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Review |
B, a Ubiquitous Transcription Factor in the Initiation of Diseases
1
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505.
2
Department of Pathology, The Pennsylvania State
University College of Medicine, Hershey, PA 17033.
a Author for correspondence. Fax (304) 285-5938; e-mail lfd3{at}cdc.gov.
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Abstract |
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 Top Abstract IntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
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B (NF-B) is a ubiquitous transcription factor that
governs the expression of genes encoding cytokines, chemokines, growth
factors, cell adhesion molecules, and some acute phase proteins in
health and in various disease states. NF-B is activated by several
agents, including cytokines, oxidant free radicals, inhaled particles,
ultraviolet irradiation, and bacterial or viral products. Inappropriate
activation of NF-B has been linked to inflammatory events associated
with autoimmune arthritis, asthma, septic shock, lung fibrosis,
glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete
and persistent inhibition of NF-B has been linked directly to
apoptosis, inappropriate immune cell development, and delayed cell
growth. Therefore, development of modulatory strategies targeting this
transcription factor may provide a novel therapeutic tool for the
treatment or prevention of various diseases. |
Introduction |
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
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B
(NF-B),1
an essential transcription factor that controls the gene
expression of cytokines, chemokines, growth factors, and cell adhesion
molecules as well as some acute phase proteins
(2)(3).
NF-B was first identified as a B-cell nuclear factor and given its
name on the basis of its ability to bind to an intronic enhancer of the
immunoglobulin -light chain gene (4). Since then, NF-B
has been identified in numerous cell types and is found to be activated
by a wide range of inducers, including ultraviolet irradiation,
cytokines, inhaled occupational particles, and bacterial or viral
products. In resting cells, NF-B resides in the cytoplasm in an
inactive form bound to an inhibitory protein known as IB. Upon
cellular activation by extracellular stimuli, IB is phosphorylated
and proteolytically degraded or processed by proteasomes and other
proteases. This proteolytic process activates NF-B, which then
translocates into the nucleus. In nuclei, NF-B can initiate or
regulate early-response gene transcription by binding to decameric
motifs, "GGGRNNYYCC (B motif)", found in the promoter or
enhancer regions of specific genes.
Although NF-B binding sites have been identified in the promoter
regions of genes whose products are intimately involved in cell-to-cell
interaction, it should be emphasized that not all of these genes are
up-regulated by NF-B in a given cell type under every stimulatory
condition. Cellular events associated with NF-B activation include
cell-to-cell adhesion (5)(6)(7)(8)(9), cell recruitment or
transmigration of inflammatory cells (10)(11),
amplification or spreading of primary pathogenic signals
(12), and initiation or acceleration of tumorigenesis
(13). With the onset of simultaneous or asynchronous
stimulatory events in any given cell population for a particular
stimulus and considering the many transcriptional units involved in
gene expression, only a few genes at any one time are affected by
NF-B-mediated transcription. Although NF-B is thought of as a
genetic switch that can control early-response gene expression, the
synergistic interaction of NF-B with other transcription factors
such as Stat (14)(15), Ap-1 (16),
cAMP-response element binding protein (17), nuclear factor
AT (18)(19), and NF-IL6 (20) is
required to achieve a purposeful induction of a particular gene.
Presently, five mammalian NF-B family members have been identified
and cloned (Table 1
). These include NF-B1 (p50/p105), NF-B2 (p52/p100), p65
(RelA), RelB, and c-Rel (1)(2). A characteristic
feature of NF-B is that all of the family members share a highly
conserved Rel homology domain. This domain is composed of ~300 amino
acid residues that are responsible for DNA binding, dimerization, and
interactions with IB, the intracellular inhibitor for NF-B. The
C-terminal regions of RelA, RelB, and c-Rel contain a transactivating
domain, which is important for NF-B-mediated gene transactivation.
The C termini of the precursor molecules for p50 and p52, p105 and
p100, however, contain multiple copies of the so-called ankyrin repeat,
which is found in IB family members, including IB
, IBß,
IB
, Bcl3, and Drosophila cactus. The most abundant
activated form of NF-B is a heterodimer composed of a p50 or p52
subunit and a p65 subunit. Other dimeric complexes, such as p50/p50,
p52/p52, RelA/RelA homodimers, and RelA/c-Rel heterodimers, have also
been detected in some cell types under certain culture conditions.
However, the transactivational properties of these dimeric complexes
have yet to be elucidated. Although all of the NF-B dimers can bind
to a common B binding motif, it has been shown that different dimers
recognize slightly different B motifs. For example, p50/p65 binds
the sequence 5'-GGGRNNYYCC-3', with high affinity, whereas the
RelA/c-Rel prefers 5'-HGGARNYYCC-3' (where H is A, C, or T; R is a
purine; and Y is a pyrimidine).
