Targeting of the c-Abl Tyrosine Kinase to Mitochondria in
the Necrotic Cell Death Response to Oxidative Stress*
Shailendra
Kumar
,
Ajit
Bharti
,
Neerad C.
Mishra§,
Deepak
Raina
,
Surender
Kharbanda
,
Satya
Saxena§, and
Donald
Kufe
¶
From the
Dana-Farber Cancer Institute, Harvard
Medical School, Boston, Massachusetts 02115 and the
§ Lovelace Respiratory Research Institute,
Albuquerque, New Mexico 87115
Received for publication, February 14, 2001
 |
ABSTRACT |
The ubiquitously expressed c-Abl tyrosine kinase
is activated in the response of cells to genotoxic and oxidative
stress. The present study demonstrates that reactive oxygen
species (ROS) induce targeting of c-Abl to mitochondria. We show that
ROS-induced localization of c-Abl to mitochondria is dependent on
activation of protein kinase C (PKC)
and the c-Abl kinase function.
Targeting of c-Abl to mitochondria is associated with ROS-induced loss
of mitochondrial transmembrane potential. The results also demonstrate that c-Abl is necessary for ROS-induced depletion of ATP and the activation of a necrosis-like cell death. These findings indicate that
the c-Abl kinase targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death.
 |
INTRODUCTION |
Reactive oxygen species
(ROS)1 have been implicated
in the regulation of both mitogenic and apoptotic signaling pathways.
Mitogenic signals induced by certain growth factors and activated Ras
are mediated by ROS production (1, 2). The generation of ROS through
normal cellular metabolism has also been associated with damage to
cellular components and the induction of apoptosis (3, 4). However, few
insights are available regarding the mechanisms responsible for
ROS-induced cell death. For example, ROS induce topoisomerase
II-mediated cleavage of chromosomal DNA and thereby cell death (5). The
p66shc adapter protein (6) and the p85
subunit of phosphatidylinositol 3-kinase (7) have also been implicated
in the apoptotic response to oxidative stress. Other studies have
indicated that p53-induced apoptosis is mediated by ROS (5, 8, 9) and
that ROS-induced apoptosis is p53-dependent (6, 7).
The ubiquitously expressed c-Abl protein-tyrosine kinase
localizes to the nucleus and cytoplasm. The nuclear form of c-Abl is
activated in the cellular response to genotoxic stress (10) and
contributes to the induction of apoptosis by mechanisms in part
dependent on p53 and its homolog, p73 (11-15). c-Abl also functions
upstream to the proapoptotic stress-activated protein kinase/c-Jun
NH2-terminal kinase and p38 MAPK pathways (10, 16-18).
Other studies have demonstrated that the cytoplasmic form of c-Abl is
activated in response to oxidative stress (19). ROS induce c-Abl
activation by a mechanism dependent on protein kinase C
(PKC
)
(20). Moreover, the evidence indicates that c-Abl is required for
ROS-induced mitochondrial cytochrome c release and apoptosis
(19). Although these findings have provided support for involvement of
c-Abl in the induction of apoptosis by oxidative stress, few insights
are available regarding the signals conferred by c-Abl in this response.
In the present studies, we show that treatment of cells with
H2O2 induces translocation of c-Abl to
mitochondria. The results demonstrate that mitochondrial targeting of
c-Abl is dependent on PKC
and the c-Abl kinase function. We also
demonstrate that c-Abl mediates ROS-induced loss of mitochondrial
transmembrane potential (
m), depletion of ATP, and a
necrosis-like cell death.
 |
MATERIALS AND METHODS |
Cell Culture--
Human U-937 myeloid leukemia cells
(ATCC, Manassas, VA) were grown in RPMI 1640 medium supplemented with
10% heat-inactivated fetal bovine serum, 100 units/ml penicillin, 100 µg/ml streptomycin, and 2 mM L-glutamine.
Wild-type c-Abl
/
, c-Abl+ mouse embryo
fibroblasts (MEFs) (10, 21), MCF-7, MCF-7/c-Abl(K-R), SH-SY5Y
(neuroblastoma), and 293T cells were maintained in Dulbecco's modified
Eagle's medium containing 10% fetal bovine serum and antibiotics.
