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1 Health Science Center, Shanghai Institute of Biological Sciences, Shanghai, Shanghai, China; Dept. of Medical Genetics, Shanghai Second Medical University, Shanghai, Shanghai, China
2 Health Science Center, Shanghai Institute of Biological Sciences, Shanghai, Shanghai, China
3 Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA
4 Dept. of Medical Genetics, Shanghai Second Medical University, Shanghai, Shanghai, China
5 Health Science Center, Shanghai Institute of Biological Sciences, Shanghai, Shanghai, China; Dept. of Medical Genetics, Shanghai Second Medical University, Shanghai, Shanghai, China; Dept. of Cell Biology, University of Cincinnati, Cincinnati, OH, USA
6 Health Science Center, Shanghai Institute of Biological Sciences, Shanghai, Shanghai, China; Dept. of Medical Genetics, Shanghai Second Medical University, Shanghai, Shanghai, China; Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA
7 Health Science Center, Shanghai Institute of Biological Sciences, Shanghai, Shanghai, China; Dept. of Medical Genetics, Shanghai Second Medical University, Shanghai, Shanghai, China; Dept. of Medicine, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: lluou{at}ucla.edu.
Voltage-gated K+ channel activities are involved in regulating growth factor-stimulated cell proliferation in a variety of cell types. Herein we report that suppression of a voltage-gated K+ channel with 4-aminopyridine (4-AP), barium and tetraethylammonium (TEA) inhibited both EGF- and insulin-stimulated myeloblastic leukemia ML-1 cell proliferation in a concentration-dependent manner. Both MAPK/ERK and AKT pathways are known to mediate cell proliferative signals of a variety of growth factors including insulin. In serum-starved ML-1 cells, insulin rapidly stimulated phosphorylation of Erk1/2 and Akt, and the phosphorylation levels peaked around 30 min post treatment. Pre-treatment of ML-1 cells with 4-AP potently and dose-dependently prevented phosphorylation of Erk1/2 and Akt. However, insulin-induced activation of AKT pathway also played a role in promoting ML-1 cell proliferation. Flow cytometry analysis revealed that while ML-1 cells were primarily arrested at G1 phase by serum starvation for 36 h, they reentered the cell cycle after treatment with serum or insulin for 24 h. However, concomitant 4-AP treatment was able to attenuate cell cycle progression in synchronized ML-1 cells stimulated with growth factors. Our results strongly suggest that a 4-AP-sensitive K+ channel activity plays an important role in controlling proliferation of ML-1 cells through affecting the activation of multiple signal transduction processes induced by insulin.
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