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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Transformation, Neoplastic*
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Cells, Cultured
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Cellular Senescence / physiology
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Fibroblasts / cytology
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Fibroblasts / physiology
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Gene Expression Regulation
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Genes, ras
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Humans
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Mice
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Mice, Knockout
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Polycomb Repressive Complex 1
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Survival Rate
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Bmi1 protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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DNA-Binding Proteins
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Elf4 protein, mouse
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Nuclear Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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Transcription Factors
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Tumor Suppressor Protein p53
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Mdm2 protein, mouse
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Polycomb Repressive Complex 1
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Proto-Oncogene Proteins c-mdm2