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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 139-145
A Requirement for K+-Channel Activity in Growth
Factor-Mediated Extracellular Signal-Regulated Kinase Activation in
Human Myeloblastic Leukemia ML-1 Cells
By
Dazhong Xu,
Ling Wang,
Wei Dai, and
Luo Lu
From the Department of Physiology and Biophysics, School of Medicine,
Wright State University, Dayton; and the Division of Hematology,
Department of Medicine, University of Cincinnati College of Medicine,
Cincinnati, OH.
 |
ABSTRACT |
Voltage-gated K+ channels have been shown to be
required for proliferation of various types of cells. Much evidence
indicates that K+-channel activity is required for
G1 progression of the cell cycle in different cell
backgrounds, suggesting that K+-channel activity is
required for early-stage cell proliferation in these cells. However,
little is known about the molecular mechanisms that underlie this
phenomenon. We have shown in human myeloblastic leukemia ML-1 cells
that K+ channels are activated by epidermal growth factor
(EGF), whereas serum starvation deprivation suppressed their activity.
In addition, voltage-gated K+ channels are required for
G1/S-phase transition of the cell cycle. We report here
that suppression of K+ channels prevented the activation
of extracellular signal-regulated protein kinase 2 (ERK-2) in response
to EGF and serum. However, blockade of K+ channels did
not prevent ERK-2 activation induced by 12-O-tetradecanoyl-phorbol 13-acetate (TPA). Elimination of extracellular Ca2+ did
not alter either ERK-2 activation or the effect of
K+-channel blockade on ERK-2 activation. Our data
demonstrate that the K+ channel is a part of the
EGF-mediated mitogenic signal-transduction process and is required for
initiation of the EGF-mediated mitogen-activated protein kinase (MAPK)
pathways. Our findings may thus explain why an increase in
K+-channel activity is associated with cell proliferation
in many types of cells, including ML-1 cells.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
GROWTH FACTORS STIMULATE the entry of
cells into the cell cycle. They stimulate cell proliferation by
initiating G1 progression to S phase of the cell
cycle.1 Growth factors transmit their mitogenic signals via
mitogen-activated protein kinase (MAPK) pathways,2,3 kinase
cascades that eventually activate MAPKs. The MAPKs that primarily
respond to growth factor stimulation are extracellular signal-regulated
kinases 1 and 2 (ERK-1 and ERK-2).2-4 Growth
factor-mediated mechanisms regulate voltage-gated K+
channels, with the activity and/or expression level of K+
channels generally increasing following mitogenic
stimulation.5-7 Voltage-gated K+ channels are
required for proliferation of a variety of cells, including T and B
lymphocytes; blockade of these K+ channels usually inhibits
cell proliferation.8,9 Substantial evidence indicates that
voltage-gated K+ channels are required for cells to
progress through the G1 phase of the cell
cycle.8,10 However, the cellular mechanisms that underlie
this phenomenon are still largely unknown.
Potassium channels are the most diverse membrane ion channels, being
essential for a variety of physiologic functions. Voltage-gated K+ channels function to modulate electrical excitability in
excitable cells.11-14 In nonexcitable cells, their main
function is to maintain proper cell membrane potential and cell
volume.15-17 Alteration of K+-channel activity
in the cell membrane can mediate functional adaptation to a variety of
chemical and physical stimulation through membrane potential
stabilization and maintenance of salt and water balance. We found that
cytokine-mediated stimulation of proliferation in myeloblastic ML-1
cells is associated with increases in K+ channel activity.
A voltage-gated delayed-rectifier K+ channel has been
identified in ML-1 human myeloblastic leukemia
cells.10,18,19 The K+ channel has a conductance
of 31 pS and is very sensitive to the traditional
K+-channel blocker 4-aminopyridine
(4-AP).10,18,19 K+-channel activity is less
sensitive to inhibitions by Ba2+ and tetraethylene ammonium
(TEA).18 K+-channel activity, which has been
shown to be strongly activated by serum growth factors,19
is high in proliferating ML-1 cells and diminished in quiescent and
differentiated cells.18,19 Suppression of the
K+ channels with K+-channel blockers inhibits
proliferation of ML-1 cells by preventing the G1/S
transition of the cell cycle.10 Blockade of K+
channels also prevents phosphorylation of the retinoblastoma protein.10 These findings indicate a possible association
of K+-channel activity with the early signaling events of
mitogenic processes in ML-1 cells. In the present study, we demonstrate that activity of voltage-gated K+ channels is required for
activation of ERKs, represented by ERK-2, in ML-1 cells in response to
growth factors, indicating that the K+ channel is one of
the early components in EGF-mediated MAPK pathway. These results may
provide an explanation for the association of K+-channel
activity with cell proliferation in other types of cells.
