c-Jun NH2-Terminal Kinase Is Essential for the Regulation of AP-1 by Tumor Necrosis Factor

ABSTRACT The c-Jun NH2-terminal kinase (JNK) is activated by the cytokine tumor necrosis factor (TNF). This pathway is implicated in the regulation of AP-1-dependent gene expression by TNF. To examine the role of the JNK signaling pathway, we compared the effects of TNF on wild-type and Jnk1 −/− Jnk2 −/− murine embryo fibroblasts. We show that JNK is required for the normal regulation of AP-1 by TNF. The JNK-deficient cells exhibited decreased expression of c-Jun, JunD, c-Fos, Fra1, and Fra2; decreased phosphorylation of c-Jun and JunD; and decreased AP-1 DNA binding activity. The JNK-deficient cells also exhibited defects in the regulation of the AP-1-related transcription factor ATF2. These changes were associated with marked defects in TNF-regulated gene expression. The JNK signal transduction pathway is therefore essential for AP-1 transcription factor regulation in cells exposed to TNF.

[1]  K. Kooistra,et al.  Growth factors can activate ATF2 via a two‐step mechanism: phosphorylation of Thr71 through the Ras–MEK–ERK pathway and of Thr69 through RalGDS–Src–p38 , 2002, The EMBO journal.

[2]  D. Goeddel,et al.  TNF-R1 Signaling: A Beautiful Pathway , 2002, Science.

[3]  M. Karin,et al.  AP-1 as a regulator of cell life and death , 2002, Nature Cell Biology.

[4]  David W. Anderson,et al.  SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Karin,et al.  Signal transduction by tumor necrosis factor and its relatives. , 2001, Trends in cell biology.

[6]  M. Karin,et al.  c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. , 2001, The Journal of clinical investigation.

[7]  R. Flavell,et al.  MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. , 2001, Genes & development.

[8]  T Takahashi,et al.  ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis , 2001, EMBO reports.

[9]  L. Glimcher,et al.  Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice. , 2001, International immunology.

[10]  W. V. Berghe,et al.  Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. , 2000, Biochemical pharmacology.

[11]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[12]  Ian F. Dunn,et al.  A Lipopolysaccharide-Specific Enhancer Complex Involving Ets, Elk-1, Sp1, and CREB Binding Protein and p300 Is Recruited to the Tumor Necrosis Factor Alpha Promoter In Vivo , 2000, Molecular and Cellular Biology.

[13]  Jiahuai Han,et al.  Regulation of TNF Expression by Multiple Mitogen-Activated Protein Kinase Pathways1 , 2000, The Journal of Immunology.

[14]  D. Bar-Sagi,et al.  Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. , 2000, Science.

[15]  M. Kelliher,et al.  The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. , 2000, Immunity.

[16]  R. Flavell,et al.  Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  N. Franchimont,et al.  Platelet-derived Growth Factor Induces Interleukin-6 Transcription in Osteoblasts through the Activator Protein-1 Complex and Activating Transcription Factor-2* , 1999, The Journal of Biological Chemistry.

[18]  J. Yasuda,et al.  A mammalian scaffold complex that selectively mediates MAP kinase activation. , 1998, Science.

[19]  W. Ansorge,et al.  Differential regulation of c‐Jun by ERK and JNK during PC12 cell differentiation , 1998, The EMBO journal.

[20]  J L Cleveland,et al.  Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. , 1998, Genes & development.

[21]  D. Goeddel,et al.  FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. , 1998, Science.

[22]  A. Sharrocks,et al.  Differential targeting of MAP kinases to the ETS‐domain transcription factor Elk‐1 , 1998, The EMBO journal.

[23]  Stefan Grimm,et al.  The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal , 1998 .

[24]  D. Goeddel,et al.  Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. , 1997, Immunity.

[25]  Jiahuai Han,et al.  Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation , 1997, Nature.

[26]  W. M. Weaver,et al.  The Proximal Regulatory Element of the Interferon-γ Promoter Mediates Selective Expression in T Cells* , 1996, The Journal of Biological Chemistry.

[27]  Masahiko Hibi,et al.  c-Jun Can Recruit JNK to Phosphorylate Dimerization Partners via Specific Docking Interactions , 1996, Cell.

[28]  H. K. Sluss,et al.  Selective interaction of JNK protein kinase isoforms with transcription factors. , 1996, The EMBO journal.

[29]  W. Fiers,et al.  The p38/RK mitogen‐activated protein kinase pathway regulates interleukin‐6 synthesis response to tumor necrosis factor. , 1996, The EMBO journal.

[30]  R. Davis,et al.  MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway , 1996, Molecular and cellular biology.

[31]  I. Herr,et al.  ATF‐2 is preferentially activated by stress‐activated protein kinases to mediate c‐jun induction in response to genotoxic agents. , 1995, The EMBO journal.

[32]  N. Jones,et al.  ATF‐2 contains a phosphorylation‐dependent transcriptional activation domain. , 1995, The EMBO journal.

[33]  Jiahuai Han,et al.  Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (*) , 1995, The Journal of Biological Chemistry.

[34]  B. Dérijard,et al.  Transcription factor ATF2 regulation by the JNK signal transduction pathway , 1995, Science.

[35]  H. K. Sluss,et al.  Signal transduction by tumor necrosis factor mediated by JNK protein kinases , 1994, Molecular and cellular biology.

[36]  D. Brenner,et al.  Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. , 1994, The Journal of biological chemistry.

[37]  J. Woodgett,et al.  The stress-activated protein kinase subfamily of c-Jun kinases , 1994, Nature.

[38]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

[39]  P. Coffer,et al.  junB promoter regulation: Ras mediated transactivation by c-Ets-1 and c-Ets-2. , 1994, Oncogene.

[40]  M. Karin,et al.  Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. , 1993, Genes & development.

[41]  M. Karin,et al.  JunB differs from c-Jun in its DNA-binding and dimerization domains, and represses c-Jun by formation of inactive heterodimers. , 1993, Genes & development.

[42]  W. Fiers,et al.  Activation of the nuclear factor kappa B is not sufficient for regulation of tumor necrosis factor-induced interleukin-6 gene expression. , 1993, Biochimie.

[43]  James R. Woodgett,et al.  Phosphorylation of c-jun mediated by MAP kinases , 1991, Nature.

[44]  N. Andrews,et al.  A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. , 1991, Nucleic acids research.

[45]  K. Mitomo,et al.  Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines , 1990, Molecular and cellular biology.

[46]  D. Brenner,et al.  Prolonged activation of jun and collagenase genes by tumour necrosis factor-α , 1989, Nature.