Cells were treated with 1 mM H2O2
(Sigma) and 30 mM
N-acetyl-L-cysteine (Sigma). Transient
transfections were performed in the presence of calcium phosphate.
Immunofluorescence Microscopy--
Cells were plated onto
poly-D-lysine-coated glass coverslips 1 day prior to
H2O2 treatment (1 h) and then fixed with 3.7% formaldehyde and phosphate-buffered saline (PBS) (pH 7.4) for 10 min.
Cells were washed with PBS, permeabilized with 0.2% Triton X-100 for
10 min, washed again, and incubated for 30 min in complete medium. The
coverslips were then incubated with 5 µg/ml anti-c-Abl (K-12) for
1 h followed by Texas Red-goat anti-rabbit Ig (H + L) conjugate
(Molecular Probes, Eugene, OR). Mitochondria were stained with 100 nM Mitotracker Green FM (Molecular Probes). Nuclei were
stained with 4,6-diamino-2-phenylindole (1 µg/ml in PBS). Coverslips
were mounted onto slides with 0.1 M Tris (pH 7.0) in 50%
glycerol. Cells were visualized by digital confocal immunofluorescence, and images were captured with a CCD camera mounted on a Zeiss Axioplan
2 microscope. Images were deconvolved using Slidebook software
(Intelligent Imaging Innovations, Inc., Denver, CO).
Isolation of Mitochondria--
Cells (3 × 106)
were washed twice with PBS, homogenized in buffer A (210 mM
mannitol, 70 mM sucrose, 1 mM EGTA, 5 mM HEPES, pH 7.4) and 110 µg/ml digitonin in a glass
homogenizer (Pyrex no. 7727-07) and centrifuged at 5000 × g for 20 min. Pellets were resuspended in buffer A,
homogenized in a small glass homogenizer (Pyrex no. 7726) and
centrifuged at 2000 × g for 5 min. The supernatant was
collected and centrifuged at 11,000 × g for 10 min.
Mitochondrial pellets were disrupted in lysis buffer (20 mM
Tris-HCl, pH 7.5, 150 mM NaCl, 1% Nonidet P-40, 1 mM dithiothreitol, 1 mM sodium orthovanadate, 1 mM phenylmethylsulfonyl fluoride, 10 mM sodium fluoride, 10 µg/ml leupeptin and aprotinin) at 4 °C and then
centrifuged at 15,000 × g for 15 min. Protein
concentration was determined by the Bio-Rad protein estimation kit.
Preparation of Cell Lysates--
Whole cell lysates were
prepared as described (10) and analyzed for protein concentration.
Immunoprecipitation and Immunoblot Analysis--
Soluble
proteins (100 µg) were incubated with anti-c-Abl (K-12; Santa Cruz
Biotechnology) for 1 h and precipitated with protein A-Sepharose
for 30 min. Immunoprecipitates and lysates (5 µg) were resolved by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analyzed
by immunoblotting with anti-c-Abl (24-11; Santa Cruz), anti-heat shock protein 60 (StressGen, Victoria BC, Canada),
anti-
-actin (Sigma), anti-proliferating cell nuclear antigen
(Calbiochem), anti-platelet-derived growth factor receptor
(Oncogene), and anti-PKC
(Santa Cruz).
Analysis of Mitochondrial Membrane Potential--
Cells were
incubated with 50 ng/ml rhodamine 123 (Molecular Probes) for 15 min at
37 °C. After washing with PBS, samples were analyzed by flow
cytometry using 488 nm excitation and the measurement of emission
through a 575/26 (ethidium) bandpass filter.
Quantitation of ATP--
ATP levels were measured using an ATP
Determination Kit (Molecular Probes).