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MATERALS AND METHODS |
Cell culture.
ML-1 cells were cultured in RPMI 1640 containing 7.5% heat-inactivated
fetal bovine serum (FBS; GIBCO, Grand Island, NY) in a humidified
incubator supplied with 5% CO2 at 37°C. Cells were passed at 3 × 105 cells/mL seeding density. Serum
starvation of the cells was achieved by maintaining cells in medium
containing 0.3% FBS for 36 hours. Blockade of K+ channel
was performed by adding K+-channel blockers in the medium
30 minutes before the treatment with EGF or FBS.
Patch clamp experiments.
Patch pipettes, with a resistance of 3 to 4 MW when filled with 150 mmol/L KCl solution, were manufactured with a two-stage puller (PP-83;
Narishige, Japan). For whole-cell K+-current
recording, the nystatin perforated-patch technique was used to provide
measurements of stable whole-cell currents without disrupting
cytoplasmic concentration of divalent ions or metabolites. The pipette
tip was filled with a solution containing (in mmol/L): KCl 140, CaCl2 0.05, MgCl2 2, adenosine triphosphate
(ATP) 2, guanosine triphosphate (GTP) 0.05, ethylene glycol-bis
( -aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) 1, and HEPES
10 (titrated with KOH to pH 7.2). The remainder of the pipette was
backfilled with the same pipette solution with the addition of 200 mg/mL nystatin. The bath solution was composed of (in mmol/L): NaCl 140, KCl 2, CaCl2 1, HEPES 10, pH 7.4. Voltage-clamp
experiments were performed using an Axopatch 200A patch-clamp
amplifier; voltage stimulation pulses were controlled with a pCLAMP
program (Axon Instruments, Inc, Foster City, CA). Whole-cell currents
were prefiltered at 1 kHz through a 4-pole Bessel low-pass
filter and digitized at 22 kHz by an A/D converter interface and video
recorder (A.R. Vetter, Rebersburg, PA). Data were collected and
analyzed with pCLAMP software. For the cell-attached single-channel
patch clamp, solutions were as follows: (1) KCl-bath solution
containing (in mmol/L): KCl 140, MgCl2 2, CaCl2
0.5, EGTA 1, and HEPES 10, pH 7.4; and (2) pipette solution containing
KCl 140, MgCl2 2, CaCl2 1, EGTA 1, HEPES 10, pH
7.4. Single-channel currents were recorded with an Axonpatch 200A
amplifier and filtered with a 4-pole Bessel low-pass filter at 2 kHz
and digitized at 22 kHz. The pCLAMP program was used to analyze the
single-channel data. Channel activity was determined as NPo, where N
represents the number of channels in the patch and Po represents the
probability of an open channel. All experiments were performed at room
temperature (21°C to 23°C).
Kinase assay and Western blot.
ML-1 cells (1 × 107/treatment at cell density of 5 × 105 cells/mL) were washed once with ice-cold
phosphate-buffered saline (PBS) and lysed with 1 mL of lysis buffer (20 mmol/L Tris, pH 7.5, 137 mmol/L NaCl, 1.5 mmol/L MgCl2, 2 mmol/L EDTA, 10 mmol/L sodium pyrophosphate, 25 mmol/L
-glycerophosphate, 10% glycerol, 1% Triton X-100, 1 mmol/L
Na-orthovanadate, 1 mmol/L phenylmethylsulfonyl fluoride, 10 mg/mL
leupeptin). Cell lysates were maintained on ice for 10 minutes and then
precleared by centrifugation at 13,000g for 25 minutes. ERK-2
proteins were immunoprecipitated with 0.5 µg rabbit polyclonal
antibody against ERK-2 (Santa Cruz Biotechnology, Santa Cruz, CA) and
Protein A-Sepharose beads (Sigma, St Louis, MO). The immunocomplex was
washed three times with lysis buffer and twice with kinase buffer (20 mmol/L HEPES, pH 7.6, 20 mmol/L MgCl2, 25 mmol/L
-glycerophosphate, 100 mmol/L sodium orthovanadate, and 2 mmol/L
dithiothreitol [DTT]) and resuspended in 90 µL of kinase buffer.
