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Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA
1Correspondence: Room 321, MSRB, DUMC 2612, Duke University Medical Center, Durham, NC 27710, USA. E-mail STAML001{at}mc.duke.edu
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ABSTRACT |
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 TOP ABSTRACT OXIDATIVE STRESSNITROSATIVE STRESSMOLECULAR RECOGNITIONREDOX AND STRUCTURAL CHANGES...CONCLUSIONNote added in proofREFERENCES |
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B, AP-1, and
p53—contain reactive thiols in their DNA binding regions, the
modification of which alters binding in vitro. Several
of these transcription factors have been found to be sensitive to both
reactive oxygen species and nitric oxide-related species in
vivo. It remains entirely unclear, however, if oxidation or
nitrosylation of eukaryotic transcription factors is an important mode
of regulation, or whether transcriptional activating pathways are
principally controlled at other redox-sensitive levels.—Marshall,
H. E., Merchant, K., Stamler, J. S. Nitrosation and oxidation
in the regulation of gene expression.
Key Words: nitric oxide • oxidative stress • nitrosative stress • S-nitrosylation • thiols • transcription factors
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OXIDATIVE STRESS |
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TOPABSTRACTOXIDATIVE STRESSNITROSATIVE STRESSMOLECULAR RECOGNITIONREDOX AND STRUCTURAL CHANGES...CONCLUSIONNote added in proofREFERENCES |
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-glutamyl cysteine synthetase (-GCS) and prompt
proteolytic degradation of oxidatively damaged proteins (1
, 2)
. The redox-sensing mechanisms underlying these cellular
defenses are at least partly controlled at the level of transcription.
However, little is known of the molecular basis of such redox
regulation in eukaryotic cells.
Antioxidant defenses are characterized best in Escherichia
coli, where the transcription factors OxyR and SoxRS induce
protective genes in response to hydrogen peroxide and superoxide,
respectively. The redox signal is sensed by an [2Fe-2S] cluster in
SoxR (3)
and a free cysteine residue in OxyR (vida
infra) (4)
. It is speculated that transcription
factors in eukaryotes use similar molecular mechanisms to orchestrate
the antioxidative response, but there are no well-elucidated examples.
The limitations of the field are highlighted by an appreciation that
the purported oxidative modifications of transcription factors have not
been produced in pure form nor have any been identified in
vivo.
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NITROSATIVE STRESS |
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TOPABSTRACTOXIDATIVE STRESSNITROSATIVE STRESSMOLECULAR RECOGNITIONREDOX AND STRUCTURAL CHANGES...CONCLUSIONNote added in proofREFERENCES |
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and that such posttranslational modification can serve
in the regulation of cellular responses (5
6
7
8
9
10
11)
. In the
strictest sense, S-nitrosylation is the only redox-related modification
of proteins that has met the criteria of a physiological signal, that
is: 1) the covalent modification has been shown to occur
in vivo; 2) it alters protein function; and
3) changes in signal amplitude
(S-nitrosylation/denitrosylation) have been documented over the time
scales of the physiological responses (10
, 11)
. The
concept of nitrosative stress has emerged from an understanding that
nitrosylation can also reach a hazardous level. Under such conditions,
nitrosylation may directly inhibit critical protein functions
(12
, 13)
and/or promote deleterious oxidative
modifications that do so (14)
. At the cellular level,
nitrosative stress has been linked to inhibition of cell growth and
apoptosis, and thus may be widely implicated in NO pathogenesis. The
response has been best studied in E. coli, which up-regulate
specific anti-nitrosative defenses, including enzymes that metabolize
NO and S-nitrosothiols (SNOs) (15
, 16)
. In particular,
genes under the control of OxyR encode for proteins that metabolize
nitrosants and confer a survival advantage for bacteria
(17)
. In other words, OxyR has evolved such that it senses
both oxidative and nitrosative events, and responds by up-regulating
genes that afford protection from both types of threat. It is of great
importance that the S-nitrosothiol derivative of OxyR has been
identified in vivo (17)
, as this remains the
only redox-related modification of a transcription factor that has been
shown to occur within a cellular context.
