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Molecular and Cellular Biology, April 2004, p. 3227-3237, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3227-3237.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Leukemia-Related Transcription Factor TEL Is Negatively Regulated through Extracellular Signal-Regulated Kinase-Induced Phosphorylation

Kazuhiro Maki,1 Honoka Arai,1 Kazuo Waga,1 Ko Sasaki,1 Fumihiko Nakamura,1 Yoichi Imai,2 Mineo Kurokawa,2 Hisamaru Hirai,2 and Kinuko Mitani1*

Department of Hematology, Dokkyo University School of Medicine, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293,1 Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan2

Received 25 April 2003/ Returned for modification 17 July 2003/ Accepted 13 January 2004

TEL is an ETS family transcription factor that possesses multiple putative mitogen-activated protein kinase phosphorylation sites. We here describe the functional regulation of TEL via ERK pathways. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser213 and Ser257. TEL binds to a common docking domain in ERK. In vivo ERK-dependent phosphorylation reduces trans-repressional and DNA-binding abilities of TEL for ETS-binding sites. A mutant carrying substituted glutamates on both Ser213 and Ser257 functionally mimics hyperphosphorylated TEL and also shows a dominant-negative effect on TEL-induced transcriptional suppression. Losing DNA-binding affinity through phosphorylation but heterodimerizing with unmodified TEL could be an underlying mechanism. Moreover, the glutamate mutant dominantly interferes with TEL-induced erythroid differentiation in MEL cells and growth suppression in NIH 3T3 cells. Finally, endogenous TEL is dephosphorylated in parallel with ERK inactivation in differentiating MEL cells and is phosphorylated through ERK activation in Ras-transformed NIH 3T3 cells. These data indicate that TEL is a constituent downstream of ERK in signal transduction systems and is physiologically regulated by ERK in molecular and biological features.

* Corresponding author. Mailing address: Department of Hematology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan. Phone: 81-282-86-1111, ext. 2744. Fax: 81-282-86-5630. E-mail: kinukom-tky{at}umin.ac.jp.

Molecular and Cellular Biology, April 2004, p. 3227-3237, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3227-3237.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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