Skip to main content
SpringerLink
Log in

Regulation of NF-κB Function

Novel Molecular Targets for Pharmacological Intervention

  • Chapter
Signaling Networks and Cell Cycle Control

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 283 Accesses

Abstract

Malignant tumor cells have usually accumulated mutations that affect a variety of cellular processes, including those that sustain cell growth, that block growth inhibition and apoptosis, that affect DNA repair, and that allow the tumor to escape immune surveillance. The Rel/NF-κB transcription factor family participates in the induction of a variety of cellular and viral genes involved in these processes. Although NF-κB was originally identified as a transcription factor required for B-cell-specific gene expression, subsequent studies demonstrated that it is ubiquitously expressed and serves as a critical regulator of the inducible expression of many genes. For this reason, the pharmaceutical industry has focused significant attention on this pathway for the identification of novel therapeutic agents. However, much remains to be understood as to how NF-κB is regulated and the specific role played by this transcription factor in the spectrum of tumors in man. This chapter briefly summarizes recent findings on the mechanisms of NF-κB regulation in cells and on the potential role of NF-κB in cancer. This information suggests that NF-κB inhibitors will represent agents with broad potential for the treatment of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Baldwin AS. The NF-KB and IKB proteins: New discoveries and insights. Annu Rev Immunol 1996; 14: 649–681.

    Article  PubMed  CAS  Google Scholar 

  2. Kopp E, Ghosh S. NF-KB and Rel proteins in innate immunity. Adv Immunol 1995; 58: 1–27.

    Article  PubMed  CAS  Google Scholar 

  3. Baeuerle PA, Baltimore D. NF-icB: Ten years after. Cell 1996; 87: 13–20.

    Article  PubMed  CAS  Google Scholar 

  4. Baeuerle PA, Henkel T. Function and activation of NF-KB in the immune system. Annu Rev Immunol 1994; 12: 141–179.

    Article  PubMed  CAS  Google Scholar 

  5. May MJ, Ghosh S. Signal transduction through NF-KB. Immunol Today 1998; 19: 80–88.

    Article  PubMed  CAS  Google Scholar 

  6. Whiteside ST, Epinat JC, Rice NR, Israel A. IiB epsilon, a novel member of the IiB family, controls Re1A and cRel NF-KB activity. EMBO J 1997; 16: 1413–1426.

    Article  PubMed  CAS  Google Scholar 

  7. Henkel T, Zabel U, Van Zee K, Muller JM, Fanning E, Baeuerle P. Intramolecular masking of the nuclear location signal and dimerization domain in the precursor for the p50 NF-KB subunit. Cell 1992; 68: 1121–1133.

    Article  PubMed  CAS  Google Scholar 

  8. Bauerle PA, Baichwal VR. NF-KB as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol 1997; 65: 111–136.

    Article  Google Scholar 

  9. Regnier CH, Song H, Gao H, Goeddel DV, Cao Z, Rothe M. Identification and characterization of an IiB Kinase. Cell 1997; 90: 373–383.

    Article  PubMed  CAS  Google Scholar 

  10. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IiB kinase that activates the transcription factor NF-KB. Nature 1997; 388: 853–862.

    Google Scholar 

  11. Zandi E, Rothwarf DM, Delhasse M, Hayakawa M, Karin M. The IiB kinase complex (IKK) contains two kinase subunits, IKKa and IKK(3, necessary for IiB phosphorylation and NF-x13 activation. Cell 1997; 91: 243–252.

    Article  PubMed  CAS  Google Scholar 

  12. Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young D, Barbosa M, Mann M, Manning AM, Rao A. IKK-1 and IKK-2: Cytokine-activated IiB kinases essential for NF-K13 activation. Science 1997; 278: 860–866.

    Article  PubMed  CAS  Google Scholar 

  13. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV. IxB kinase-p: NF-KB activation and complex formation with IiB kinase-a and NIK. Science 1997; 278: 866–869.

    Article  PubMed  CAS  Google Scholar 

  14. Stancovski I, Baltimore D. NF-xB activation: The IiB kinase revealed? Cell 1997; 91: 299–302.

    Article  PubMed  CAS  Google Scholar 

  15. Maniatis T. Catalysis by a multiprotein IxB kinase complex. Science 1997; 278: 818–819.

    Article  PubMed  CAS  Google Scholar 

  16. Verma IM, Stevenson J. IiB kinase: Beginning, not end. Proc Nat Acad Sci USA 1997; 94: 11758–11760.

    Article  PubMed  CAS  Google Scholar 

  17. Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, Ben-Neriah Y. Stimulation-dependent IiBa phosphorylation marks the NF-KB inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1995; 92:10, 599–10, 603.