In the inflammatory response, many of the same cells that generate
reactive oxygen species (ROS) also express NO synthases. In some cases,
interactions between nitrosants and oxidants may produce products that
are more toxic than either reactant alone. In other instances,
nitrosative mechanisms of cellular injury predominate (13
, 14)
. One might therefore speculate that eukaryotic cells would
have evolved transcriptional control mechanisms analogous to bacteria
that sense and respond to both oxidative and nitrosative stress. In
this scenario, NO- and O2-related modifications
of proteins would likely constitute biological signaling events in
cellular defense mechanisms (e.g., cytokine stimulation). Here we
review the response of a number of transcription factors to oxidative
and nitrosative stresses. In our attempt to elucidate the molecular
events that constitute biological signals, we draw correlates between
prokaryotic and eukaryotic transcription factors.
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MOLECULAR RECOGNITION |
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TOPABSTRACTOXIDATIVE STRESSNITROSATIVE STRESSMOLECULAR RECOGNITIONREDOX AND STRUCTURAL CHANGES...CONCLUSIONNote added in proofREFERENCES |
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. Nevertheless, it has been difficult to ascribe this
event to relevant oxidants in vivo. That is, superoxide can
oxidize SoxR but does not achieve a cellular steady-state concentration
high enough to activate transcription. In contrast, NO cannot oxidize
SoxR, but clearly regulates protein activity in vivo
(15)
. Thus, it has been alternatively proposed that SoxR
responds to a change in the redox state of the cell (between -260 and
-280 mV). Specifically, the redox potential of the [2Fe-2S] cluster
is approximately -280 mV (18)
, which would make it
responsive to NADPH/NADP+ ratios at the cellular
level (19)
. A remaining conundrum, however, is that SoxR
is not activated by H2O2,
which can both oxidize the cluster and raise the redox potential of the
cell above -285 mV. The nature of the redox sensor notwithstanding,
SoxR has no known eukaryotic homologue, and none of the eukaryotic
transcription factors identified to date contains a redox-active
transition metal.
OxyR
The OxyR protein is a homotetramer that is activated by both
hydrogen peroxide and S-nitrosothiols (SNOs) (17)
. The
protein contains six cysteines, one of which is absolutely essential
for activity and two that are required for maximal activation
(4)
. The protein does not contain a redox-active
transition metal. It is unclear from available data what the molecular
basis is for OxyR activation. Recent studies with a mutant protein (in
which 4 of 6 cysteines per monomer were replaced with alanines)
suggested that oxidation of a single thiol to a sulfenic acid may
represent the sensor mechanism, whereas the activation mechanism was
ascribed to formation of an intramolecular disulfide (S-S) (4
, 20)
. These data are, however, difficult to reconcile with the
observation that a stable SNO can form in wild-type OxyR, because
S-nitrosylation should have catalyzed disulfide formation with release
of the NO group (14
, 21)
; therefore, the data do not rule
out the possibility of alternative mechanisms of activation in
vivo. Indeed, the redox potential of OxyR is approximately -185
mV, making the protein susceptible to thiol/disulfide exchange
(20)
. Accordingly, S-thiolation with glutathione, for
example, may serve as a regulatory posttranslational modification in
cells. Although there are no known eukaryotic homologues of OxyR, the
bacterial OxyR binding motif has been shown to function as a
redox-dependent transcriptional enhancer in murine cells
(22)
.
Activation of OxyR by SNOs has been attributed to S-nitrosylation of a
single cysteine residue. Components of an S-nitrosylation motif, X (H,
R, K) C (D, E), surround Cys 199 in OxyR, making it a likely candidate
site of posttranslational modification (23
, 24)
. However,
these data do not definitively exclude involvement of a second thiol or
an oxidative mechanism of activation because S-nitrosylation can
promote oxidative chemistry (17)
, and broader usage of the
S-nitrosylation motif to include additional redox modifications has
been considered (23)
. In one scenario, the molecular
modification may be dictated by the identity of the nitrosant or by the
protein structure. That being said, the stability of the S-NO bond in
nitrosylated OxyR argues against further oxidation of the critical
thiol (Cys 199) by SNOs. It is therefore tempting to speculate that the
second conserved thiol in OxyR (Cys 208) plays a role in stabilization
of the S-NO bond (as in formation of an N-hydroxysulfenamide) analogous
to complexes formed from sulfenic acids (20
, 25)
. More
generally, redox responsiveness in proteins may be conferred by S-NO,
S-OH, S-S (intramolecular disulfide), and S-SR (mixed disulfide), all
potential reversible modifications of reactive cysteines
(14)
(Table 1
). Most redox-responsive transcriptional activators in mammalian cells
are likely to be regulated by one of these modifications (i.e., they
possess cysteines subject to redox control) and to contain an
S-nitrosylation/redox motif (or at least critical components of it)
(23)
. It is as yet unknown, however, whether these
oxidative modifications occur in vivo or if proteins can
process these different signaling modifications into distinct
functional responses.