Myelin basic protein (MBP; 2.5 µg) was added to 30 µL of the
immunocomplex. Kinase reactions were initiated by adding 2 µL of ATP
cocktail (20 mmol/L ATP and 10 µCi [ -32P]ATP;
Amersham, Arlington Heights, IL). Reactions were allowed to proceed at room temperature for 15 minutes before termination by the
addition of 30 µL of 2X Laemmli buffer. Phosphorylation of MBP was
visualized by autoradiography after sodium dodecyl sulfate
polyacrylamide gel electrophoresis (SDS-PAGE). MBP phosphorylation levels were quantified by densitometry.
ERK-2 protein levels were determined by Western blotting. Briefly, an
equal volume of 2X Laemmli buffer was added to 20 mL of immunocomplex
and boiled for 5 minutes. After resolution by 12% SDS-PAGE, proteins
were transferred to a polyvinylidene fluoride (PVDF) membrane
(Millipore, Bedford, MA) and incubated with the anti-ERK-2 antibody. The membranes were then incubated with goat anti-rabbit IgG conjugated with alkaline phosphatase (Santa Cruz Biotechnology). Secondary antibodies were detected with a
Phototope-Star Western Blot Detection Kit (New England Biolabs,
Beverly, MA). Data shown are from three independent experiments.
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RESULTS |
Using the nystatin-perforated whole-cell technique, the whole-cell
current in ML-1 cells was activated by depolarization of the membrane
potential from a holding potential of  60 to +80 mV in 20-mV
increments. Upon exposure of ML-1 cells to 50 ng/mL of EGF, the
amplitude of the K+ current increased markedly (Fig
1A and B). The time course showed that the
amplitude of the K+ current doubled within 2 to 3 minutes
after exposure to EGF stimulation and reached the maximum amplitude
within 5 to 10 minutes. EGF-evoked K+ current was sensitive
to 4-AP, being completely blocked by 2 mmol/L 4-AP (Fig 1A and B). The
time course for 4-AP blockade of EGF-stimulated K+ channel
activity is shown in Fig 1C.
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| Fig 1.
Activation of a 4-AP-sensitive K+ channel
by EGF stimulation. (A) Effect of EGF on the 4-AP-sensitive
K+ current. The membrane potential was depolarized from a
holding potential of 60 mV to +80 mV at 20-mV increments with a
pulse protocol showing in the top panel. Whole-cell currents were
recorded from (1) ML-1 cells in the absence (control) and presence of 2 mmol/L 4-AP (as indicated); and (2) ML-1 cells simulated with 10 ng/mL
EGF in the absence (EGF) and presence of 4-AP (EGF + 4-AP). (B)
Current-voltage relationship of the 4-AP-sensitive K+
current activated by EGF in the absence and presence of 4-AP. (C) Time
course of EGF-activated K+ current in the absence and
presence of 4-AP. Currents were normalized as IEGF
/IC , where IEGF represents amplitudes of the
EGF-induced K+ current and IC represents the
K+ current measured from control ML-1 cells. (D)
Single-channel recording of K+ channel in ML-1 cells.
Inward current recorded as a downward deflection was obtained from
cell-attached patches at a membrane potential of 60 mV in the
symmetrical 140/140 mmol/L KCl condition. EGF (50 ng/mL) was directly
applied to the patch chamber to activate K+ channels in
the same patch. (E) Current trace demonstrates that application of 100 µmol/L 4-AP in the patch pipette prevented the EGF-induced increase
of K+-channel activity. Channel activity (NPo) was
plotted as a function of time in the lower portion of D and E. (F)
Statistics of K+-channel activity stimulated by EGF and
FBS in the absence and presence of 100 µmol/L 4-AP. Vertical bars
represent mean K+-channel activity (horizontal bars
represent standard error of the mean [SE]). *Significant difference
(statistical tests: ANOVA and Tukey, P < .001). Data were
collected from five independent experiments.
