p53- and Mdm2-independent repression of NF-kappa B transactivation by the ARF tumor suppressor

Mol Cell. 2003 Jul;12(1):15-25. doi: 10.1016/s1097-2765(03)00223-5.


One mechanism by which a cell affords protection from the transforming effects of oncogenes is via the action of the tumor suppressor, ARF, which activates p53 by inactivating Mdm2. Many oncogenes have also been shown to activate the transcription factor NF-kappa B, which can contribute toward the malignant phenotype in many ways, including an ability to antagonize p53. Here we find that ARF inhibits NF-kappa B function and its antiapoptotic activity independent of Mdm2 and p53. ARF represses the transcriptional activation domain of the NF-kappa B family member RelA by inducing its association with the histone deacetylase, HDAC1. Further, we show that the response of NF-kappa B to the oncogene Bcr-Abl is determined by the ARF status of the cell. These results reveal an important function of ARF that can regulate the NF-kappa B response to oncogene activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p16
  • Eukaryotic Cells / metabolism*
  • Gene Expression Regulation, Neoplastic / genetics
  • Genes, Regulator / genetics
  • Genes, abl / genetics
  • Histone Deacetylase 1
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nuclear Proteins*
  • Protein Structure, Tertiary / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Transcription Factor RelA
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p14ARF / genetics*
  • Tumor Suppressor Protein p14ARF / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • NF-kappa B
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Transcription Factor RelA
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases