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J. Biol. Chem., Vol. 278, Issue 5, 2921-2927, January 31, 2003

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Regulation of Myeloid Zinc Finger Protein 2A Transactivation Activity through Phosphorylation by Mitogen-activated Protein Kinases^*

Hironori Ogawa, Ayako Murayama, Shigekazu Nagata, and Rikiro Fukunaga

From the Department of Genetics B-3, Graduate School of Medicine and Graduate School of Frontier Biosciences, Osaka University, and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

The myeloid zinc finger protein (MZF)-2 is a C₂H₂ zinc finger transcription factor that is expressed in myeloid cells and involved in the growth, differentiation, and tumorigenesis of myeloid progenitors. Here we describe a novel isoform of MZF-2, designated MZF-2A, and show that it is phosphorylated by the mitogen-activated protein (MAP) kinases. An in vitro phosphorylation experiment revealed that the transactivation domain (TAD) of MZF-2A was phosphorylated strongly by extracellular signal-regulated kinase (ERK) and phosphorylated weakly by p38 MAP kinase but not by Jun N-terminal kinase. Experiments using "add-back" mutants showed that three serine residues (Ser²⁵⁷, Ser²⁷⁵, and Ser²⁹⁵) in the TAD were phosphorylated in vitro by ERK. In myeloid LGM-1 cells, various extracellular stimuli induced the phosphorylation of these serine residues, which was differentially inhibited by the protein kinase inhibitors U0126 and SB203580. Substitution of these phosphorylation sites with alanines resulted in a strong enhancement of the ability of MZF-2A to activate transcription in a luciferase reporter assay. Taken together, these results indicate that MZF-2A is a novel target for the ERK and p38 MAP kinase signaling pathways, and its transactivation activity is negatively regulated by MAP kinase-mediated phosphorylation of the TAD.

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