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To further confirm the effect of EGF stimulation on single
K+-channel activity, the cell-attached patch clamp
technique was used in our study. The single-channel current was
recorded at a membrane potential of 60 mV in vivo (Fig 1D).
Exposure to 50 ng/mL EGF or 10% FBS (data not shown) stimulation
strongly activated K+-channel activity (NPo). Activity
increased from 9.6% ± 1.6% to 36.0% ± 3.6% for EGF
stimulation and from 9.6% ± 1.6% to 52% ± 9.8% for FBS
stimulation within 5 minutes (Fig 1F). In the presence of 100 µmol/L
4-AP in the patch pipette, EGF and FBS stimulation failed, in seven
independent patches, to activate K+-channel activity. NPo
remained unchanged at 12.2% ± 3.5% (Fig 1E and F). These results
indicate that an early effect of EGF or FBS is to activate
cell-membrane K+-channel activity in ML-1 cells.
To examine if K+-channel activity is associated with the
activation of MAPKs in response to serum growth factors, we studied the
effect of K+-channel blockade on MAPK activation. FBS
caused persistent, although variable, activation of ERK-2 during the
75-minute period following the addition of FBS to the culture medium
(Fig 2A). Blockade of the
K+ channel with 4-AP prevented the induction of ERK-2
activation by FBS (Fig 2B). Because ERK-2 is a component of the MAPK
pathway, these results indicate that K+-channel activity is
required for activation of the MAPK pathway when induced by serum
growth factors in ML-1 cells.
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| Fig 2.
Effect of K+-channel blockade on ERK-2
activation. (A) Time-dependent activation of ERK-2 by FBS.
Serum-starved ML-1 cells were left untreated or stimulated with FBS
(10%). At the indicated time points, cells were collected and measured
for ERK-2 activity and ERK-2 protein levels. (B) Effect of
K+-channel blockade on FBS-induced ERK-2 activation in
ML-1 cells. ML-1 cells were serum-starved and either untreated or
stimulated with FBS (10%) for 15 minutes in the presence or absence of
2 mmol/L 4-AP. Cells were collected at the end of the treatment. ERK-2
activities protein levels were measured. (C) Time-dependent activation
of ERK-2 by EGF in ML-1 cells. Serum-starved ML-1 cells were either
untreated or stimulated with EGF (50 ng/mL). At the indicated time
points, cells were collected and measured for ERK-2 activity and ERK-2
protein levels. (D) Effect of K+-channel blockade on
EGF-induced ERK-2 activation in ML-1 cells. Serum-starved ML-1 cells
were untreated or stimulated with EGF (50 ng/mL) for 15 minutes in the
presence or absence of 2 mmol/L 4-AP. The cells were collected at the
end of the treatment, and ERK-2 activities were measured. (E) Dose-dependent inhibitions of EGF-induced
ERK-2 activation by K+-channel blockade with 4-AP.
Serum-starved ML-1 cells were either untreated or stimulated with EGF
(50 ng/mL) for 15 minutes in the presence of the indicated dosages of
4-AP. The cells were collected at the end of the treatment, and ERK-2
activities were measured.
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FBS contains multiple growth factors, cytokines, and hormones, any one
of which may be responsible for the observed ERK-2 activation. To
isolate the possible components in growth factor-mediated MAPK
pathways affected by the K+-channel activity, we examined
the role of the K+ channels in MAPK pathways mediated by a
single growth factor, that is, EGF-mediated MAPK pathways. EGF (50 ng/mL) induced a transient ERK-2 activation that lasted approximately
25 minutes (Fig 2C). Suppression of the K+ channels with
4-AP (2 mmol/L) prevented the ERK-2 activation (Fig 2D). The inhibition
of ERK-2 activation by 4-AP was dose-dependent, reaching a maximum at 2 mmol/L (Fig 2E). These results, indicating that K+-channel
activity was required for EGF-induced ERK-2 activation, indicate that
K+ channels may interact with receptor tyrosine
kinase-mediated MAPK pathways in ML-1 cells.
