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.
Goro Sashida  1 ,  Yan Liu ,  Shannon Elf ,  Yasuhiko Miyata ,  Kazuma Ohyashiki ,  Miki Izumi ,  Silvia Menendez ,  Stephen D Nimer
Affiliations
  • 1. Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA.
PMID: 19380490 DOI: 10.1128/MCB.01551-08
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.