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Kinase Cascade for the Activation of NF-B
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
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B, the inhibitory protein bound to NF-B,
is a key step required for the activation of NF-B. This process is
initiated through signal-induced phosphorylation of two serines (Ser32
and Ser36) on the IB molecule (21)(22)(23)(24). The
phosphorylation event in turn induces polyubiquitination of IB on
lysines 21 and 22. Phosphorylated and ubiquitinated IB can be
rapidly recognized and degraded by proteasome, a multiprotease complex
(25). Replacement of Ser32 and Ser36 by threonine or alanine
residues substantially decreases signal-induced phosphorylation and
degradation of the IB protein. This suggests the presence of a
serine-specific kinase for the phosphorylation of IB.
During the past several years, a number of laboratories have
investigated the specific serine kinase(s) for IB. Although in
vitro studies have shown that some known kinases, such as protein
kinase C (26), protein kinase A (27), protein
kinase R (28), Raf (29), casein kinase II
(30), eukaryotic initiation factor-2 kinase (31),
and mitogen-activated ribosomal S6 protein kinase (32), are
capable of phosphorylating IB, none of these kinases is
serine-specific or site-specific for IB. The first report about a
putative IB kinase was by Chen et al. (33), who
identified a 700-kDa complex that contains kinase activity capable of
phosphorylating IB at the two crucial serine sites. It is
interesting to note that the in vitro activation of this kinase complex
requires MAPKKK and/or ubiquitination. At that time, however, no
detailed sequence data regarding the structural and molecular
characteristics of this IB kinase complex were available. In
1997, a major breakthrough in the search for an IB-specific
kinase occurred with reports by Zandi et al. (34), DiDonato
et al. (35), Regnier et al. (36), Woronicz et al.
(37), and Mercurio et al. (38). Zandi et al.
(34) and DiDonato et al. (35) purified a 900-kDa
IB kinase (IKK) complex from tumor necrosis factor-
(TNF)-challenged HeLa cells and cloned an 85-kDa subunit of IKK
complex, named IKK. A gene bank database search demonstrated that
IKK was identical to a putative serine/threonine kinase with unknown
function named CHUK (conserved helix-loop-helix ubiquitous kinase). An
additional 87-kDa subunit of the IKK complex, IKKß, was subsequently
identified using the same strategy or using a DNA sequence database
search. IKK was also identified independently by Regnier et al.
(36) and Woronicz et al. (37), who used the
NF-B-inducing kinase (NIK), a MAPKKK family member, as bait in a
yeast two-hybrid screen from a human B-cell cDNA library. The
polypeptides of IKK and IKKß have 52% homology. Both IKK and
IKKß can phosphorylate Ser32 and Ser36 of the IB molecule. A
unique structural characteristic of IKK and IKKß that
differentiates them from other serine/threonine kinases is that both
IKK and IKKß contain a C-terminal leucine zipper motif and a
helix-loop-helix motif. On the basis of the observation that MAPKKK or
NIK is required for the in vitro activation of IKK (33) and
the identification of a canonical MAPKK activation loop motif (SxxxS)
on both IKK and IKKß (34)(35)(36)(37)(38), researchers have
speculated that NIK is a direct upstream kinase that can phosphorylate
and activate IKK and IKKß. Indeed, a coexpression study
demonstrated that NIK can phosphorylate IKK at Ser176, but weakly
phosphorylates IKKß (39). A second potential upstream
kinase that activates IKK and IKKß is MEKK1, another MAPKKK family
member responsible for the activation of Jun-N-terminal kinase and p38.
Whereas NIK preferentially activates IKK, MEKK1 apparently is more
potent in the phosphorylation of IKKß (40). Although NIK
has been demonstrated to interact with both IKK and IKKß directly
(36) and MEKK1 has been identified to be a component of the
large IKK complex (38), it remains unclear whether other
intermediate kinases are involved in the cascade between NIK/MEKK1 and
IKK/IKKß.
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NF-B and Cell Apoptosis
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
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B is activated during or immediately before
cell apoptosis under certain stimulatory conditions has led to the
suggestion that this transcription factor may function to promote
apoptosis (41)(42). Several lines of evidence
support this suggestion. Treatment of human thymocytes and
promyelocytic leukemia cells with etoposide activates NF-B and
induces apoptosis (43). NF-B is concomitantly activated
with TNF-induced apoptosis in certain cell types
(44)(45). It has also been shown that inhibition
of NF-B by certain antioxidants prevents apoptosis (43).
Indeed, NF-B binding sites have been identified in the promoters of
interleukin-1ß converting enzyme protease (46),
c-myc (47), and TNF (48) genes,
which are commonly involved in signal-induced programmed cell death.