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NF-B
The prototypic form of the redox-sensitive transcription factor
NF-B is the p50-p65 heterodimer, but other hetero- and homodimeric
species are found. In its inactive state, NF-B (p50-p65) is bound to
an inhibitory protein, IB
, and is sequestered in the cytoplasm.
With an appropriate stimulus, NF-B is released from IB and
translocates to the nucleus, where it can activate target gene
transcription (26)
. NF-B was initially described in
lymphoid cells, but its immunomodulatory role has been clearly
established in macrophages, respiratory epithelial cells, endothelial
cells, and smooth muscle cells (27
28
29
30)
. NF-B regulates
a wide array of genes involved in the inflammatory response including
the cytokines tumor necrosis factor (TNF-), interleukin 2, and
interleukin 8; adhesion molecules ICAM-1 and VCAM-1; and nitric oxide
synthase 2 (NOS2) (31)
.
Initial studies were unclear as to whether an oxidizing or reducing
environment favored NF-B activation (32
, 33)
. It now
seems more certain that reducing conditions are required in the nucleus
for NF-B DNA binding (34
35
36)
, whereas oxidizing
conditions in the cytoplasm promote NF-B activation
(37
38
39)
. Pretreatment of cells with the antioxidants
N-acetyl-L-cysteine or pyrrolidine dithiocarbamate (PDTC) prevents
cytokine-induced NF-B activation (32
, 38
, 39)
.
Furthermore, hydrogen peroxide
(H2O2) and superoxide
(O2-) activate NF-B in
certain cell systems (38
, 40
, 41)
. In the cytosol,
mitochondrial ROS may mediate the changes in cytoplasmic redox state
that signal NF-B activation. Specifically, blocking production of
oxygen radicals from the electron transport chain prevents the
activation of NF-B in cytokine-stimulated cells (42)
;
mitochondrial MnSOD expression is increased by NF-B, perhaps in
anticipation of redox signaling (29)
. However, the
redox-sensitive step or ‘on switch’ for NF-B in the cytoplasm is
still not known. One potential target is p21 ras, which is activated by
oxidative stress leading to an increase in NF-B activity
(43)
. The activation of NF-B by ras is not dependent on
nuclear translocation of p50-p65, but rather ras initiates a MAP kinase
cascade that results in the phosphorylation of the p65 subunit
(44
, 45)
. Phosphorylation of p65 then augments
NF-B-dependent gene transcription (46)
.
Once NF-B is released from the IB regulatory protein, it rapidly
translocates to the nucleus. However, for NF-B to bind to DNA, a
cysteine residue in the DNA binding region of the p50 subunit (cysteine
62) must be in a reduced state (36
, 47)
. This cysteine has
been shown to participate in intermolecular disulfide formation
(34)
. Moreover, thioredoxin, a protein that reduces
disulfides, and redox factor 1 (Ref-1), a reducing molecule unique to
the nucleus, function to regulate the redox status of NF-B in the
nucleus (35)
. Recently it has been shown that thioredoxin
translocates to the nucleus concomitant with NF-B activation and may
physically interact with the p50 subunit prior to DNA binding
(48)
.
Taken together, these data make an excellent case for the redox
regulation of NF-B responses. However, for all of these data there
is no firm evidence that NF-B proteins undergo oxidative
posttranslational modifications in situ. In other words, the
particular sites within NF-B that might undergo redox modification
(i.e., p50, p65, IB proteins, IB kinases) in cells have not been
clearly identified and the nature of the posttranslational
modifications that serve in these cellular control mechanisms are not
known (Fig. 1A
).
