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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Insulin-activated, K⁺-channel-sensitive Akt pathway is primary mediator of ML-1 cell proliferation

¹Health Science Center, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, and ²Department of Medical Genetics, Shanghai Second Medical University, Shanghai, China; ³Department of Cell Biology Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio; ⁴Division of Molecular Medicine, Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California-Los Angeles, Torrance, California; and ⁵Division of Molecular Carcinogenesis, Department of Medicine, New York Medical College, Valhalla, New York

Submitted 11 January 2005 ; accepted in final form 21 March 2005

Voltage-gated K⁺ channel activities are involved in regulating growth factor-stimulated cell proliferation in a variety of cell types. Here we report that suppression of a voltage-gated K⁺ channel with 4-aminopyridine (4-AP), barium, and tetraethylammonium 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 30 min after treatment. Pretreatment of ML-1 cells with 4-AP potently and dose-dependently prevented phosphorylation of ERK1/2 and Akt. However, insulin-induced activation of the Akt pathway also played a role in promoting ML-1 cell proliferation. Flow cytometry analysis revealed that although 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 by affecting the activation of multiple signal transduction processes induced by insulin.

growth factors; myeloblastic cells; signaling; ion channel blocker

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