Caspase- and serine protease-dependent apoptosis by the death domain of FADD in normal epithelial cells.
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.
Thorburn
Jacqueline
J
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Bender
Laura M
LM
Morgan
Michael J
MJ
Thorburn
Andrew
A
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D012697:Serine Endopeptidases; D020169:Caspases