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NO is the prototypic redox-signaling molecule—more versatile than
O2- or
H2O2 and clearly better
identified with redox-related modifications of intracellular proteins
(6
, 14)
. NO and NF-B signaling pathways are intimately
linked. NF-B activation is essential for NOS2 gene transcription
(49)
, and NO-related molecules modulate NF-B signal
transduction in a cell- and stimulus-specific manner. For example, low
concentrations (0.1 to 10 µM) of NO, or related donors, activate
NF-B in human lymphocytes (50)
. Here, the mechanism is
indirect: S-nitrosylation of a conserved cysteine residue in the
guanine binding domain of p21 ras leads to NF-B activation
(8)
. Epstein-Barr virus-infected lymphocytes may take
advantage of this pathway to selectively control the expression of a
virus-specific transcriptional activator termed Zta (51)
.
Higher concentrations of NO species (0.2 to 0.5 mM), on the other hand,
inhibit NF-B activation in hepatocytes (52)
, T cells
(53)
, endothelial (27)
, and vascular smooth
muscle cells (28)
and prevent DNA binding of both the
NF-B p50-p65 heterodimer and p50 and p65 homodimers in
vitro (54)
. Conversely, inhibition of endogenous
production of NO-related activity augments NF-B activity in
macrophages and endothelial cells (27
, 55)
.
NO or related molecules appear to inhibit NF-B activation through a
multiplicity of mechanisms. Studies in endothelial cells show that
nitrosothiols prevent the proteolytic degradation of the IB
complex in the cytoplasm by increasing transcription of I-B
and/or stabilizing the mRNA transcripts (27)
. But other
work in vitro indicates that nitrosylation of the cysteine
62 residue in the p50 subunit prevents NF-B from binding to DNA and
activating transcription, and we have recently detected S-nitrosylated
NF-B in cells (unpublished observations). The physiological
significance of this posttranslational modification is, however, less
clear (54)
. A summary of the available data suggests that
NO affects NF-B differently depending on the cell type, activating
stimulus, NO-related species, NO concentration, and redox state of the
cell (Fig. 1B
and Table 2
). This is nicely exemplified in murine macrophages, where a biphasic
response to NO-related molecules is seen for NF-B-dependent
expression of NOS2 (56)
.
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AP-1, c-Jun, and c-Fos
AP-1 is a transcription factor that belongs to the basic leucine
zipper (bZip) family. It is a heterodimeric protein consisting of c-Fos
and a Jun (c-Jun, JunB, JunD) subunit, with the primary activating form
being c-Fos/c-Jun. Jun-Jun homodimers also form, however, and can
activate transcription, albeit less efficiently then the Fos/Jun
heterodimer (57)
. Other proteins of the Fos family (i.e.,
FosB, Fra1, Fra2) can form dimers with Jun proteins and bind to the
AP-1 site, but do not have trans-activation potential
(58)
. AP-1 activation has an important role in the control
of cell proliferation and differentiation. Several different growth
factors (e.g., bFGF, EGF), cytokines (e.g., TNF-, TGFß), and tumor
promoters (e.g., phorbol esters, asbestos fibers) increase cellular
AP-1 activity in vitro (57
, 59
, 60)
.
Classical regulation of cellular AP-1 activity occurs through two
mechanisms: an increase in the transcription of c-fos and c-jun, and
the phosphorylation of c-Fos and c-Jun proteins. The serum response
element and TPA response element regulate the transcription of c-fos
and c-jun respectively (61)
. JNK1/2 (c-Jun
NH2-terminal kinase), ERK1/2 (extracellular
stimulus responsive kinase), and other members of the MAP kinase
family, participate in the phosphorylation of the c-Jun and c-Fos
proteins (61
62
63)
.
The existing data on the redox regulation of AP-1 are quite confusing.
