Hepatocyte Fas-associating death domain protein/mediator of receptor-induced toxicity (FADD/MORT1) levels increase in response to pro-apoptotic stimuli.
We examined the regulation of Fas-associating death domain (FADD) protein as an important adaptor molecule in apoptosis signaling and hypothesized that the regulation of FADD could contribute to hepatocyte death. FADD/mediator of receptor-induced toxicity (MORT1) is required for activation of several signaling pathways of cell death. In this study we report the interesting and unexpected result that actinomycin D increased the expression of FADD protein, and we demonstrate that other cellular stresses like ultraviolet irradiation or heat shock could also increase FADD levels in hepatocytes. In cells treated with actinomycin D, FADD levels were elevated homogeneously in the cytoplasm. The increase in cytoplasmic FADD protein by actinomycin D or FADD overexpression alone both correlated with cell death, and specific antisense inhibition of FADD expression consistently diminished approximately 30% of the cell death induced by actinomycin D. These data indicate that FADD protein expression can increase rapidly in hepatocytes exposed to broadly cytotoxic agents.
Kim
Peter K M
PK
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. kimp@msx.upmc.edu
Wang
Yinna
Y
Gambotto
Andrea
A
Kim
Young-Myeong
YM
Weller
Richard
R
Zuckerbraun
Brian S
BS
Hua
Yun
Y
Watkins
Simon C
SC
Billiar
Timothy R
TR
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D006358:Hot Temperature; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014466:Ultraviolet Rays
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D018840:HSP70 Heat-Shock Proteins; D011500:Protein Synthesis Inhibitors; D003609:Dactinomycin; D003513:Cycloheximide; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases