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

Goro Sashida1, Yan Liu, Shannon Elf

  • 1Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA.

Molecular and Cellular Biology
|April 22, 2009
PubMed

Insights

ELF4/MEF promotes cancer by activating Mdm2, which suppresses the tumor-suppressing p53 pathway. It also inhibits the p16/Rb pathway, promoting cell proliferation and tumorigenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ETS transcription factors, including ELF4/MEF, are implicated as oncogenes in cancer.
  • Overexpression of ELF4/MEF is observed in human cancers, suggesting a role in tumorigenesis.

Purpose of the Study:

  • To investigate the role of ELF4/MEF in regulating key tumor suppressor pathways.
  • To elucidate the mechanisms by which ELF4/MEF promotes tumorigenesis.

Main Methods:

  • Utilized mouse embryonic fibroblasts (MEFs) with varying Elf4 and p53 gene expression.
  • Assessed Mdm2 expression, p53 protein accumulation, and senescence.
  • Investigated the impact of oncogenic H-Ras(V12) and c-myc on cell transformation.
  • Analyzed the INK4a/ARF locus, including p19ARF and p16 expression.
  • Examined the effects of Bmi-1 expression and p16 knockdown on cell transformation.

Main Results:

  • ELF4/MEF activates Mdm2 expression, leading to reduced Mdm2 levels and p53 accumulation in its absence.
  • Lack of ELF4/MEF induces p53-dependent senescence.
  • In ELF4/MEF and p53-deficient cells, oncogenes H-Ras(V12) and c-myc fail to induce transformation.
  • ELF4/MEF deficiency increases p19ARF and p16 expression, inhibiting transformation.
  • Restoration of transformation in ELF4/MEF and p53-deficient cells is achieved by Bmi-1 expression or p16 knockdown.

Conclusions:

  • ELF4/MEF promotes tumorigenesis by concurrently inhibiting the p53 and p16/Rb tumor suppressor pathways.
  • Targeting ELF4/MEF could be a therapeutic strategy for cancers overexpressing this oncogene.

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