Assessment of Apoptosis and Necrosis by Flow
Cytometry--
Cells were analyzed by staining with
annexin-V-fluorescein and propidium iodide (Annexin-V-FLOUS staining
kit; Roche Diagnostics). Samples were analyzed by flow cytometry (BD
Bioscience, San Jose, CA) using 488 nm excitation and a
515-nm bandpass filter for fluorescein detection and a >600 nm-filter
for propidium iodide detection.
 |
RESULTS AND DISCUSSION |
To assess the effects of ROS on c-Abl, we investigated the
subcellular localization of c-Abl in response to
H2O2 by measuring intracellular fluorescence
with a high sensitivity CCD camera and image analyzer. Examination of
the distribution of fluorescence markers in control MEFs showed
distinct patterns for anti-c-Abl (red signal) and a
mitochondrion-selective dye (Mitotracker; green signal). By contrast exposure to H2O2 was
associated with a marked change in fluorescence signals (red
and green
yellow and orange) supporting translocation of c-Abl to mitochondria (Fig.
1A). To confirm targeting of
c-Abl to mitochondria in response to ROS, mitochondria were isolated
from MEFs treated with H2O2. Analysis of the
mitochondrial fraction by immunoblotting with anti-c-Abl demonstrated
an increase in c-Abl protein that was detectable at 30 min and through
3 h (Fig. 1B). Densitometric scanning of the signals
demonstrated over a 5-fold increase in c-Abl protein at 0.5-1 h of
H2O2 treatment (Fig. 1B).
Immunoblotting for the mitochondrial HSP60 protein was used to assess
loading of the lanes (Fig. 1B). Moreover, purity of the
mitochondrial fraction was confirmed by reprobing the blots with
antibodies against the cytoplasmic
-actin protein, the proliferating
cell nuclear antigen protein, and the cell membrane platelet-derived
growth factor receptor (Fig. 1B). To estimate the amount of
c-Abl protein that localizes to mitochondria, we subjected whole cell
and mitochondrial lysates, each prepared from 3 × 106
cells, to immunoblotting with anti-c-Abl. Densitometric scanning of the
signals (Fig. 1C) and adjustment for lysate volume indicated that mitochondrial c-Abl is ~4% of the total cellular c-Abl protein. Following treatment with H2O2, ~20% of total
c-Abl localized to mitochondria (Fig. 1B). As an additional
control, mitochondrial lysates were first subjected to
immunoprecipitation with anti-c-Abl. Immunoblot analysis of the
immunoprecipitates with anti-c-Abl showed
H2O2-induced increases in levels of
mitochondrial c-Abl protein (Fig. 1D). The demonstration
that c-Abl levels are increased in the mitochondria of
H2O2-treated human U-937 leukemia cells (Fig.
1E) and human neuroblastoma cells (data not shown) further indicated that this response occurs in diverse cell types.

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Fig. 1.
Localization of c-Abl to mitochondria in
response to H2O2 treatment. A,
MEFs were treated with 1 mM H2O2
for 1 h. After washing, the cells were fixed and incubated with
anti-c-Abl followed by Texas Red-conjugated goat anti-rabbit IgG.
Mitochondria were stained with the mitochondrial selective dye
Mitotracker Green and nuclei with 4,6-diamino-2-phenylindole. The
slides were visualized using a fluorescence microscope coupled to a
high sensitivity CCD camera and image analyzer. Red signal,
c-Abl. Green signal, Mitotracker. Yellow/orange
signals, colocalization of c-Abl and Mitotracker.
B, MEFs were treated with 1 mM
H2O2 for the indicated times. The mitochondrial
fraction (5 µg) was subjected to immunoblotting with anti-c-Abl,
anti-HSP60, anti-actin, anti-proliferating cell nuclear antigen (PCNA)
and anti-platelet-derived growth factor receptor (PDGF-R).
C, MEFs (6 × 106) were divided into two
aliquots for preparation of whole cell lysates (WCL) and
mitochondrial lysates. Samples (25 µl) of the whole cell lysates
(total volume 500 µl) and of the mitochondrial lysate (total volume
100 µl) were subjected to immunoblot analysis with anti-c-Abl.
D, mitochondrial lysates were immunoprecipitated with
anti-c-Abl and then analyzed by blotting with anti-c-Abl. E,
mitochondrial lysates from U-937 myeloid leukemia cells treated with 1 mM H2O2 for the indicated times
were subjected to immunoblot analysis with the indicated
antibodies.
|
|
To confirm involvement of ROS in targeting of c-Abl to mitochondria,
MEFs were treated with N-acetyl-L-cysteine, a
scavenger of reactive oxygen intermediates and precursor of glutathione (22, 23). N-Acetyl-L-cysteine treatment
inhibited H2O2-induced translocation of c-Abl
to mitochondria (Fig. 2A).