To test whether the inhibition of ERK-2 activation by 4-AP was by
suppression of the K+ channel rather than by nonspecific
inhibition of the EGF-mediated MAPK pathway, we tested the direct
effect of 4-AP on ERK-2 activity. No direct effect of 4-AP was found on
ERK-2 activity, which was measured by directly adding 3 mmol/L 4-AP to
the kinase reaction (Fig 3A),
indicating that 4-AP inhibits the activation of components that are
upstream of ERK-2. We further tested effects of other classic
K+-channel blockers on ERK-2 activation, reasoning that, if
different K+ channel blockers have similar effects on ERK-2
activation, then the effect of 4-AP, more likely, would be specific for
the K+ channel. Indeed, TEA (10 mmol/L) and
Ba2+ (5 mmol/L) significantly inhibited ERK-2 activation
(Fig 3B). Inhibition of ERK-2 activation also was achieved by
increasing the concentration of extracellular K+ (Fig 3C).
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| Fig 3.
Specificity of the effect of K+-channel
blockade on ERK-2 activation. (A) Direct effect of 4-AP on ERK-2
activity. ERK-2 was immunoprecipitated and measured for activity in the
presence and absence of 3 mmol/L 4-AP in kinase buffer. (B) Effects of
different K+-channel blockers on EGF-induced ERK-2
activation. Serum-starved ML-1 cells were either untreated or were
stimulated with EGF (50 ng/mL) for 15 minutes in the presence or
absence of 4-AP (2 mmol/L), TEA (10 mmol/L), or Ba2+ (5 mmol/L). The cells were collected at the end of the treatment, and
ERK-2 activities were measured. (C) Effect of high extracellular
K+ on EGF- and FBS-induced ERK-2 activation.
Serum-starved ML-1 cells were either untreated or were stimulated with
EGF (50 ng/mL) or FBS (10%) for 15 minutes in normal medium or in
medium containing high K+ (60 mmol/L). The cells were
then collected and assayed for ERK-2 activity. (D) Effect of 4-AP on
TPA-induced ERK-2 activation. Serum-starved ML-1 cells were untreated
or treated with TPA (1 nmol/L) for 10 or 30 minutes in the presence or
absence of 4-AP. At the end of the treatment, cells were collected and
measured for ERK-2 activity. (E) Effect of 4-AP on high-osmolarity-induced
ERK-2 activation. Serum-starved ML-1 cells were untreated or treated
with high-osmolarity medium (600 mmol/L sorbitol) in the presence or
absence of 2 mmol/L 4-AP. The cells were then collected and measured
for ERK-2 activity. (F) Effect of extracellular Ca2+ on
EGF-induced ERK-2 activation and on the inhibition of ERK-2 activation
by K+-channel blockade. Serum-starved ML-1 cells were
untreated, treated with EGTA alone, or treated with EGTA plus 4-AP (2 mmol/L) for 30 minutes. Cells were then left untreated or stimulated
with EGF (50 ng/mL) for 15 minutes. The cells were collected at the
end of the treatment and measured for ERK-2 activity and protein
levels.
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The effect of 4-AP on TPA-induced ERK-2 activation was also tested. TPA
(1 nmol/L) induced a robust increase in ERK-2 activity 10 minutes after
treatment and 30 minutes after treatment (Fig 3D). 4-AP (2 mmol/L) had
no effect on this ERK-2 activation (Fig 3D). Because TPA is a PKC
activator, which can activate ERKs by activating MAPK
kinase kinase, Raf-1,20-23 these results indicate that 4-AP
is not an inhibitor of Raf-1 or of the components below Raf-1 in the
ERK-signaling cascade. The results lend further support to the
hypothesis that K+-channel activity may be required for the
upstream components of an EGF-mediated ERK pathway.
We also measured the effect of 4-AP on high-osmolarity stress-induced
ERK-2 activation. High osmolarity (600 mmol/L sorbitol) induced a
slight increase in ERK-2 activity (Fig 3E). No inhibitory effect of
4-AP was found on this ERK-2 activation (Fig 3E), which again indicates
that 4-AP does not nonspecifically inhibit the ERK-2 pathway and/or
high osmolarity may overcome the effects of K+-channel blockade.
