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Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029 [Z. Y., V. N. I., H. H., Z. R.]; Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [K. T.]
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ABSTRACT |
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-kinase (IKK), and reduced phosphorylation of MAP
kinase kinase 7 and Jun NH2-terminal kinase (JNK). Whereas
H2O2 treatment of cells induced JNK, p38, and
IKK activities, in the presence of H2O2 and
elevated GSTp expression there was an additional increase in ERK, p38,
and IKK activities and a decrease in JNK activity. GSTp-mediated
protection from H2O2-induced death was
attenuated upon inhibition of p38, nuclear factor B, or MAP kinase
by dominant negative or pharmacological inhibitors. Conversely,
expression of a dominant negative JNK protected cells from
H2O2-mediated death. These data suggest that
the coordinated regulation of stress kinases by GSTp, as reflected by
increased p38, ERK, and nuclear factor B activities together with
suppression of JNK signaling, contributes to protection of cells
against reactive oxygen species-mediated death. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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A key determinant of the cellular response to oxidative stress relates to the level and form of glutathione. Changes in glutathione levels have been associated with the activation of stress kinases (3) , although the underlying mechanisms are not known. A major factor that affects glutathione homeostasis is its utilization by conjugation, primarily via GST (reviewed in Refs. 4 , 5 ). The ability of GST to alter levels of cellular glutathione in response to production of ROS has been implicated in protection of cells from ROS-inducing agents (6 , 7) .
Accumulation of ROS in response to UV or
H2O2 treatment results in
the activation of multiple stress kinase cascades, including the ASK1,
MEKK1, MAPK, (8
, 9)
, ERK (10)
, and IKK-NFB
(11
, 12) signaling pathways. Among the substrates for
these signaling cascades are p53, NFB, c-Jun, ATF2, and c-Fos, which
dictate protection from, or promotion of, cell death (13
, 14)
. Importantly, the balance between different stress signaling
cascades appears to be among the key determinants in dictating the
cell’s fate (reviewed in Refs. 15
, 16
), although the
mechanisms underlying the coordinated regulation of the kinases
involved are not understood.
Recent studies revealed an association of GSTp with JNK through which it regulates the low basal level of JNK activity in nonstressed cells. Stress in the form of UV or H2O2 causes multimerization of GSTp, which impedes its inhibition of JNK (17) . This is remarkably similar to thioredoxin’s association with and inhibition of ASK1 activities, which limit ASK1 activities under nonstressed growth conditions (18) . Given the ability of ROS to activate stress kinases and the link between stress-activated kinases and altered redox potential, we explored mechanisms underlying the ability of GST to elicit protection against ROS-producing agents. The present study demonstrates that GSTp coordinates ERK/p38/IKK activation and JNK suppression as part of the mechanism underlying its ability to elicit protection against H2O2-induced cell death.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Chemicals.
H2O2, GSTp, pepstatin,
leupeptin, aprotinin, sodium vanadate, and sodium fluoride were
purchased from Sigma. SB203580 and PD98059 were purchased from
CalBiochem.
Constructs.
MEKK1, a constitutively active form of MEKK1 that lacks amino acids
1–351, was kindly provided by Audrey Minden (Columbia University, New
York, NY). MKK6D/D, a constitutive activator of
p38; JNK2APF, a dominant negative of JNK2;
p38ASP, a dominant negative form of p38;
flagMKK7, flagMKK4, and GST-ATF2
expression vectors were kindly provided by Roger Davis (University of
Massachusetts, Worcester, MA). IBN, a superstable form of IB,
was provided by Dean Ballard (School of Medicine, Vanderbilt
University, Nashville, TN). IKKßSE, a
constitutively active IB kinase ßS177; 181E; GST-IB;
2xNFB-Luciferase; and MEKEL, a constitutively
active form of MEK, were kindly provided by Michael Karin (University
of California, San Diego, CA). GSTp cDNA was cloned into pcDNA3.1.
5xJun2tk-Luciferase was kindly provided by Hans Van Dam (Silvius
Laboratory, Leiden, the Netherlands).
Antibodies, Immunoprecipitations, and Immunoblots.
Antibodies to c-Jun were purchased (Santa Cruz Biotechnology).
Polyclonal antibodies to JNK were generated using bacterially expressed
JNK as an antigen. Polyclonal antibodies to GSTp were generated using
purified GSTp (Sigma). Phospho-antibodies to MKK4 and MKK7 were gifts
from Michael Comb of New England Biolabs., Beverly, MA.