Antioxidants have been shown to increase cellular AP-1 activity (i.e.,
the reverse of what is seen with NF-B) and AP-1 activity is highest
in cells that have the highest levels of thioredoxin (37
, 64)
. However, many of the studies that show activation of AP-1
and JNK by antioxidants were performed using PDTC and butylated
hydroxyanisole. While these compounds do have antioxidant
properties, they can also induce oxidative stress in cellular systems
(65)
and/or modify protein thiols directly. In addition,
the activation of AP-1 by these compounds is attenuated by an increase
in cellular thiol levels (65)
. Thus, the precept that AP-1
is activated by antioxidants needs to be reexamined.
Indeed, the evidence seems stronger that oxidative stress induces AP-1
transcriptional activity. Hydrogen peroxide and superoxide-generating
systems increase the transcription of c-fos and c-jun, which leads to
an increase in AP-1 activity (66
67
68)
. The stimulation of
AP-1 activity by cytokines and growth factors also appears to be
dependent on superoxide production (69
, 70)
. Moreover,
increased cellular glutathione levels inhibit the expression of c-Fos
and Jun proteins as well as the activation of AP-1 by numerous stimuli
(65
, 70
71
72
73)
. This redox sensitivity is likely transduced
through the JNK and ERK pathways (70)
. In conclusion,
review of the available data to date indicates that AP-1 is not
antioxidant responsive, but rather is activated by either oxidants or
oxidative stress.
Just as there is debate over whether oxidants or antioxidants activate
AP-1, there is some uncertainty as to whether AP-1 trans-activates the
antioxidant response element (ARE). The ARE has been found in several
antioxidant genes including NAD(P)H:quinone reductase, glutathione
S-transferase, and -GCS (74
, 75)
. Although AP-1 or AP-1
like elements exist in the ARE, AP-1 dimers containing c-Fos or Fra1
subunits actually inhibit transcription (76)
and the
consensus is that AP-1 is not the primary trans-activating protein
(76
77
78)
. Rather, two other bZip transcription factors,
Nrf1 and Nrf2, are viewed as the primary regulators of the ARE
(76
, 79
80
81)
.
Much like NF-kappa B, AP-1 binding to DNA is favored under reducing
conditions. A single cysteine residue in the basic region (i.e., DNA
binding domain) of the c-Fos and c-Jun proteins confers this redox
sensitivity (82)
. Ref-1 appears to be the principal
regulator of the redox status of AP-1 (83)
. Ref-1, in
turn, is regulated by thioredoxin, which translocates to the nucleus on
cell stimulation and interacts with Ref-1 purportedly through the
formation of a disulfide bond (84)
. Deletion of a single
cysteine residue in the thioredoxin molecule prevents this interaction,
thereby decreasing AP-1 activation. The reducing capability of Ref-1 is
further dependent on a cysteine residue located at the
NH2-terminal end of the protein
(85)
. Of note, Ref-1 also has DNA repair activity that is
located in a different domain of the protein (86)
. None of
these data elucidate the molecular basis of the redox sensitivity of
AP-1 as it relates to DNA binding.
Recent studies with c-Jun in vitro demonstrate that a
decrease in the GSH:GSSG ratio induces S-glutathiolation of the
redox-sensitive cysteine in the basic region and prevents c-Jun DNA
binding (87)
. Oxidative modification of a single cysteine
is therefore key to modulation of its activity in vitro. In
principle, a sulfenic acid, a related condensation, intramolecular and
intermolecular disulfides, or combinations of the above are all
potential posttranslational modifications of AP-1 that may serve as
part of a transcriptional control mechanism.
Cellular treatment with NO donor compounds inhibits AP-1 binding to DNA
(88)
. Additional in vitro studies show that NO
or related molecules inhibit c-Jun and c-Jun/c-Fos DNA binding in a
reversible manner (89)
. This inhibition is mediated via
reactions with conserved cysteines in the DNA binding region of both
c-Jun and c-Fos and is best rationalized by S-nitrosylation. Recent
experiments showing that high NO donor concentrations can induce
S-glutathiolation of the critical cysteine in c-Jun make it clear,
however, that oxidation of this residue can not be definitively
excluded (90)
. NO effects on AP-1 activity in biological
systems are moreover cell type specific and concentration dependent
(Table 3
). In one system, NO-related compounds actually increased AP-1 binding
and transcription of c-fos and c-jun (91
92
93)
. This
activity may have been secondary to stimulation of guanylate cyclase as
comparable degrees of AP-1 activation were elicited with cGMP analogs
(92
, 94)
; the authors also implicated a cGMP-independent
pathway but offered no further insight. One explanation for the NO
effect is that it activates JNK (95
, 96)
. Although JNK
itself may be a NO target (97)
, it is probably a kinase
further upstream in the JNK pathway that transduces the NO signal
(98)
.
