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Molecular and Cellular Biology, July 2009, p. 3687-3699, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.01551-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

ELF4/MEF Activates MDM2 Expression and Blocks Oncogene-Induced p16 Activation To Promote Transformation{triangledown} ,{dagger}

Goro Sashida,1 Yan Liu,1 Shannon Elf,1 Yasuhiko Miyata,1 Kazuma Ohyashiki,3 Miki Izumi,4 Silvia Menendez,1 and Stephen D. Nimer1,2*

Molecular Pharmacology and Chemistry Program of the Sloan-Kettering Institute,1 Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York,2 Department of Hematology,3 Department of Diagnostic Pathology, Tokyo Medical University, Tokyo, Japan4

Received 3 October 2008/ Returned for modification 11 November 2008/ Accepted 13 April 2009

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.

* Corresponding author. Mailing address: Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-7871. Fax: (212) 794-5849. E-mail: nimers{at}mskcc.org

{triangledown} Published ahead of print on 20 April 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2009, p. 3687-3699, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.01551-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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