Cell Death Differ. 2001 Jul;8(7):696-705.

An apoptosis signaling pathway induced by the death domain of FADD selectively kills normal but not cancerous prostate epithelial cells.External

Morgan, M. J., Thorburn, J., Thomas, L., Maxwell, T., Brothman, A. R., Thorburn, A.,
--- - Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
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.
PMID: 11464214External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vitro interaction
  DD1 DD2 Reference
Family DD1 DD2 Method Species Region Expression Species Region Expression
DD FADD Link Fas Yeast two-hybrid Human 80-208 Yeast Human 177-335 Yeast 11464214
DD FADD Link RIP Yeast two-hybrid Human 80-208 Yeast Human Full length Yeast 11464214
DD FADD Link TRADD Yeast two-hybrid Human 80-208 Yeast Human Full length Yeast 11464214
(Link: click this icon to show interactions only between the two corresponding DDs)