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The theme that emerges from all of these studies is one in which NO- and O2-related molecules do not just interact with AP-1 itself. Instead, they regulate other molecular components in the signal transduction pathway. It is therefore understandable why a consensus does not exist as to whether NO is an activator or inhibitor of AP-1 or whether AP-1 mediates or counters oxidative and nitrosative stresses. That is, there is no single redox paradigm into which AP-1 can be fit. Rather, the AP-1 activation pathway seems to be capable of sensing diverse redox-related signals in a variety of signaling circuits. The nature of these redox-related signals and the components of the circuitry remain to be elucidated.
p53, EGR-1, and other nitrosant/oxidant-sensitive transcription
factors
Numerous additional mammalian transcription factors exhibit
redox sensitivity (Table 4
). The difficulty lies in placing the sparse data into physiological
context. The tumor suppressor protein p53, for example, binds to its
specific DNA sites more favorably in a reducing environment
(99
100
101
102
103)
, and mutation of cysteine residues in the p53
core binding domain prevents DNA binding and p53-induced transcription
(101)
. It also appears that Ref-1, similar to its redox
role with NF-B and AP-1, regulates p53 DNA binding and gene
trans-activation (104
, 105)
. But whereas alkylation or
oxidation of thiols inhibits DNA binding of p53 (99
100
101
102
103)
,
zinc as well as thiol-reducing agents are needed to reverse the
oxidative inhibition. These data suggest that at least some of the
cysteines are involved in the coordination of zinc within p53
(103)
.
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One cannot deduce from these studies a clear understanding of the
molecular mechanism by which p53 is redox modulated. It has been
suggested that oxidation of p53 may involve either the formation of a
sulfenic acid, a mixed disulfide, or an intramolecular disulfide;
however, this is only speculation (100
, 102)
. Moreover,
this explanation does not reconcile well with the increase in DNA
binding seen on zinc coordination to the cysteine redox centers. An
intriguing notion that zinc somehow protects the cysteines from
oxidation has been forwarded (100
, 101
, 103)
, but this is
not a common function for the metal and the result in vitro
cannot easily be extrapolated to biological systems.
Zinc/cysteine interactions are also important in the redox sensitivity
displayed by Sp-1 EGR-1 and the glucocorticoid receptor (GR)—members
of the zinc finger family of DNA binding proteins. Both reducing
conditions and zinc are required for Sp-1 and EGR-1 to bind their
target DNA sites (106
107
108)
. Thus, production of ROS,
which tend to oxidize thiols and eject zinc, decreases Sp-1 DNA binding
and transcription of Sp-1-responsive genes in cell systems
(109)
. This effect, however, is unlikely to be regulatory.
The glucocorticoid receptor displays NO/redox-sensitive DNA binding
(110
, 111)
. The question arises as to whether these
reactions with critical cysteines are regulatory or representative of
nitrosative stress. In the former instance, NO-related molecules might
protect thiols from oxidation through covalent modification or even
promote reversible oxidative modifications that change protein
structure (14)
. In the latter instance, however, they
eject zinc and thereby disrupt the zinc finger domains that are
essential for transcription factor functioning (112)
; it
would be more difficult to restore activity in this scenario.