Phospho-antibodies to MKK6, ERK1/2, AKT, p38, IB, and JNK were
purchased (New England Biolabs). Immunoprecipitations were carried out
using 1 mg of protein extract and 1 µg of the respective antibodies
and protein G beads (Life Technologies) for 16 h at 4°C
as described previously (17)
. Immunoblotting analysis was
performed as described (17)
. Quantification of the results
was performed by computerized densitometry.
H2O2 Treatment.
Medium taken from the culture dish was mixed with freshly diluted
H2O2 and immediately
applied to the cultured fibroblasts.
Immunokinase Assays.
Immunokinase assays were carried out using immunoprecipitated material
(of 1 mg of protein) that had been incubated with the respective
substrates (17)
. IP with JNK was followed by
phosphorylation of GST-Jun1–87, IP of p38 was
followed by phosphorylation of GST-ATF2, IP of ERK was followed by
phosphorylation of myelin basic protein, and IP of IKK was
followed by phosphorylation of GST-IB.
Apoptosis Studies.
Analysis of cell death was carried out as described by Kumar et
al. (20)
, using triplicates of >5000 cells per
measurement, at the time points indicated in "Results."
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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). Using cells maintained in the presence or absence of tet,
we monitored changes in stress kinases. Removal of tet caused a
time-dependent gradual increase in GSTp expression (Fig. 1a
). Within the initial 8 h, the levels of GSTp were
increased 2–4-fold, whereas during the 12–24 h period, GSTp
expression was increased 10–20-fold (Fig. 1a
). MKK4 and
MKK6 were among the kinases that were not affected within the first
8 h after increased GSTp expression in nonstressed 3T3 cells.
Kinases that were inhibited by low levels of GSTp expression included
JNK, MKK3, p38, and MKK7. Conversely, upon higher expression of GSTp,
p38 exhibited a substantial increase in its phosphorylation. ERK
phosphorylation revealed a marked increase at later time points (Fig. 1a
). A modest increase was seen in phosphorylation of MKK7
after 24 h of elevated GSTp expression (Fig. 1a
).
Higher levels of GSTp expression (absence of tet for 12–24 h)
attenuated inhibition of JNK phosphorylation. This observation is in
line with our former findings, which revealed a concentration-dependent
inhibition of JNK activity by GSTp (17)
. Increased GSTp
expression also caused a noticeable increase in the degree of IB
phosphorylation (not shown). Of the various stress-activated kinases
tested, PKB/AKT was not affected by either low or high levels of
GSTp expression (Fig. 1a
). These results document the
ability of GSTp to elicit coordinated regulation of various stress
kinases in a dose-dependent manner. These observations also imply that
the subset of activated stress kinases affected by GSTp depends on the
expression level of GSTp. Whereas at low levels GSTp inhibited
phosphorylation of JNK, MKK3, MKK7, and p38, higher expression of GSTp
led to marked ERK1/2, MKK4, and p38 phosphorylation. Changes in the
level of GSTp expression, as generated in these GSTp-inducible cells
(Fig. 1a
, lowest panel), mimic the increase in
GSTp expression seen after exposure to various DNA-damaging agents
(21
, 22)
. Similarly, elevated expression of GSTp has been
reported to exist in a wide range of human tumors and often is
associated with increased drug resistance (7
, 23)
.
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) but not c-Jun, probably because of an increase in p38
activity (Fig. 1a
). Together, these data establish the
effect of GSTp expression on the activity of key stress kinases and
their respective substrates. The biological significance of
GSTp-mediated changes in various stress kinases was elucidated using
cell death as a relevant biological end point.
Effect of GSTp Expression on Stress Kinases following Exposure to
H2O2 Treatment.
We next examined the effect of GSTp expression on the activities of
stress kinases after exposure to
H2O2 treatment, which
generates high levels of ROS (1
, 24)
. Analysis of
H2O2-elicited changes
revealed increased activity of ERK, p38, JNK, and IKK, measured via
immunokinase reactions of the respective substrates (Fig. 2
). H2O2 treatment in the
presence of GSTp expression further increased ERK, p38, and IKK
activities as clearly seen at the 3-h time point (Fig. 2
). Conversely,
GSTp expression reduced the degree of
H2O2-induced JNK
phosphorylation, although the level of JNK phosphorylation was still
higher than in control or in GSTp-expressing cells (Fig. 2
). The
ability of GSTp to limit the degree of JNK activation after
H2O2 treatment points to a
mechanism by which GSTp may also serve to limit the magnitude of this
stress kinase output. Together, changes seen in stress kinases upon
H2O2 treatment of
GSTp-expressing cells revealed the nature of coordinated regulation of
stress kinases as reflected in the increased activities of IKK, p38,
and ERK while limiting the JNK output.