Also to determine whether ROS-induced activation of the c-Abl kinase
function is necessary for targeting of c-Abl to mitochondria, MCF-7
cells stably expressing a kinase-inactive c-Abl(K-R) mutant at levels comparable with that of kinase-active c-Abl in MCF-7/neo cells (Fig.
2B, left panel) (11) were treated with
H2O2. The finding that MCF-7/neo, but not
MCF-7/c-Abl(K-R), cells respond to H2O2 with
translocation of c-Abl to mitochondria supported a requirement for the
c-Abl kinase function (Fig. 2B, right panel).
These results indicate that ROS-induced c-Abl activation is associated
with the targeting of c-Abl to mitochondria.

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Fig. 2.
Targeting of c-Abl to mitochondria is
dependent on ROS-induced c-Abl activation. A, MEFs were
pretreated with 30 mM
N-acetyl-L-cysteine (NAC) for 1 h before adding H2O2 for an additional 1 h. Mitochondrial lysates were subjected to immunoblot analysis with
anti-c-Abl, anti-HSP60, and anti- -actin. B, mitochondrial
lysates from MCF-7 and MCF-7/c-Abl(K-R) cells treated with
H2O2 were analyzed by immunoblotting with
anti-c-Abl and anti- -actin.
|
|
The available evidence indicates that ROS activate c-Abl by a mechanism
dependent on the PKC
kinase (19, 20). To determine whether PKC
contributes to mitochondrial targeting of c-Abl, MEFs were treated with
the selective PKC
inhibitor, rottlerin (24). Although rottlerin had
no effect on constitutive levels of mitochondrial c-Abl, this agent
inhibited H2O2-induced c-Abl translocation
(Fig. 3A). To extend the
interaction of PKC
and c-Abl, 293 cells were cotransfected with
HA-c-Abl and PKC
. Analysis of the mitochondrial fraction by
immunoblotting with anti-HA demonstrated that targeting of HA-c-Abl to
mitochondria is increased by H2O2 treatment
(Fig. 3B). By contrast, cotransfection of HA-c-Abl and kinase-inactive PKC
was associated with less targeting of c-Abl to
mitochondria and no apparent effect of H2O2
treatment (Fig. 3B). These findings provide support for the
involvement of ROS-induced activation of PKC
in mitochondrial
targeting of c-Abl.

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Fig. 3.
PKC is required for
targeting of c-Abl to mitochondria. A, MEFs were
pretreated with 10 µM rottlerin for 0.5 h and then
with H2O2 for 1 h. Mitochondrial lysates
were analyzed by immunoblotting with anti-c-Abl. B, 293T
cells were cotransfected to express HA-c-Abl and GFP-PKC or
GFP-PKC (K-R). At 24 h, the cells were treated with
H2O2 for 2 h. Lysates prepared from the
mitochondrial fraction and intact cells were subjected to immunoblot
analysis with anti-GFP and anti-HA.
|
|
Although the results indicate that c-Abl targets mitochondria in the
ROS response, we hypothesized that c-Abl may directly induce
mitochondrial dysfunction. To determine whether c-Abl is necessary for
ROS-induced loss of
m, wild-type and c-Abl
/
cells
were treated with H2O2 and then stained with
rhodamine 123. Mitochondrial transmembrane potential was substantially
diminished in H2O2-treated wild-type cells
(Fig. 4A). By contrast, the
m was protected from ROS-induced loss in c-Abl
/
cells, but not in c-Abl
/
cells transfected to stably
express c-Abl (c-Abl+) (Fig. 4A). Cyclosporin A
prevents the reduction in
m induced by various agents that open
mitochondrial permeability transition pores (25). In this context,
pretreatment of wild-type MEFs with cyclosporin A (100 µM
for 1 h) abrogated the H2O2-induced change
in
m (data not shown). Both apoptosis and necrosis are associated
with decreases in
m, whereas necrosis is distinguished from
apoptosis by depletion of ATP and an early loss of plasma membrane
integrity (26, 27). To assess the involvement of c-Abl in ROS-induced
necrosis, wild-type, c-Abl
/
, and
c-Abl+ cells were treated with H2O2
and assayed for ATP levels. The results demonstrate that, whereas
H2O2 treatment of wild-type and
c-Abl+ cells is associated with depletion of ATP, this
response was attenuated in c-Abl
/
cells (Fig.