    Article  CAS  Google Scholar 

  18. Yaron A, Gonen H, Alkalay I, Hatzubai A, et al. Inhibition of NF-KB cellular function via specific targeting of the IiB ubiquitin ligase. EMBO J 1997; 16: 6486–6494.

    Article  PubMed  CAS  Google Scholar 

  19. Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T. Signal-induced site-specific phosphorylation targets IiB a to the ubiquitin-proteasome pathway. Genes Dev 1995; 9: 1586–1597.

    Article  PubMed  CAS  Google Scholar 

  20. Lee FS, Hagler J, Chen ZJ, Maniatis T. Acitvation of the IiBa complex by MEKK1, a kinase of the JNK pathway. Cell 1997; 88: 213–222.

    Article  PubMed  CAS  Google Scholar 

  21. Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1. Nature 1997; 385: 540–544.

    Article  PubMed  CAS  Google Scholar 

  22. Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H, Okumura K. Differential regulation of IiB kinase a and x by two upstream kinases, NF-KB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc Natl Acad Sci USA 1998; 95: 3537–3542.

    Article  PubMed  CAS  Google Scholar 

  23. Yin M-J, Christerson LB, Yamamoto Y, Kwak Y-T, Xu S, Mercurio F, Barbosa M, Cobb MH, Gaynor RB. HTLV-I Tax protein binds to MEKK1 to stimulate IiB kinase activity and NF-x13 activation. Cell 1998; 93: 875–884.

    Article  PubMed  CAS  Google Scholar 

  24. Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk H, Kay RJ, Israël A. Complementation cloning of NEMO, a component of the IiB kinase complex essential for NF-KB activation. Cell 1998; 93: 1231–1240.

    Article  PubMed  CAS  Google Scholar 

  25. Mercurio F, Murray B, Bennett BL, Pascaul G, Shevchenko A, Zhu H, Young D, Li J, Mann M, Manning A. IKKAP-1, a novel regulator of NF-KB activation, reveals heterogeneity in IxB complexes. Mol Cell Biol 1999; 19: 1526–1538.

    PubMed  CAS  Google Scholar 

  26. Orian A, Whiteside S, Israel A, Stancovski I, Schwartz AL, Ciechanover A. Ubiquitinmediated processing of NF-KB transcriptional activator precursor p105. Reconstitution of a cell-free system and identification of the ubiquitin-carrier protein, E2, and a novel ubiquitinprotein ligase, E3, involved in conjugation. J Biol Chem 1995; 270:21, 707–21, 714.

    Google Scholar 

  27. Yaron A, Alkalay I, Hatzubai A, Jung S, Beyth S, Mercurio F, Manning AM, Gonen H, Ciechanover A, Ben-Neriah Y. Inhibition of NF-KB cellular function via specific targeting of the IxB ubiquitin ligase. EMBO J 1997; 16: 101–107

    Article  Google Scholar 

  28. Zhong H, Yang HS, Erdjument-Bromage H, Tempst P, Ghosh S. The transcriptional activity of NF-KB is regulated by the IKB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 1997; 89: 413–424.

    Article  PubMed  CAS  Google Scholar 

  29. Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ. Regulation of NF-x13 by cyclin-dependent kinases associated with the p300 coactivator. Science 1997; 275: 523–527.

    Article  PubMed  CAS  Google Scholar 

  30. Zhong H, Voll RE, Ghosh S. Phosphorylation of NF-KB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivatorCBP/p300. Mol Cell 1998; 1: 661–671.

    Article  PubMed  CAS  Google Scholar 

  31. Matthew S, Murty VV, Dalla-Favera R, Chaganti R.S. Chromosomal localization of genes encoding the transcription factors c-Rel, NF-KB p50, NF-KB p65 and lyt10 by fluoresence in situ hybridization. Oncogene 1993; 8: 191–193.

    Google Scholar 

  32. Gilmore TD, Morin PJ. The IxB proteins: Members of a multifunctional family. Trends Genet. 1993; 9: 427–433.

    Article  PubMed  CAS  Google Scholar 

  33. Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD, Grinstein E, Greiner A, Scheidereit C, Dorken B. Constitutive NF-KB RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 1997; 100: 2961–2969.

