QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: E02-04-0207v1 14/1/67    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thorburn, J. Articles by Thorburn, A. Search for Related Content PubMed PubMed Citation Articles by Thorburn, J. Articles by Thorburn, A.

Vol. 14, Issue 1, 67-77, January 2003

Caspase- and Serine Protease-dependent Apoptosis by the Death Domain of FADD in Normal Epithelial Cells

Jacqueline Thorburn, Laura M. Bender, Michael J. Morgan, and Andrew Thorburn^*

Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

The adapter protein FADD consists of two protein interaction domains: a death domain and a death effector domain. The death domain binds to activated death receptors such as Fas, whereas the death effector domain binds to procaspase 8. An FADD mutant, which consists of only the death domain (FADD-DD), inhibits death receptor-induced apoptosis. FADD-DD can also activate a mechanistically distinct, cell type-specific apoptotic pathway that kills normal but not cancerous prostate epithelial cells. Here, we show that this apoptosis occurs through activation of caspases 9, 3, 6, and 7 and a serine protease. Simultaneous inhibition of caspases and serine proteases prevents FADD-DD-induced death. Inhibition of either pathway alone does not prevent cell death but does affect the morphology of the dying cells. Normal prostate epithelial cells require both the caspase and serine protease inhibitors to efficiently prevent apoptosis in response to TRAIL. In contrast, the serine protease inhibitor does not affect TRAIL-induced death in prostate tumor cells suggesting that the FADD-DD-dependent pathway can be activated by TRAIL. This apoptosis pathway is activated in a cell type-specific manner that is defective in cancer cells, suggesting that this pathway may be targeted during cancer development.

---

Online version of this article contains video material. Online version is available at www.molbiolcell.org.

^* Corresponding author. E-mail address: athorbur{at}wfubmc.edu.

---

Molecular Biology of the Cell
Vol. 14, 67-77, January 2003
Copyright © 2003 by The American Society for Cell Biology

This article has been cited by other articles:

				R. V. Warke, K. J. Martin, K. Giaya, S. K. Shaw, A. L. Rothman, and I. Bosch TRAIL Is a Novel Antiviral Protein against Dengue Virus J. Virol., January 1, 2008; 82(1): 555 - 564. [Abstract] [Full Text] [PDF]

				W. Zhu, J. Chen, X. Cong, S. Hu, and X. Chen Hypoxia and Serum Deprivation-Induced Apoptosis in Mesenchymal Stem Cells Stem Cells, February 1, 2006; 24(2): 416 - 425. [Abstract] [Full Text] [PDF]

				Y. Song and C. O. Jacob The Mouse Cell Surface Protein TOSO Regulates Fas/Fas Ligand-induced Apoptosis through Its Binding to Fas-associated Death Domain J. Biol. Chem., March 11, 2005; 280(10): 9618 - 9626. [Abstract] [Full Text] [PDF]

				J. Thorburn, F. Moore, A. Rao, W. W. Barclay, L. R. Thomas, K. W. Grant, S. D. Cramer, and A. Thorburn Selective Inactivation of a Fas-associated Death Domain Protein (FADD)-dependent Apoptosis and Autophagy Pathway in Immortal Epithelial Cells Mol. Biol. Cell, March 1, 2005; 16(3): 1189 - 1199. [Abstract] [Full Text] [PDF]

				K. R. Kalli, K. E. Devine, M. C. Cabot, C. R. Arnt, M. P. Heldebrant, P. A. Svingen, C. Erlichman, L. C. Hartmann, C. A. Conover, and S. H. Kaufmann Heterogeneous Role of Caspase-8 in Fenretinide-Induced Apoptosis in Epithelial Ovarian Carcinoma Cell Lines Mol. Pharmacol., December 1, 2003; 64(6): 1434 - 1443. [Abstract] [Full Text] [PDF]