4B). Because these findings support the involvement of c-Abl
in a necrosis-like cell death, cells were stained with both
annexin-V and propidium iodide to assess plasma membrane integrity. The
results demonstrate that, compared with wild-type and
c-Abl+ MEFs, loss of plasma membrane integrity in response
to H2O2 is attenuated in
c-Abl
/
cells (Fig. 4C). These findings
demonstrate that ROS-induced targeting of c-Abl to mitochondria is
associated with loss of mitochondrial membrane potential, ATP
depletion, and necrotic cell death.

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Fig. 4.
Targeting of c-Abl to mitochondria is
associated with loss of mitochondrial transmembrane potential
( m), depletion of ATP, and necrosis-like cell
death. Wild-type (solid bars), c-Abl /
(open bars) and c-Abl+ (hatched bars)
MEFs were treated with H2O2 for the indicated
times. A, cells were stained with Rhodamine 123 and analyzed
by flow cytometry (upper panels). Percentage (mean ± S.E.) of control m obtained from 3 separate experiments (lower
panels). B, cells were analyzed for ATP levels. The
data represent the percentage (mean ± S.E.) of control ATP
levels obtained from three separate experiments. C, cells
stained with annexin-V-fluorescein and propidium iodide were analyzed
by flow cytometry. The data represent the percentage (mean ± S.E.) of annexin-V-positive, propidium iodide-positive cells
obtained in three separate experiments.
|
|
Activation of the c-Abl kinase in the cellular response to oxidative
stress is dependent on PKC
and associated with release of
mitochondrial cytochrome c (19, 20). These findings provided support for involvement of c-Abl in the regulation of mitochondrial signaling. The present studies demonstrate that ROS target the c-Abl
protein to mitochondria and that this response is dependent on the
c-Abl kinase function. Moreover, in concert with the demonstration that
PKC
is required for ROS-induced activation of c-Abl (20), we show
that PKC
is necessary for targeting of c-Abl to mitochondria. Importantly localization of c-Abl to mitochondria is associated with
loss of the mitochondrial transmembrane potential. Apoptosis and
necrosis both involve the loss of mitochondrial transmembrane potential, whereas depletion of ATP is found selectively in necrosis (28). Thus, the demonstration that mitochondrial targeting of c-Abl is
associated with depletion of ATP indicated that c-Abl is functional in
necrosis-like cell death. In this context, wild-type, but not
c-Abl
/
, MEFs also responded to oxidative stress with
dysfunction of the plasma membrane. These findings and the previous
demonstration that c-Abl is involved in ROS-induced cytochrome
c release (19) indicate that targeting of c-Abl to
mitochondria confers both proapoptotic and pronecrotic cell death signals.
 |
FOOTNOTES |
*
This work was supported by Grant CA42802 awarded by the NCI,
National Institutes of Health, the Department of Health and Human Services, and by the office of Health and Biological Research, United
States Department of Energy cooperative agreement DE-FC04-96AL76406.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
¶
To whom correspondence should be addressed: Dana-Farber
Cancer Inst., 44 Binney St., Boston, MA 02115. Tel.: 617-632-3141; Fax: 617-632-2934; E-mail: donald_kufe@dfci.harvard.edu.
Published, JBC Papers in Press, February 28, 2001, DOI 10.1074/jbc.M101414200
 |
ABBREVIATIONS |
The abbreviations used are:
ROS, reactive oxygen
species;
PKC, protein kinase C;
m, mitochondrial transmembrane
potential;
HA, hemagglutinin;
MEF, mouse embryo fibroblast;
PBS, phosphate-buffered saline;
GFP, green fluorescent protein..
 |
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13978-13982[Abstract/Free Full Text]
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