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Papers In Press, published online ahead of print November 17, 2003
Derald H. Ruttenberg Cancer Center, The Mount Sinai School of Medicine, New York, NY 10029
Corresponding Author: Toru.Ouchi{at}mssm.edu
STAT1 (signal transducer and activator of transcription 1) has been implicated as a mediator of a variety of biological responses in response to stimulation by specific growth factors and cytokines. To better understand the role of STAT1 in the interferon (IFN) g-induced phenotype, we generated an active form of STAT1 (STAT1C) by substituting Cys residues for both Arg 656 and Asn 658 within the C-terminal loop of the STAT1 SH2 domain. The IFNg activation site (GAS) element was stimulated and bound efficiently by STAT1C without IFNg treatment. STAT1C was found to be tyrosine-phosphorylated in the nucleus for more than 30h after IFNg stimulation. STAT1-negative U3A cells re-expressing STAT1C showed retarded cell growth and underwent apoptosis when treated with IFNg. Further analysis demonstrated that apoptosis was preceded by proteolytic cleavage of caspases 2, 3 and 7, and wild type STAT1 also induced cleavage of caspase 7 when expressed in STAT1-negative U3A cells, indicating that STAT1C augments potential activity of wild type STAT1. Studies with cycloheximide treatment showed that protein synthesis induced in the first 24h after IFNg treatment was required for apoptosis under these conditions. Finally, we found that STAT1C-induced apoptosis was, in part, mediated by caspase 2, 3 and 7 since Z-VDVAD-FMK treatment partially blocked apoptosis. These results suggest that prolonged nuclear localization of activated STAT1 results in apoptosis involving specific regulation of caspase pathway.
J. Biol. Chem, 10.1074/jbc.M307774200
Submitted on July 18, 2003
Revised on November 17, 2003
Accepted on November 17, 2003
STAT1-induced apoptosis is mediated by cspases 2,3 and 7
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