It has shown that elevation of intracellular Ca2+ is
required for T-cell activation.27 A similar increase in
Ca2+ influx may happen in ML-1 cells and, therefore, may
contribute to ERK-2 activation. This mechanism may contribute to the
effect of K+-channel blockade on ERK-2 activation. To test
this possibility, we examined whether EGF could induce ERK-2 activation
under conditions of diminished extracellular Ca2+. In
culture media from which free Ca2+ was chelated with either
0.5 or 5 mmol/L EGTA, we found that ERK-2 activation in response to EGF
was unaffected, compared with the response of the cells in normal
medium (Fig 3F). Suppression of K+-channel activity with
4-AP inhibited EGF-induced ERK-2 activation of the cells equally in
media that contained different concentrations of EGTA (Fig 3F). These
results, therefore, rule out the possible involvement of
Ca2+ influx in the EGF-induced ERK-2 activation in ML-1
cells and show that prevention of ERK-2 activation was not due to
inhibition of Ca2+ influx.
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DISCUSSION |
Other researchers have suggested a few possibilities regarding how the
K+-channel activity is involved in cell proliferation.
These include Ca2+ influx as a result of hyperpolarization
induced by K-channel activation, cell volume change caused by loss of
K+ as a result of K+-channel activation, and
expression of cell cycle-regulator proteins such as cyclin
D1.8 Hyperpolarization could also facilitate Na+-dependent transport of metabolic substrates by
increasing the electrochemical gradient for
Na+.8 Our finding that K+-channel
activity is required for MAPK activation indicates that K+
channels are involved in the initiation stage of the cell cycle in ML-1
cells instead of a later stage of the G1 phase. Our data demonstrate that the K+ channels are part of the growth
factor-mediated mitogenic signal transduction processes and are
required for initiation of the growth factor-mediated MAPK pathways.
We propose that K+-channel activity is required for early,
membrane-associated events of the growth factor signal-transduction pathways.
In the present study, we have also examined the possibility that
Ca2+ influx may play a role in the EGF-induced mitogenic
effect in ML-1 cells. Calcium may activate the MAPK pathway by
activating CAM kinase in some cells.24,25 One of the early
events of the EGF-mediated signaling pathway is the transient elevation
of intracellular Ca2+.26 An increase in
intracellular calcium may arise from either the release of stored
intracellular Ca2+ or from an influx of extracellular
Ca2+.24,25 Intracellular Ca2+
release from storage is induced by second-messenger inositol trisphosphate3 (IP3), produced by hydrolysis of
polyphosphoinositides as a result of activation of phospholipase C-
(PLC-) by activated EGF receptors.24,25 Extracellular
Ca2+ influx may be caused by EGF-induced membrane
hyperpolarization as a result of activation of
Ca2+-activated K+ channels, which is caused by
intracellular Ca2+ release.27 In other studies,
voltage-gated K+ channels have been shown to be a component
in the activation of T cells27 and of T-cell
receptors.28 The elevation of cell membrane potential as a
result of increased K+-channel activity increases the
driving force for Ca2+ influx thereby increasing
intracellular Ca2+. Our results shown in Fig 3F clearly
demonstrate that extracellular Ca2+ did not have any effect
on either EGF-induced mitogenic pathway or the interaction between
K+-channel activity and the EGF-mediated pathway in ML-1 cells.
Because our study ruled out the possible involvement of
Ca2+ influx in the activation of MAPK by EGF in ML-1 cells,
mechanisms other than alteration of Ca2+ influx may be
involved. Change in cell volume, induced by loss of K+ as a
result of K+-channel activation, is one possible
explanation. The findings that high osmolarity alone can induce EGF
receptor clustering and activation in HeLa cells give support to this
hypothesis.29 The transient cell shrinkage caused by
high-osmolarity shock could greatly facilitate, or be required for,
activation of EGF receptors in ML-1 cells. This hypothesis is supported
by the finding that K+-channel blockade did not inhibit
ERK-2 activation induced by high-osmolarity shock in ML-1 cells (Fig
3E), because the strong force of cell shrinkage caused by high
osmolarity may far overcome the swelling effect of
K+-channel blockade. The present results could explain our
previous findings that K+-channel blockade inhibits cell
proliferation in ML-1 cells and may provide an answer to why
K+-channel activity is required for proliferation of other cells.
| |
FOOTNOTES |
Submitted October 16, 1998; accepted March 9, 1999.
Supported by National Institutes of Health (NIH) Grants No. GM46834 and
EY11653 to L.L. and supported in part by NIH Grant No. CA59985 to W.D.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Luo Lu, MD, PhD, Department of
Physiology and Biophysics, School of Medicine, Wright State University,
Dayton, OH 45435; e-mail: LLU{at}WRIGHT.EDU.
| |
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