ELF4/MEF activates MDM2 expression and blocks oncogene-induced p16 activation to promote transformation

Mol Cell Biol. 2009 Jul;29(13):3687-99. doi: 10.1128/MCB.01551-08. Epub 2009 Apr 20.

Abstract

Several ETS transcription factors, including ELF4/MEF, can function as oncogenes in murine cancer models and are overexpressed in human cancer. We found that Elf4/Mef activates Mdm2 expression; thus, lack of or knockdown of Elf4/Mef reduces Mdm2 levels in mouse embryonic fibroblasts (mef's), leading to enhanced p53 protein accumulation and p53-dependent senescence. Even though p53 is absent in Elf4(-/-) p53(-/-) mef's, neither oncogenic H-Ras(V12) nor c-myc can induce transformation of these cells. This appears to relate to the INK4a/ARF locus; both p19(ARF) and p16 are increased in Elf4(-/-) p53(-/-) mef's, and expression of Bmi-1 or knockdown of p16 in this context restores H-Ras(V12)-induced transformation. Thus, ELF4/MEF promotes tumorigenesis by inhibiting both the p53 and p16/Rb pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic*
  • Cells, Cultured
  • Cellular Senescence / physiology
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation
  • Genes, ras
  • Humans
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Polycomb Repressive Complex 1
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Survival Rate
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Bmi1 protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • Elf4 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Mdm2 protein, mouse
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins c-mdm2