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* Department of Biochemistry and Molecular Biology and
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912; and
Sarcoma Research Center, Department of Cancer Biology, M. D. Anderson Cancer Center, Houston, TX 77030
IFN regulatory factor 8 (IRF8) is a transcription factor that was originally identified in myeloid cells and has been shown to be essential for differentiation and function of hemopoietic cells. Mice with a null mutation of IRF8 exhibit uncontrolled expansion of the granulocytic and monocytic lineages that progress into a phenotype resembling human chronic myelogenous leukemia. In human patients with chronic myelogenous leukemia, IRF8 transcript levels are frequently diminished. Therefore, IRF8 is a key regulator of myeloid tumor development. In this study, we report that IRF8 is a critical regulator of apoptosis in nonhemopoietic tumor cells. Disruption of IRF8 function with IRF8 dominant-negative mutants diminished Fas-mediated apoptosis in sarcoma tumor cells. Both constitutively expressed and IFN-
-activated IRF8 were involved in regulation of apoptosis. Furthermore, it was found that constitutively expressed IRF8 is associated with the Fas promoter to activate Fas transcription. In addition, disruption of constitutively expressed IRF8 function diminished JAK1 expression and thereby inhibited IFN--initiated induction of STAT1 phosphorylation, which in turn, blocked IFN--induced Fas up-regulation. Interestingly, the constitutively expressed IRF8 was also essential for TNF-
sensitization of Fas-mediated apoptosis because disruption of IRF8 function also inhibited TNF--sensitized and Fas-mediated apoptosis. Taken together, our data suggest that IRF8 is an essential mediator of Fas-mediated apoptosis and that IRF8 mediates apoptosis through regulation of Fas expression in nonhemopoietic tumor cells.
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.
1 Address correspondence and reprint requests to Dr. Kebin Liu, Department of Biochemistry and Molecular Biology, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912. E-mail address: Kliu{at}mcg.edu
2 Abbreviations used in this paper: IRF, IFN regulatory factor; CML, chronic myelogenous leukemia; PI, propidium iodide; ChIP, chromatin immunoprecipitation; GAS, IFN--activation site; shRNA, short hairpin RNA.
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