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Discovery and Optimization of a TRAIL R2 Agonist for Cancer Therapy

  • Yvonne M. Angell
  • Ashok Bhandari
  • M. Nuria De Francisco
  • Brian T. Frederick
  • Jennifer M. Green
  • Karen Leu
  • Kerstin Leuther
  • Reuben Sana
  • Peter J. Schatz
  • Erik A. Whitehorn
  • Kathy Wright
  • Christopher P. Holmes
Part of the Advances in Experimental Medicine and Biology book series (volume 611)

Introduction

TRAIL is a cytokine that induces apoptosis in a wide variety of tumor cells but rarely in normal cells. The TRAIL R2 ligand triggers tumor cell apoptosis independently of the p53 tumor-suppressor gene [1, 2, 3, 4, 5]; thus, peptide agonists may offer a complementary approach to conventional cancer therapy. Ligands belonging to the TNF family are anticipated to function as a homotrimer as suggested by the crystal structures of a subset of the family (TNFα, TNFβ, CD40L, and TRAIL). The TNFR family members are transmembrane proteins. The extracellular domain of the receptors is characterized by the concatenated cysteine-rich domains (CRDs) [6] that are responsible for ligand binding. TRAIL R2 is a single transmembrane receptor arranged as a homo-trimeric complex on the cell membrane, and TRAIL ligand is a Zn-coordinated trimer [7]. Formation of a complex between TRAIL and its signaling receptors, DR4 and DR5, triggers apoptosis by inducing the oligomerization of...

Keywords

Intracellular Death Domain Carcinoma Cell Line HCT116 Synthetic Dimer Colon Carcinoma Cell Line HCT116 NH4OAc Buffer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Wiley, S. R., Schooley, K., Smolak, P.J., Din, W.S., Huang, C.P., Nicholl, J.K., Sutherland, G.R., Smith, T.D., Rauch, C., and Smith, C.S. Immunity, 3, 673–682 (1995).CrossRefGoogle Scholar
  2. 2.
    Pan, G., O'Rourke, K., Chinnaiyan, A. M., Gentz, R., Ebner, R., Ni, J., and Dixit, V. M. Science, 276, 111–113 (1997).CrossRefGoogle Scholar
  3. 3.
    Sheridan, J. P., Marsters, S. A., Pitti, R. M., Gurner, A., Skubatch, M., Baldwin, D., Ramakrishnan, L., Gray, C.L., Baker, D., Wood, W. I., Goddard, A. D., Godowski, P., and Ashkenazi, A. Science, 277, 818–821 (1997).CrossRefGoogle Scholar
  4. 4.
    Pan, G., Ni, J., Wei, Y. F., Yu, G., Gentz, R., and Dixit, V. M. Science, 277, 815–818 (1997).CrossRefGoogle Scholar
  5. 5.
    Walczak, H., Degli-Esposti, M. A., Johnson, R. S., Smolak, P. J., Waugh, J. Y., Boiani, N., Timour, M. S., Gerhart, M. J., Schooley, K. A., Smith, C. A., Goodwin, R. G., and Rauch, C. T. EMBO J. 16, 5386–5397 (1997).CrossRefGoogle Scholar
  6. 6.
    Bazan, J. F. Curr. Biol. 3, 603–606 (1993).CrossRefGoogle Scholar
  7. 7.
    Hymowitz, S. G., Christinger, H. W., Guh, G., Ultsch, M., O'Connell, M., Kelley, R. F., Ashkenazi, A., and de Vos, A. M. Mol. Cell, 4, 563–571 (1999).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Yvonne M. Angell
    • 1
  • Ashok Bhandari
    • 1
  • M. Nuria De Francisco
    • 1
  • Brian T. Frederick
    • 1
  • Jennifer M. Green
    • 1
  • Karen Leu
    • 1
  • Kerstin Leuther
    • 1
  • Reuben Sana
    • 1
  • Peter J. Schatz
    • 1
  • Erik A. Whitehorn
    • 1
  • Kathy Wright
    • 1
  • Christopher P. Holmes
    • 1
  1. 1.Affymax, Inc.Palo AltoUSA

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