An apoptosis signaling pathway induced by the death domain of FADD selectively kills normal but not cancerous prostate epithelial cells.
The adaptor protein FADD directly, or indirectly via another adaptor called TRADD, recruits caspase 8 to death receptors of the tumor necrosis factor receptor family. Consequentially, a dominant-negative mutant (FADD-DN, which consists only of the FADD death domain) that binds to receptors but cannot recruit caspase 8 has been widely used to inhibit apoptosis by various stimuli that work via death receptors. Here, we show that FADD-DN also has another cell type- and cancer-dependent activity because it induces apoptosis of normal human prostate epithelial cells but not normal prostate stromal cells or prostate cancer cells. This activity is independent of FADD-DN's ability to bind to three known interacting proteins, Fas, TRADD or RIP suggesting that it is distinct from FADD's functions at activated death receptors. FADD-DN induces caspase activation in normal epithelial cells as demonstrated using a Fluorescence Resonance Energy Transfer assay that measures caspase activity in individual living cells. However, caspase-independent pathways are also implicated in FADD-DN-induced apoptosis because caspase inhibitors were inefficient at preventing prostate cell death. Therefore, the death domain of FADD has a previously unrecognized role in cell survival that is epithelial-specific and defective in cancer cells. This FADD-dependent signaling pathway may be important in prostate carcinogenesis.
Morgan
M J
MJ
Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
Thorburn
J
J
Thomas
L
L
Maxwell
T
T
Brothman
A R
AR
Thorburn
A
A
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D053200:Fas-Associated Death Domain Protein; D005453:Fluorescence; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D051020:bcl-X Protein; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D047990:TNF Receptor-Associated Factor 1; D051020:bcl-X Protein; D019014:fas Receptor; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020169:Caspases