Notwithstanding these examples, zinc is not essential for
molecular recognition of redox signals and reducing conditions do not
always promote DNA binding of transcription factors. Examples of
transcription factors whose binding to DNA is facilitated under
reducing conditions independently of zinc include c-Myb
(113)
, USF (114)
, NFI (115)
,
NF-Y (116)
, HIF-1 (117)
, HLF
(118)
, PEBP2 (119)
, GABP
(120)
, TTF-1 (121
, 122)
, and Pax-8
(122)
. In contrast, the DNA binding of Hox B5 is increased
under oxidative conditions (123)
. All of these
transcription factors have critical cysteine residues that alone confer
the redox sensitivity. GABP has two cysteines that regulate DNA
binding and one that is required for dimerization with GABPß, the
trans-activating subunit (120)
. In Pax-8, 3 cysteines
confer redox-sensitive DNA binding, which involves intramolecular
disulfide formation (124)
. HIF-1 has a single cysteine
in the carboxyl-terminal trans-activating domain, which participates in
protein–protein interactions that activate transcription, e.g., with
the transcription factor, CREB binding protein (125)
. The
GR contains reactive cysteines in the ligand binding and nuclear
localization sequences distinct from those in the zinc finger (DNA
binding) domain that must be reduced for transcriptional activation
(126
, 127)
. Two lines of evidence suggest that both redox
and NO responsiveness are likely to be shared features of this group of
transcription factors. First, NO inhibits the DNA binding of c-Myb as
well as GR via interactions with thiols in structurally distinct
regions of these protein (128
, 129)
. Second, the reducing
protein systems thioredoxin and Ref-1 regulate the transcriptional
activity of GABP, Pax-8, PEBP, HIF-1, HLF, and the GR
(117
118
119
, 130
131
132)
, implying a general mechanism of
redox control. Taken as a whole, these data make a compelling case for
redox/NO responsivity; but does this mean that the transcriptional
responses under the control of these proteins are redox- or
NO-regulated in vivo?
It is understood from the foregoing discussion that the effects
of the redox state on DNA binding of transcriptional regulators
in vitro must be placed into physiological context. That is,
DNA binding assays in vitro may or may not relate to the
cellular control mechanism in vivo. Take the case of the
heat shock transcription factor (HSF), which is activated by reductants
in vitro and by oxidizing conditions in cell systems
(133
, 134)
. HSF may be analogous to NF-B, which is
activated by oxidation in the cytoplasm while reducing conditions in
the nucleus promote DNA binding. In the case of p53, the in
vitro inhibition by NO-related molecules (135)
has no
known correlate of physiological relevance. Indeed, induction of iNOS
or treatment with nitrosothiols results in up-regulation of p53 in
macrophages, fibroblasts, and epithelial cells (136
, 137)
.
p53, in turn, decreases the expression of iNOS through binding to the
iNOS promoter (137)
. Thus, nitrosation or oxidation of p53
evidently is not occurring in these systems. It is more likely that
nitrosative damage is being sustained by the DNA, which leads to p53
activation. In contrast, the inhibitory effects of NO on EGR-1 activity
in cells are at least consistent with the data from in vitro
binding studies (138
, 139)
. These studies imply that
S-nitrosylation is the mechanism of inhibition, but in fact alternative
mechanisms of regulation cannot be discounted.
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REDOX AND STRUCTURAL CHANGES AT THE MOLECULAR LEVEL |
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TOPABSTRACTOXIDATIVE STRESSNITROSATIVE STRESSMOLECULAR RECOGNITIONREDOX AND STRUCTURAL CHANGES...CONCLUSIONNote added in proofREFERENCES |
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The binding of a transcription factor to DNA usually induces
conformational changes in the transcription factor, the target DNA
site, or both. For example, when NF-B p50 homodimers bind to DNA, a
conformational change in the protein is observed (e.g., by circular
dichroism) (140)
. It has been surmised that the structural
change results in the formation of an -helix in the AB loop of the
p50 NH2-terminal DNA binding domain. This AB loop
is highly unstructured in the absence of bound DNA and is in the same
region where the redox-active cysteines are located. Other studies have
shown that NF-B binds to DNA only when these cysteines are reduced
and that redox-related modifications of these cysteines, such as the
formation of disulfides (34)
or nitrosothiols
(54)
, disrupts DNA binding ability. Furthermore, a
structural variation in the DNA only occurs if the protein is bound to
a specific B site. Similarly, the DNA-recognizing paired domain of
Pax-8 is composed of helix-turn-helix subdomains, which also contain
the conserved redox-active cysteines (124)
. The protein
shows an increase in -helical structure that is conducive to DNA
binding when these cysteines are reduced. This redox-regulated activity
is confined to only one of the paired domains and is controlled by the
reversible formation of a disulfide bond between the conserved
cysteines. These two examples do not, however, explain differences in
transcriptional response to different redox-related stimuli. Rather,
they suggest that no matter what redox stress the cell is exposed to,
the ultimate molecular response by the transcription factor will be the
same. This model, therefore, would not explain the differential binding
affinities of oxidized, reduced, and S-nitrosylated NF- B
(141)
, and raise the possibility of distinct structural
changes in the protein that alternatively effect DNA binding.
