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Molecular and Cellular Biology, November 2002, p. 7439-7448, Vol. 22, No. 21
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.21.7439-7448.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

Takeshi Kuwata,1 Celine Gongora,1 Yuka Kanno,1 Kazuyasu Sakaguchi,2 Tomohiko Tamura,1 Tomohiko Kanno,1 Venkatesha Basrur,2 Robert Martinez,3 Ettore Appella,2 Todd Golub,3 and Keiko Ozato1*

Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development,1 Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021153

Received 26 February 2002/ Returned for modification 8 April 2002/ Accepted 24 July 2002

ICSBP (IRF-8) is a transcription factor of the IRF family expressed only in the immune system. It is induced in macrophages by gamma interferon (IFN-{gamma}) and contributes to macrophage functions. By interacting with Ets family protein PU.1, ICSBP binds to the IRF/Ets composite element and stimulates transcription. ICSBP binds to another DNA element, the IFN-stimulated response element (ISRE), a common target of the IRF family. Limited knowledge as to how ICSBP and other IRF proteins regulate ISRE-dependent transcription in IFN-{gamma}-activated macrophages is available. By mass-spectrometric analysis of ISRE-bound proteins in macrophages, we identified TEL, another Ets member, as a factor recruited to the element in an IFN-{gamma}-dependent manner. In vitro analysis with recombinant proteins indicated that this recruitment is due to a direct interaction between ICSBP and TEL, which is enhanced by the presence of ISRE. Significantly, the interaction with TEL in turn resulted in the recruitment of the histone deacetytase HDAC3 to the ISRE, causing increased repression of IFN-{gamma}-mediated reporter activity through the ISRE. This repression may provide a negative-feedback mechanism operating after the initial transcriptional activation by IFN-{gamma}. By associating with two different Ets family proteins, ICSBP exerts a dual function in IFN-{gamma}-dependent gene regulation in an immune system-specific manner.

* Corresponding author. Mailing address: Laboratory of Molecular Growth Regulation, Bldg. 6, Rm. 2A01, National Institute of Child Health and Human Development, National Institutes of Health, 6 Center Dr., MSC-2753, Bethesda, MD 20892-2753. Phone: (301) 496-9184. Fax: (301) 480-9354. E-mail: ozatok{at}nih.gov.

Molecular and Cellular Biology, November 2002, p. 7439-7448, Vol. 22, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.21.7439-7448.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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