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

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 t...

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Bibliographic Details
Published in:The Journal of biological chemistry 2006-08, Vol.281 (32), p.23092-23102
Main Authors: Eckert, Mirjam, Meek, Sarah E.M., Ball, Kathryn L.
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Amino Acid Sequence
Cell Line, Tumor
Cyclin-Dependent Kinase 2 - chemistry
Enhancer Elements, Genetic
Gene Expression Regulation, Neoplastic
Humans
Interferon Regulatory Factor-1 - chemistry
Interferon Regulatory Factor-1 - metabolism
Molecular Sequence Data
Mutation
Oligonucleotides - chemistry
Protein Structure, Tertiary
Transcription, Genetic
Transcriptional Activation
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M512589200