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J. Biol. Chem., Vol. 279, Issue 6, 4066-4074, February 6, 2004

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STAT1-induced Apoptosis Is Mediated by Caspases 2, 3, and 7^*

Juan J. Sironi and Toru Ouchi

From the Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York University, New York, New York 10029

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 understand better the role of STAT1 in the interferon- (IFN-)-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 IFN- activation site element was stimulated and bound efficiently by STAT1C without IFN- treatment. STAT1C was found to be tyrosine-phosphorylated in the nucleus for more than 30 h after IFN- stimulation. STAT1-negative U3A cells reexpressing STAT1C showed retarded cell growth and underwent apoptosis when treated with IFN-. 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 24 h after IFN- 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 because benzyloxycarbonyl-valyl-aspartyl-valyl-alanyl-aspartic acid fluoromethyl ketone (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.

Received for publication, July 18, 2003 , and in revised form, October 13, 2003.

^* This work was supported by the New York City Council Speaker's Fund, EMPIRE Grant of the State of New York, and NCI, National Institutes of Health Grants CA79892 and CA90631 (to T. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, Box 1130, One Gustave L. Levy Place, New York, NY 10029. Tel.: 212-659-5475; Fax: 212-987-2240; E-mail: Toru.Ouchi{at}mssm.edu.

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