Induction of human myeloblastic ML-1 cell G1 arrest by suppression of K+ channel activity.
Our previous studies have shown that a voltage-gated K+ channel is highly expressed in proliferating human myeloblastic ML-1 cells and is suppressed in the early stages of 12-O-tetradecanoylphorbol-13-acetate-induced ML-1 cell differentiation. In the present study, we report that inhibition of the K+ channel activity by 4-aminopyridine (4-AP) suppressed ML-1 cell proliferation, as measured by DNA synthesis. Cell cycle mapping indicated that ML-1 cells were arrested in G1 phase after 24-h treatment with 4-AP. Blockade of ML-1 cells at the G1/S boundary of the cell cycle with aphidicolin revealed that ML-1 cells past the G1 checkpoint were capable of entering S phase and synthesizing DNA independently of the channel blockade. ML-1 cell differentiation, measured by CD14 marker protein expression, revealed that the effect of 4-AP was to cause growth arrest and that it did not cause differentiation. Dephosphorylation of retinoblastoma protein accompanied inhibition of ML-1 cell proliferation and suggested that suppression of K+ channel activity by 4-AP is associated with retinoblastoma protein-mediated G1 arrest in ML-1 cells. Moreover, we found that ML-1 cell volume increased 35 +/- 7% after 4-AP treatment, which could be an early event triggering inhibition of ML-1 cell proliferation. These findings suggest that a 4-AP-sensitive K+ channel may play an important role in the transduction of mitogenic signals in ML-1 cells.
Xu
B
B
Department of Physiology, Wright State University, School of Medicine, Dayton, Ohio 45435, USA.
Wilson
B A
BA
Lu
L
L
D015761:4-Aminopyridine / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D026902:Potassium Channel Blockers; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D026902:Potassium Channel Blockers; D016160:Retinoblastoma Protein; D015761:4-Aminopyridine