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

Abstract

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 approximately 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 G(1) 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.

• Authors: Taylor B Guo, Jiawei Lu, Tie Li, Zhenyu Lu, Guotong Xu, Ming Xu, Luo Lu, Wei Dai
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 289 Issue 2 Pg. C257-63 (Aug 2005) ISSN: 0363-6143 [Print] United States
• PMID: 15800056 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Potassium Channel Blockers
• Potassium Channels
• Proto-Oncogene Proteins
• Barium
• Epidermal Growth Factor
• Tetraethylammonium
• 4-Aminopyridine
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase Kinases

Topics

• 4-Aminopyridine (pharmacology)
• Barium (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Epidermal Growth Factor (metabolism)
• Flow Cytometry
• Humans
• Insulin (metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Phosphorylation
• Potassium Channel Blockers (pharmacology)
• Potassium Channels (drug effects, metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Signal Transduction (drug effects, physiology)
• Tetraethylammonium (pharmacology)