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J. Biol. Chem., Vol. 281, Issue 32, 23092-23102, August 11, 2006

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A Novel Repressor Domain Is Required for Maximal Growth Inhibition by the IRF-1 Tumor Suppressor^*

From the Cancer Research UK (CRUK) Interferon and Cell Signalling Group, Cell Signalling Unit, The University of Edinburgh Cancer Research Centre, Edinburgh EH4 2XR, United Kingdom

Interferon regulatory factor-1 (IRF-1) is a transcription factor and tumor suppressor that can regulate gene expression in a manner requiring either its sequence specific DNA binding activity or its ability to bind the p300 coactivator. We show that IRF-1-mediated growth inhibition is dependent on the integrity of a C-terminal transcriptional enhancer domain. An enhancer subdomain (amino acids 301-325) that differentially regulates IRF-1 activity has been identified and this region mediates the repression of Cdk2. The repressor domain encompasses an LXXLL coregulator signature motif and mutations or deletions within this region completely uncouple transcriptional activation from repression. The loss of growth suppressor activity when the Cdk2-repressor domain of IRF-1 is mutated implicates repression as a determinant of its maximal growth inhibitory potential. The data link IRF-1 regulatory domains to its growth inhibitory activity and provide information about how differential gene regulation may contribute to IRF-1 tumor suppressor activity.

Received for publication, November 28, 2005 , and in revised form, March 22, 2006.

^* 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 Supported by a Cancer Research UK (CRUK) studentship.

² Supported by a CRUK program grant (to K. L. B.).

³ Supported by a CRUK program grant. To whom correspondence should be addressed: E-mail: kathryn.ball{at}ed.ac.uk.

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