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Molecular and Cellular Biology, April 2006, p. 3114-3123, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3114-3123.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The ETS Protein MEF Is Regulated by Phosphorylation-Dependent Proteolysis via the Protein-Ubiquitin Ligase SCFSkp2

Yan Liu,1 Cyrus V. Hedvat,1,3 Shifeng Mao,1 Xin-Hua Zhu,2 Jinjuan Yao,3 Hoang Nguyen,2 Andrew Koff,2 and Stephen D. Nimer1,4*

Laboratory of Molecular Aspects of Hematopoiesis,1 Molecular Biology Program, Sloan-Kettering Institute,2 Department of Pathology,3 Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 100214

Received 14 September 2005/ Returned for modification 14 October 2005/ Accepted 17 January 2006

MEF is an ETS-related transcription factor with strong transcriptional activating activity that affects hematopoietic stem cell behavior and is required for normal NK cell and NK T-cell development. The MEF (also known as ELF4) gene is repressed by several leukemia-associated fusion transcription factor proteins (PML-retinoic acid receptor {alpha} and AML1-ETO), but it is also activated by retroviral insertion in several cancer models. We have previously shown that cyclin A-dependent phosphorylation of MEF largely restricts its activity to the G1 phase of the cell cycle; we now show that MEF is a short-lived protein whose expression level also peaks during late G1 phase. Mutagenesis studies show that the rapid turnover of MEF in S phase is dependent on the specific phosphorylation of threonine 643 and serine 648 at the C terminus of MEF by cdk2 and on the Skp1/Cul1/F-box (SCF) E3 ubiquitin ligase complex SCFSkp2, which targets MEF for ubiquitination and proteolysis. Overexpression of MEF drives cells through the G1/S transition, thereby promoting cell proliferation. The tight regulation of MEF levels during the cell cycle contributes to its effects on regulating cell cycle entry and cell proliferation.

* Corresponding author. Mailing address: Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 575, New York, NY 10021. Phone: (212) 639-7198. Fax: (212) 794-5849. E-mail: nimers{at}mskcc.org.

Molecular and Cellular Biology, April 2006, p. 3114-3123, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3114-3123.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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