A novel repressor domain is required for maximal growth inhibition by the IRF-1 tumor suppressor

Mirjam Eckert, Sarah E M Meek, Kathryn L Ball

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)23092-102
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number32
DOIs
Publication statusPublished - 11 Aug 2006

Keywords

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 2
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferon Regulatory Factor-1
  • Molecular Sequence Data
  • Mutation
  • Oligonucleotides
  • Protein Structure, Tertiary
  • Transcription, Genetic
  • Transcriptional Activation

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