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

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.

SUBMITTER: Sashida G

PROVIDER: S-EPMC2698769 | biostudies-other | 2009 Jul

REPOSITORIES: biostudies-other

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

Sashida Goro G Liu Yan Y Elf Shannon S Miyata Yasuhiko Y Ohyashiki Kazuma K Izumi Miki M Menendez Silvia S Nimer Stephen D SD

Molecular and cellular biology 20090420 13

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 cel ...[more]

PMID: 19380490

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