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). Analysis at a later time point (48 h) revealed higher degrees of cell
death, which were dependent on the dose of
H2O2 used (not shown).
Exposure to higher doses of
H2O2 (100 µM)
also revealed GSTp-mediated protection against cell death (39%
versus 25%). GSTp maintained its protection even at higher
doses of H2O2 (40%
versus 30% at 200 µM; Fig. 3
).
These data suggest that the
H2O2-induced cell death of
3T3 cells was efficiently reduced by GSTp expression. Analysis of the
type of H2O2-induced cell
death revealed that it is primarily late apoptosis/necrosis (not
shown), which is in line with previous studies indicating that necrosis
is the major form of death induced by
H2O2 (11)
.
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B Activation and JNK Suppression Are Required
for GSTp’s Ability to Mediate Protection against ROS-induced Cell
Death.B, or were subjected to
treatment with pharmacological inhibitors of MAPK (PD98059) or p38
(SB203580). An ability to reduce the degree of GSTp-elicited protection
would point to the role of the respective kinase in this response.
Forced expression of JNKAPF, a dominant negative
form of JNK, caused a minimal increase (5%) in the level of cell death
in untreated cells, in a manner that was not affected by GSTp
expression (Fig. 4a
). The level of
H2O2-induced cell death was
reduced upon expression of GSTp (from 36% to 22%) and upon
coexpression of JNKAPF and GSTp (from 17% to
8%; Fig. 4a
). This observation suggests that JNK promotes
cell death after exposure to
H2O2. The ability of GSTp
expression to further reduce the degree of
H2O2-mediated cell death in
the presence of JNKAPF expression could be
attributed to the limited effectiveness of this dominant negative
vector, and suggests that GSTp complements the limited effect of
JNKAPF through inhibition of additional
JNK molecules.
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BN-expressing cells to
H2O2 did not cause
additional changes in the degree of cell death (from 36% to 34%),
probably because of experimental conditions that were set to a high
dose effect of H2O2.
Importantly, upon expression of GSTp, there was an increase in
H2O2-induced cell death
(from 21% to 28%), indicating that the lack of NFB attenuates
GSTp-elicited protection against
H2O2-induced death (Fig. 4a
). Forced expression of the IB super-repressor
IBN in the presence of elevated GSTp caused a 5-fold increase in
the basal level of cell death before exposure to
H2O2 (Fig. 4a
),
suggesting that without exogenous damage, NFB cooperates with GSTp
to promote cell survival. These findings are in line with the effect of
GSTp on IB phosphorylation (Fig. 3
) and suggest that NFB is a
part of the GSTp-coordinated response that elicits protection against
H2O2-induced cell death.
Forced expression of p38ASP, a dominant negative
p38 construct, did not alter the level of
H2O2-induced cell death;
however, it attenuated the decrease mediated by GSTp. Whereas GSTp led
to a 40% inhibition of
H2O2-mediated cell death
(from 37% to 20%), in the presence of p38ASP,
there was no protection from
H2O2-induced cell death
(Fig. 4b
), but rather an increase from 38% to 48%.
Observations made with the dominant negative form of p38 were confirmed
using the pharmacological inhibitor SB203580, which efficiently
increased the degree of
H2O2-mediated cell death in
the presence of GSTp expression from 20% to 52% (Fig. 4b
).
These results indicate that p38 is among the stress kinases used by
GSTp to elicit its protective effect against
H2O2-induced cell death.
Treatment of cells with the pharmacological inhibitor of MAPK kinase,
PD98059, attenuated GSTp-elicited protection as reflected in the
substantial increase (from 22% to 42%) in the level of
H2O2-mediated cell death
(Fig. 4c
). This finding points to the role of ERK in the
ability of GSTp to protect against
H2O2-induced cell
death.
