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Molecular and Cellular Biology, June 1999, p. 4121-4133, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Transcriptional Repressor ERF Is a Ras/Mitogen-Activated Protein Kinase Target That Regulates Cellular Proliferation

Lionel le Gallic,1 Dionyssios Sgouras,2,dagger Gregory Beal Jr.,3 and George Mavrothalassitis1,4,*

IMBB-FORTH1 and School of Medicine,4 University of Crete, Voutes, Heraklion, Crete 714-09, Greece, and Laboratory of Molecular Oncology2 and Laboratory of Cellular Biochemistry,3 SAIC Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, Maryland 21702-1201

Received 14 December 1998/Returned for modification 1 February 1999/Accepted 25 February 1999

A limited number of transcription factors have been suggested to be regulated directly by Erks within the Ras/mitogen-activated protein kinase signaling pathway. In this paper we demonstrate that ERF, a ubiquitously expressed transcriptional repressor that belongs to the Ets family, is physically associated with and phosphorylated in vitro and in vivo by Erks. This phosphorylation determines the ERF subcellular localization. Upon mitogenic stimulation, ERF is immediately phosphorylated and exported to the cytoplasm. The export is blocked by specific Erk inhibitors and is abolished when residues undergoing phosphorylation are mutated to alanine. Upon growth factor deprivation, ERF is rapidly dephosphorylated and transported back into the nucleus. Phosphorylation-defective ERF mutations suppress Ras-induced tumorigenicity and arrest the cells at the G0/G1 phase of the cell cycle. Our findings strongly suggest that ERF may be important in the control of cellular proliferation during the G0/G1 transition and that it may be one of the effectors in the mammalian Ras signaling pathway.

* Corresponding author. Mailing address: IMBB-FORTH and School of Medicine, University of Crete, Voutes, Heraklion, Crete 714-09, Greece. Phone: 30-81-394537, 394545. Fax: 30-81-394537, 394530. E-mail: mavro{at}nefeli.imbb.forth.gr.

dagger Present address: Diagnostic Genetic Center, Athens 115 28, Greece.

Molecular and Cellular Biology, June 1999, p. 4121-4133, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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