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.
Sashida
Goro
G
Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA.
Liu
Yan
Y
Elf
Shannon
S
Miyata
Yasuhiko
Y
Ohyashiki
Kazuma
K
Izumi
Miki
M
Menendez
Silvia
S
Nimer
Stephen D
SD
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D011905:Genes, ras; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C491779:Elf4 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D063150:Polycomb Repressive Complex 1; D051736:Proto-Oncogene Proteins c-mdm2