C-Jun N-terminal Protein Kinase 1 (JNK1), but Not JNK2, is Essential for Tumor Necrosis Factor Alpha-induced C-Jun Kinase Activation and Apoptosis

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2004 Dec 2

PMID 15572687

Citations 94

Authors

Jing Liu

Yuzuru Minemoto

Anning Lin

Affiliations

Soon will be listed here.

Abstract

Two ubiquitously expressed isoforms of c-Jun N-terminal protein kinase (JNK), JNK1 and JNK2, have shared functions and different functions. However, the molecular mechanism is unknown. Here we report that JNK1, but not JNK2, is essential for tumor necrosis factor alpha (TNF-alpha)-induced c-Jun kinase activation, c-Jun expression, and apoptosis. Using mouse fibroblasts deficient in either Jnk1 or Jnk2, we found that JNK1 was activated by TNF-alpha, whereas JNK2 activation was negligible. In addition, JNK2 interfered with JNK1 activation via its "futile" phosphorylation by upstream kinases. Consequently, expression and activation of c-Jun, which depends on JNK activity, were impaired in Jnk1 null cells but enhanced in Jnk2 null cells. TNF-alpha-induced apoptosis was also suppressed in Jnk1 null fibroblasts but increased in Jnk2 null cells. Thus, our results provide a molecular mechanism underlying the different biological functions of JNK isoforms.

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References

Karin M . The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem. 1995; 270(28):16483-6. DOI: 10.1074/jbc.270.28.16483. View

Lin A, Minden A, Martinetto H, Claret F, Mercurio F, Johnson G . Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995; 268(5208):286-90. DOI: 10.1126/science.7716521. View

Wisdom R, Johnson R, Moore C . c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. EMBO J. 1999; 18(1):188-97. PMC: 1171114. DOI: 10.1093/emboj/18.1.188. View

Kuan C, Yang D, Samanta Roy D, Davis R, Rakic P, Flavell R . The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron. 1999; 22(4):667-76. DOI: 10.1016/s0896-6273(00)80727-8. View

Zheng C, Xiang J, Hunter T, Lin A . The JNKK2-JNK1 fusion protein acts as a constitutively active c-Jun kinase that stimulates c-Jun transcription activity. J Biol Chem. 1999; 274(41):28966-71. DOI: 10.1074/jbc.274.41.28966. View

Sabapathy K, Jochum W, Hochedlinger K, Chang L, Karin M, Wagner E . Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech Dev. 1999; 89(1-2):115-24. DOI: 10.1016/s0925-4773(99)00213-0. 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

Davis R . Signal transduction by the JNK group of MAP kinases. Cell. 2000; 103(2):239-52. DOI: 10.1016/s0092-8674(00)00116-1. View

Chang L, Karin M . Mammalian MAP kinase signalling cascades. Nature. 2001; 410(6824):37-40. DOI: 10.1038/35065000. View

10.

Tang G, Minemoto Y, Dibling B, Purcell N, Li Z, Karin M . Inhibition of JNK activation through NF-kappaB target genes. Nature. 2001; 414(6861):313-7. DOI: 10.1038/35104568. View

11.

Tang G, Yang J, Minemoto Y, Lin A . Blocking caspase-3-mediated proteolysis of IKKbeta suppresses TNF-alpha-induced apoptosis. Mol Cell. 2001; 8(5):1005-16. DOI: 10.1016/s1097-2765(01)00380-x. View

12.

Karin M, Lin A . NF-kappaB at the crossroads of life and death. Nat Immunol. 2002; 3(3):221-7. DOI: 10.1038/ni0302-221. View

13.

She Q, Chen N, Bode A, Flavell R, Dong Z . Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 2002; 62(5):1343-8. View

14.

Conze D, Krahl T, Kennedy N, Weiss L, Lumsden J, Hess P . c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. J Exp Med. 2002; 195(7):811-23. PMC: 2193724. DOI: 10.1084/jem.20011508. View

15.

Hochedlinger K, Wagner E, Sabapathy K . Differential effects of JNK1 and JNK2 on signal specific induction of apoptosis. Oncogene. 2002; 21(15):2441-5. DOI: 10.1038/sj.onc.1205348. View

16.

Shaulian E, Karin M . AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002; 4(5):E131-6. DOI: 10.1038/ncb0502-e131. View

17.

Tang F, Tang G, Xiang J, Dai Q, Rosner M, Lin A . The absence of NF-kappaB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol. 2002; 22(24):8571-9. PMC: 139858. DOI: 10.1128/MCB.22.24.8571-8579.2002. View

18.

Hirosumi J, Tuncman G, Chang L, Gorgun C, Uysal K, Maeda K . A central role for JNK in obesity and insulin resistance. Nature. 2002; 420(6913):333-6. DOI: 10.1038/nature01137. View

19.

Lin A . Activation of the JNK signaling pathway: breaking the brake on apoptosis. Bioessays. 2003; 25(1):17-24. DOI: 10.1002/bies.10204. View

20.

Eferl R, Ricci R, Kenner L, Zenz R, David J, Rath M . Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell. 2003; 112(2):181-92. DOI: 10.1016/s0092-8674(03)00042-4. View