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

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.