    Article  PubMed  CAS  Google Scholar 

  34. Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM, Sonenshein GE. Aberrant NF-KB expression and the pathogenesis of breast cancer. J Clin Invest 1997; 100: 2952–2960.

    Article  PubMed  CAS  Google Scholar 

  35. Nakshatri H, Bhat-Nakshatri P, Martin D, Goulet R, Sledge G. Constitutive activation of NF-KB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 1997; 17: 3629–3639.

    PubMed  CAS  Google Scholar 

  36. Bours V, Dejardin E, Goujon-Letawe F, Merville MP, Castronovo V. The NF-xB transcription factor and cancer: High expression of NF-KB and IKB-related proteins in tumor cell lines. Biochem Pharmacol 1994; 47: 145–149.

    Article  PubMed  CAS  Google Scholar 

  37. Visconti R, Cerutti J, Battista S, Fedele M, Trapasso F, Zeki K, Miano MP, de Nigris F, Casalino L, Curcio F, Santoro M, Fusco A. Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NF-KB p65 protein expression. Oncogene 1997; 15: 1987–1994.

    Article  PubMed  CAS  Google Scholar 

  38. Hammarskjold ML, Simurda MC. Epstein Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-KB activity. J Virol 1992; 66: 6496–6501.

    PubMed  CAS  Google Scholar 

  39. Finco TS, Westwick JK, Norris JL, Beg AA, Der CJ, Baldwin AS. Oncogenic Ha-Rasinduced signalling activates NF-KB transcriptional activity, which is required for cellular transformation. J Biol Chem 1997; 272:24, 113–24, 116.

    Google Scholar 

  40. Fisher DE. Apoptosis in cancer therapy: Crossing the threshold. Cell 1994; 78: 539–542.

    Article  PubMed  CAS  Google Scholar 

  41. Wang C, Mayo M, Baldwin AS. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-KB. Science 1996 274: 784–787.

    Article  PubMed  CAS  Google Scholar 

  42. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNFa-induced apoptosis by NF-KB. Science 1996; 274: 787–789.

    Article  PubMed  Google Scholar 

  43. Beg AA, Baltimore D. An essential role for NF-KB in preventing TNFa-induced cell death. Science 1996; 274: 782–784.

    Article  PubMed  CAS  Google Scholar 

  44. Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW. Suppression of TNFinduced cell death by inhibitor of apoptosis c-IAP2 is under NF-KB control. Proc Natl Acad Sci USA 1997, 94:10, 057–10, 062.

    Google Scholar 

  45. You M, Ku PT, Hrdlickova R, Bose HR. ch-IAP1, a member of the inhibitor of apoptosis family, is a mediator of the anti-apoptotic activity of the v-Rel oncoprotein. Mol Cell Biol 1997; 17: 7328–7341.

    PubMed  CAS  Google Scholar 

  46. Wu MX, Ao Z, Prasad KV, Wu R, Schlossman SF. IEX-1L, an apoptosis inhibitor involved in NF-KB-mediated cell survival. Science 1998; 281: 998–1001.

    Article  PubMed  CAS  Google Scholar 

  47. Wang C-Y, Mayo MW, Korneluk RG, Goeddell DV, Baldwin AS. NF-KB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to supress caspase 8 activation. Science 1998; 281: 1680–1683.

    Article  PubMed  CAS  Google Scholar 

  48. Sokoloski JA, Sartorelli AC, Rosen CA, Narayanan R. Antisense oligonucleotides to the p65 subunit of NF--KB block CD1 lb expression and adhesion properties of differentiated HL-60 granulocytes. Blood 1993; 82: 625–632.

    PubMed  CAS  Google Scholar 

  49. Higgins KA, Perez JR, Coleman TA, Dorshkind K, McComas WA, Sarmiento UM, Rosen CA, Narayanan R. Antisense inhibition of the p65 subunit of NF-KB blocks tumorigenicity and causes tumor regression. Proc Natl Acad Sci USA 1993; 90: 9901–9905.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Frank Mercurio PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony M. Manning PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    J. Silvio Gutkind PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Mercurio, F., Manning, A.M. (2000). Regulation of NF-κB Function. In: Gutkind, J.S. (eds) Signaling Networks and Cell Cycle Control. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-218-0_23

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-218-0_23

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4684-9695-6

  • Online ISBN: 978-1-59259-218-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation