Role of the proto-oncogene Pokemon in cellular transformation and ARF repression

Nature. 2005 Jan 20;433(7023):278-85. doi: 10.1038/nature03203.

Abstract

Aberrant transcriptional repression through chromatin remodelling and histone deacetylation has been postulated to represent a driving force underlying tumorigenesis because histone deacetylase inhibitors have been found to be effective in cancer treatment. However, the molecular mechanisms by which transcriptional derepression would be linked to tumour suppression are poorly understood. Here we identify the transcriptional repressor Pokemon (encoded by the Zbtb7 gene) as a critical factor in oncogenesis. Mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated cellular transformation. Conversely, Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. We find that Pokemon is aberrantly overexpressed in human cancers and that its expression levels predict biological behaviour and clinical outcome. Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Transformation, Neoplastic*
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / genetics*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Proto-Oncogenes / genetics
  • Proto-Oncogenes / physiology*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Substrate Specificity
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / genetics
  • Tumor Suppressor Protein p14ARF / deficiency
  • Tumor Suppressor Protein p14ARF / genetics*
  • Tumor Suppressor Protein p14ARF / metabolism

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • Repressor Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p14ARF
  • Zbtb7a protein, mouse