Integration of TNF-a Signaling: Crosstalk between IKK, JNK, and Caspases

  • Anning Lin
Chapter

Abstract

The pro-inflammatory cytokine tumor necrosis factor-a (TNF-a) is a key regulator in immune responses, inflammation and programmed cell death (apoptosis). TNF-a exerts its biological activities through activation of multiple signaling effectors, including IKK, JNK and caspases. Activation of caspases is required for apoptosis, whereas IKK activation results in inhibition of apoptosis through the transcription factor NF-kB, which can induce expression of inhibitors of apoptosis. Activation of JNK stimulates the transcription factor c-Jun/AP-1, which regulates expression of many genes. In contrast to IKK and caspases, the role of JNK activation in apoptosis is highly controversial. Recent studies reveal that crosstalk between IKK, JNK and caspases determines the life or death of a cell in response to TNF-a. Here we propose a model that can explain how integration of TNF-a signaling affects the process of apoptosis.

Key Words

NF-kB JNK Apoptosis TNF-a Crosstalk 
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References

  1. 1.
    Tartaglila, L.A., and Goeddel, D.V. (1992). Two TNF receptors. Immunol. Today 13, 151–153.CrossRefGoogle Scholar
  2. 2.
    Tracey, K.J., and Cerami, A. (1993). Tumor necrosis factor: an updeated review of its biology. Crit. Care Med. 21, S415 - S422.PubMedCrossRefGoogle Scholar
  3. 3.
    Karin, M., and Lin, A. (2002). NF-kB at the crossroads of life and death. Nature Immunol. 3, 221–227.CrossRefGoogle Scholar
  4. 4.
    Cryns, V., and Yuan, J. (1998). Proteases to die for. Genes Dev. 12, 1551–1570.PubMedCrossRefGoogle Scholar
  5. 5.
    Bydihardjo, I., Oliver, H., Lutter, M., Luo, X., and Wang, X. (1999). Biochemical pathways of caspase activation during apoptosis. Annu. Rev. Cell Dev. Biol. 15, 269–290.Google Scholar
  6. 6.
    Green, D.R., and Reed, J. C. (1998). Mitochondria and apoptosis. Science 281, 1309–1313.PubMedCrossRefGoogle Scholar
  7. 7.
    Ghosh, S., and Karin, M. (2002) Missing pieces in the NF-kB puzzle. Cell 109, Suppl: S81–96.Google Scholar
  8. 8.
    Karin. M., and Ben-Neriah, Y. (2000). Phosphorylation meets ubiquitination: the control of NF-kB activity. Annu Rev Immunol. 18, 621–663.PubMedCrossRefGoogle Scholar
  9. 9.
    Lin, A. (2003). Activation of the JNK signaling pathway: breaking the brake on apoptosis. BioEssays 25, 17–24.PubMedCrossRefGoogle Scholar
  10. 10.
    Lin, A., Minden, A., Martinetto, H., Claret, F.X., Lange-Carter, C., Mercurio, F., Johnson, G.L., and Karin, M. (1995). Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science 268, 286–290.PubMedCrossRefGoogle Scholar
  11. 11.
    Lu, X., Nemoto, S., and Lin, A. (1997). Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. J. Biol. Chem. 272, 24751–24754.PubMedCrossRefGoogle Scholar
  12. 12.
    Davis, R.J. (2000). Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252.PubMedCrossRefGoogle Scholar
  13. 13.
    Chinnaiyan, A. M., O’Rourke, K., Tewari, M., and Dixit, V.M. (1995). FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81, 505–512.PubMedCrossRefGoogle Scholar
  14. 14.
    Tang, G., Yang, J., Minemoto, Y., Lin, A. (2001a). Blocking caspase-3-mediated proteolysis of IKKb suppresses TNF-a -induced apoptosis. Mol. Cell 8, 1005–1016.PubMedCrossRefGoogle Scholar
  15. 15.
    Lin, Y., Devin, A., Rodriguez, Y., Liu, Z.G. (1999). Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev 13, 2514–2526.PubMedCrossRefGoogle Scholar
  16. 16.
    Duckett, C.S., and Thompson, C.B. (1997). CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival. Genes Dev 11, 2810–2821.PubMedCrossRefGoogle Scholar
  17. 17.
    Barkett, M., Xue, D., Horvitz, H.R., Gilmore, T.D. (1997). Phosphorylation of IkBa inhibits its cleavage by caspase CPP32 in vitro. J. Biol. Chem. 272, 29419–29422.PubMedCrossRefGoogle Scholar
  18. 18.
    Tang, G., Minemoto, Y., Dibling, B., Purcell, N.H., Li, Z., Karin, M., and Lin, A. (2001 b). Inhibition of JNK activation through NF-kB target genes. Nature 414, 313–317.Google Scholar
  19. 19.
    Javelaud, D., Besancon, F. (2001). NF-kB activation results in rapid inactivation of JNK in TNF-a-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-kB. B. Oncogene 20, 4365–4372.CrossRefGoogle Scholar
  20. 20.
    De Smaele, E., Zazzeroni, F., Papa, S., Nguyen, D.U., Jin, R., Jones, J., Cong, R., Franzoso, G. (2001). Induction of gadd45b by NF-kB downregulates pro-apoptotic JNK signaling. Nature 414, 308–311.PubMedCrossRefGoogle Scholar
  21. 21.
    Tang, F., Tang, G, Xiang, J., Dai, Q., Rosner, M.R., and Lin, A. (2002). The absence of NF-kB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor a -induced apoptosis. Mol. Cell. Biol. 22, 8571–8579.Google Scholar
  22. 22.
    Zheng, C., Xiang, J., Hunter, T., and Lin, A. (1999). The JNKK2–JNK1 fusion protein acts as a constitutively active c-Jun kinase that stimulates c-Jun transcription activity. J. Biol. Chem. 274, 28966–28971.PubMedCrossRefGoogle Scholar
  23. 23.
    Tournier, C., Hess, P., Yang, D.D., Xu, J., Turner, T.K., Nimnual, A., Bar-Sagi, D., Jones, S.N., Flavell, R.A., and Davis, R.J. (2000). Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288, 870–874.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Anning Lin
    • 1
  1. 1.Ben May Institute for Cancer ResearchThe University of ChicagoChicagoUSA

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