The ability to attenuate protection elicited by elevated expression of GSTp via the genetic or pharmacological inhibitors of the respective kinases establishes the contribution of ERK, p38, and IKK to GSTp-elicited protection from H2O2-mediated cell death. At the same time, the increased survival of H2O2-treated cells by the dominant negative form of JNK points to its proapoptotic signal, which is down-regulated by GSTp, as part of the GST-elicited integrated stress response.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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B, and ERK cascades, while limiting the degree of JNK signaling.
Although each of the stress kinases alone, when uncoordinated
(i.e., overexpression), is capable of eliciting either
promotion of or protection against cell death, GSTp contributes to a
coordinated regulation that is likely to play an important role in its
ability to elicit protective effects. The coordinated regulation of
stress kinases by GSTp is better appreciated in light of the
differences seen in the activities of the kinases following exposure to
ROS-generating treatment, as demonstrated in the present study for
H2O2. GSTp
efficiently amplified the degree of IKK, p38, and ERK activities while
suppressing the level of the JNK-elicited signal. Cell death elicited
by H2O2 is efficiently
inhibited by forced expression of the dominant negative form of JNK.
Conversely, inhibition of p38/ERK/NFB attenuated GSTp-elicited
protection. The system used in the present studies reflects two physiological scenarios where GSTp expression is elevated: (a) an increase in the expression of GSTp has been reported in response to ROS-generating agents and is mediated by c-Jun (21 , 25) ; and (b) elevated levels of GSTp expression are found as often in human tumors as in their cell line derivatives. The latter observation has been correlated with multidrug resistance and poor apoptotic response to chemotherapeutic drugs (4 , 7 , 23) .
Because ROS-generating agents also activate transcription of GSTp via the JNK/Jun cascade, our finding points to the possible existence of a feedback regulatory loop for regulation of stress kinases. According to this model, exposure to ROS-generating agents generates multimers of GSTp that no longer elicit JNK inhibition and thus enables the activation of JNK. Through transcriptionally active JNK substrates, including c-Jun, a new synthesis of GSTp takes place, which is expected to resume JNK inhibition. Such a feedback loop points to redox-dependent regulation of the duration and magnitude of stress kinase activity.
Among possible explanations for coordinated regulation of various stress kinases by GSTp are (a) the possible association of GSTp with other upstream signal transduction components; (b) the effect of GSTp on scaffold proteins; and (c) a possible link between GSTp and caspases, which are required for H2O2-mediated cell death.
Altogether, the current study provides insight into the mechanism
underlying the regulation of key signal transduction components that
play pivotal roles in the response to stress and damage by altered ROS
and redox potential. The delicate balance between inhibition of JNK and
activation of ERK, IB kinase, and p38 points to the mechanism by
which GSTp is capable of eliciting protection against cell death
induced by ROS-generating agents. The widely documented deregulation of
GSTp expression in human tumors represents one important setting where
changes in the coordinated regulation of stress kinases are expected to
take place and impact on cell protection from cell death in response to
ROS-generating treatments.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Support from the National Cancer Institute
(Grant CA77389) to Z. R. is gratefully acknowledged. 
2 To whom requests for reprints should be
addressed, at Ruttenberg Cancer Center, Mount Sinai School of Medicine,
One Gustave Levy Place, Box 1130, New York, NY 10029. Fax:
(212) 849-2446; E-mail: ronaiz01{at}doc.mssm.edu
3 Abbreviations used are: ROS, reactive oxygen species; GST,
glutathione S-transferase; ASK1, apoptosis
signal-regulating kinase 1; MEKK1, MAPK/ERK kinase kinase; MAPK,
mitogen-activated protein kinase; ERK, extracellular receptor kinase;
IKK, inhibitor of -kinase; NFB, nuclear factor B; ATF2,
activating transcription factor 2; GSTp, glutathione
S-transferase 
; JNK, Jun NH2-terminal
kinase; MEK, MAPK/ERK kinase; MKK, MAPK kinase; IB, inhibitor of
nuclear factor B; tet, tetracycline; IP, immunoprecipitation; PKB,
protein kinase B/AKT.
Received 3/ 7/00. Accepted 6/ 8/00.
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T. Wang, P. Arifoglu, Z.'e. Ronai, and K. D. Tew Glutathione S-transferase P1-1 (GSTP1-1) Inhibits c-Jun N-terminal Kinase (JNK1) Signaling through Interaction with the C Terminus J. Biol. Chem., June 8, 2001; 276(24): 20999 - 21003. [Abstract] [Full Text] [PDF]
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