Hepatocyte Fas-associating Death Domain Protein/Mediator of Receptor-induced Toxicity (FADD/MORT1) Levels Increase in Response to Pro-apoptotic Stimuli

• Published in: The Journal of biological chemistry 2002-10, Vol.277 (41), p.38855-38862
• Main Authors: Kim, Peter K.M., Wang, Yinna, Gambotto, Andrea, Kim, Young-Myeong, Weller, Richard, Zuckerbraun, Brian S., Hua, Yun, Watkins, Simon C., Billiar, Timothy R.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adenoviridae - genetics; Adenoviridae - metabolism; Animals; Apoptosis - physiology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase 8; Caspase 9; Caspases - metabolism; Cell Survival; Cells, Cultured; Cycloheximide - pharmacology; Dactinomycin - pharmacology; Dose-Response Relationship, Drug; Enzyme Activation; Fas-Associated Death Domain Protein; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - radiation effects; Hot Temperature; HSP70 Heat-Shock Proteins - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Protein Synthesis Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Time Factors; Ultraviolet Rays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M203484200

We examined the regulation ofFas-associating deathdomain (FADD) protein as an important adaptor molecule in apoptosis signaling and hypothesized that the regulation of FADD could contribute to hepatocyte death. FADD/mediatorof 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 ∼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.