The two-state (oxidized/reduced) model also falls short in explaining
the behavior of other redox-active transcription factors. For example,
the conserved cysteines in PEBP2 have vastly different redox potentials
and do not participate in disulfide bond formation. Yet both are
involved in DNA binding (119)
. In addition, the spatial
arrangement of the conserved cysteines in the GABP does not favor
the formation of disulfides (120)
. Rather, it has been
proposed that these cysteines regulate transcription by either
electrostatic interference with DNA binding, when in close proximity to
the binding site or by inducing a conformational change in the protein
if distant from the binding site. As a whole, such observations lead to
an interesting speculation that redox-initiated differential regulation
by a protein is possible. In other words, depending on the nature
of the redox-related posttranslational modification (i.e., S-OH,
S-SR or S-NO), different genes will be transcribed.
|
CONCLUSION |
|---|
|
TOPABSTRACTOXIDATIVE STRESSNITROSATIVE STRESSMOLECULAR RECOGNITIONREDOX AND STRUCTURAL CHANGES...CONCLUSIONNote added in proofREFERENCES |
|---|
What is the molecular basis of the signal? At the simplest level, nitrosylation or oxidation of thiols regulates transcription of target genes. But in practice, each redox-related modification may have its own functional consequences. Moreover, regulation in cells may occur at multiple levels in signal transduction pathways and different incoming signals may be subject to different redox control mechanisms. Although it remains to be seen in how many ways transcription factors integrate nitrosative and oxidative signals into functional responses, it should not be forgotten that the molecular events underlying redox control of mammalian gene expression have not been elucidated in any well-defined cellular system or physiological response.
|
Note added in proof |
|---|
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TOPABSTRACTOXIDATIVE STRESSNITROSATIVE STRESSMOLECULAR RECOGNITIONREDOX AND STRUCTURAL CHANGES...CONCLUSIONNote added in proofREFERENCES |
|---|
|
REFERENCES |
|---|
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TOPABSTRACTOXIDATIVE STRESSNITROSATIVE STRESSMOLECULAR RECOGNITIONREDOX AND STRUCTURAL CHANGES...CONCLUSIONNote added in proofREFERENCES |
|---|
B P50 DNA binding kinetics by S-nitrosylation. Biochem. Biophys. Res. Commun. 238,703-706[Medline]
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|
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|
|
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|
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|
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|
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|
|
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|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
X. Fan, E. Roy, L. Zhu, T. C. Murphy, M. Kozlowski, M. S. Nanes, and J. Rubin Nitric Oxide Donors Inhibit Luciferase Expression in a Promoter-independent Fashion J. Biol. Chem., March 14, 2003; 278(12): 10232 - 10238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
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|
|
|
|
 |
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|
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J. Hoffmann, J. Haendeler, A. M. Zeiher, and S. Dimmeler TNFalpha and oxLDL Reduce Protein S-Nitrosylation in Endothelial Cells J. Biol. Chem., October 26, 2001; 276(44): 41383 - 41387. [Abstract] [Full Text] [PDF]
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D. Stuehr, S. Pou, and G. M. Rosen Oxygen Reduction by Nitric-oxide Synthases J. Biol. Chem., April 27, 2001; 276(18): 14533 - 14536. [Full Text] [PDF]
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W. Palinski, F. P. D'Armiento, J. L. Witztum, F. de Nigris, F. Casanada, M. Condorelli, M. Silvestre, and C. Napoli Maternal Hypercholesterolemia and Treatment During Pregnancy Influence the Long-Term Progression of Atherosclerosis in Offspring of Rabbits Circ. Res., November 23, 2001; 89(11): 991 - 996. [Abstract] [Full Text] [PDF]
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