Abstract
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-RasV12 nor c-myc can induce transformation of these cells. This appears to relate to the INK4a/ARF locus; both p19ARF and p16 are increased in Elf4−/− p53−/− mef's, and expression of Bmi-1 or knockdown of p16 in this context restores H-RasV12-induced transformation. Thus, ELF4/MEF promotes tumorigenesis by inhibiting both the p53 and p16/Rb pathways.
