in serum/nerve growth factor-deprived PC12 cells. J Biol Chem. 1996; 271(36):21898-905. DOI: 10.1074/jbc.271.36.21898. View

15.

Dickens M, Rogers J, Cavanagh J, Raitano A, Xia Z, Halpern J . A cytoplasmic inhibitor of the JNK signal transduction pathway. Science. 1997; 277(5326):693-6. DOI: 10.1126/science.277.5326.693. View

16.

Yang D, Kuan C, Whitmarsh A, Rincon M, Zheng T, Davis R . Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature. 1998; 389(6653):865-70. DOI: 10.1038/39899. View

17.

Eilers A, Whitfield J, Babij C, Rubin L, Ham J . Role of the Jun kinase pathway in the regulation of c-Jun expression and apoptosis in sympathetic neurons. J Neurosci. 1998; 18(5):1713-24. PMC: 6792616. View

18.

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

19.

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

20.

Dijkers P, Medema R, Lammers J, Koenderman L, Coffer P . Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol. 2000; 10(19):1201-4. DOI: 10.1016/s0960-9822(00)00728-4. View