Abstract
The myeloid zinc finger protein (MZF)-2 is a C(2)H(2) 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 (Ser(257), Ser(275), and Ser(295)) 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.
Highlights
The development of mature blood cells occurs through the proliferation and differentiation of hematopoietic progenitor cells and is controlled by the combined effects of hematopoietic cytokines and transcription factors [1,2,3,4]
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 Myeloid zinc finger protein (MZF)-2A to activate transcription in a luciferase reporter assay. These results indicate that MZF-2A is a novel target for the extracellular signal-regulated kinase (ERK) and p38 Mitogen-activated protein (MAP) kinase signaling pathways, and its transactivation activity is negatively regulated by MAP kinase-mediated phosphorylation of the transactivation domain (TAD)
By the extensive screening of mouse and human cDNA libraries, we identified an alternative MZF product, termed MZF-2, which shares the sequence of its C terminus, including the zinc finger domains, with MZF-1 and contains a long N-terminal extension consisting of an acidic domain, a leucine-rich (LeR; called SCAN box) domain, and a transactivation domain (TAD) [7]
Summary
The development of mature blood cells occurs through the proliferation and differentiation of hematopoietic progenitor cells and is controlled by the combined effects of hematopoietic cytokines and transcription factors [1,2,3,4]. 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.
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