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

Juan J. Sironi, Toru Ouchi

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

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-γ (IFN-γ)-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-γ activation site element was stimulated and bound efficiently by STAT1C without IFN-γ treatment. STAT1C was found to be tyrosine-phosphorylated in the nucleus for more than 30 h after IFN-γ stimulation. STAT1-negative U3A cells reexpressing STAT1C showed retarded cell growth and underwent apoptosis when treated with IFN-γ. 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-γ 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.

Original languageEnglish (US)
Pages (from-to)4066-4074
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number6
DOIs
StatePublished - Feb 6 2004
Externally publishedYes

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Caspase 2
STAT1 Transcription Factor
Caspase 7
Caspase 3
Apoptosis
Interferons
Nuclear Localization Signals
src Homology Domains
Cell growth
Cycloheximide
Caspases
Ketones
Aspartic Acid
Tyrosine
Intercellular Signaling Peptides and Proteins
Chemical activation
Cytokines
Phenotype

ASJC Scopus subject areas

  • Biochemistry

Cite this

STAT1-induced Apoptosis Is Mediated by Caspases 2, 3, and 7. / Sironi, Juan J.; Ouchi, Toru.

In: Journal of Biological Chemistry, Vol. 279, No. 6, 06.02.2004, p. 4066-4074.

Research output: Contribution to journalArticle

Sironi, Juan J. ; Ouchi, Toru. / STAT1-induced Apoptosis Is Mediated by Caspases 2, 3, and 7. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 6. pp. 4066-4074.
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