The role of NF-B in the apoptosis process is not straightforward,
however. For example, although TNF and interleukin (IL)-1 are
well-known, potent activators for NF-B, in most cases they do not
cause apoptosis unless cells are pretreated with agents that block RNA
or protein synthesis (49). In fact, numerous recent studies
have clearly demonstrated an antiapoptotic role for NF-B. Important
evidence to support this was provided by the study of p53-independent
apoptosis induced by oncogene Ras (50). In Ras-transformed
NIH 3T3 cells or p53-deficient (p53-/-) mouse embryo
fibroblasts, Mayo et al. (50) demonstrated that the
inhibition of NF-B by cotransfection of a superrepressor form of
IB caused a dramatic loss of cell viability. When a similar
approach was used, NF-B was found to be required to overcome cell
killing in the human fibrosarcoma cell line HT 1080, in a Jurkat T-cell
line, and in human bladder carcinoma induced by TNF and cancer
chemotherapeutic compounds (51)(52). Recently, a
NF-B relA gene knockout mouse model was reported, which
has an embryonic lethal phenotype associated with massive liver cell
apoptosis (53). This model was created by targeted
disruption of the relA gene by homologous recombination.
Treatment of RelA-deficient (RelA-/-) mouse embryonic
fibroblasts and macrophages with TNF led to a substantial reduction
in viability, whereas RelA+/+ cells from a wild-type mouse
were unaffected. Reintroduction of RelA into RelA-/-
fibroblasts enhanced cell survival (54). These data suggest
that NF-B is an essential antiapoptotic factor for these cell types.
Additional evidence that NF-B inhibits apoptosis was obtained from
the study of anti-IgM-induced apoptosis in WEHI 231 immature B-lymphoma
cells. After treatment of these cells with
L-1-p-tosylamino-2-phenylethyl chloromethyl
ketone or microinjection of
glutathione-S-transferase-IB, the protective role of
NF-B against anti-IgM-induced cell apoptosis was eliminated
(55). Furthermore, NF-B was found to be protective in
HIV-Tat and exogenous nitric oxide (NO)-induced apoptosis (Chen et al.,
unpublished data).
How can NF-B mediate both life and death signals in cells? One
possibility is that different NF-B members mediate different
signals. Evidence in favor of this possibility comes from the studies
of NF-B gene knockout mice. For example, relA gene
disruption caused embryonic death in mice (53). However, no
developmental abnormalities were found in p50 gene knockout mice
(56)(57). A second possibility is that the role
of NF-B in apoptosis depends on the cell type or the type of
stimulation that determines which simultaneous and asynchronous
signaling pathway are activated. Evidence to support this possibility
comes from the studies of oncogenic Ras-transformed cells and
Bcr-Abl-transformed cells. Whereas NF-B is clearly protective for
the cells against Ras-induced apoptosis (50), it is not
required in the protection of apoptosis induced by IL-3 withdrawal or
exposure to etoposide and ionizing radiation in Bcr-Abl-transfected
cells (58).
The protective role of NF-B against apoptosis may occur through the
up-regulation of genes encoding antiapoptotic products such as IL-1,
IL-2, IL-6, macrophage colony-stimulating factor (M-CSF), granulocyte
colony-stimulating factor (G-CSF), granulocyte-macrophage
colony-stimulating factor (GM-CSF), superoxide dismutase, and the zinc
finger protein A20 (1)(2)(3). The regulation of NF-B on
other antiapoptotic genes remains to be further elucidated. For
example, the expression of a newly cloned antiapoptotic gene,
bcl-x, may be involved as a downstream protective gene of
NF-B. In this regard, we recently characterized several B-like
elements in the 5'-flanking region of the mouse bcl-x gene
(Chen et al., unpublished data). These B-like elements may be
involved in the regulation of the bcl-x gene. Additional
genes implicated include the genes that code for mammalian inhibitor of
apoptosis (IAP), where both c-IAP1 and c-IAP2 have been shown to be
up-regulated by NF-B. In human blood T cells and a Jurkat T-cell
line, the expression of c-IAP2 is under the control of NF-B
(59). Furthermore, the accumulation of c-IAP2 mRNA induced
by TNF can be substantially attenuated by the inhibition of NF-B
either by transfection of cells with degradation-resistant IB or
by treating the cells with a proteasome inhibitor. Changes in NF-B,
however, had little effect on the expression of c-IAP1, which is in
disagreement with the observation reported by You et al.
(60), who showed that c-IAP1 was highly expressed in chicken
fibroblasts transfected with NF-B v-rel. The involvement
of cIAPs in NF-B-mediated antiapoptosis was further demonstrated by
the studies of intracellular expression of cIAPs. In the HT1080
fibrosarcoma cell line, in which NF-B was inactive, expression of
cIAPs was sufficient to suppress etoposide-induced apoptosis
(61). Because of the lack of detailed genomic DNA sequence
data for either mammalian c-IAP1 or c-IAP2, one cannot determine at
this time if the dependence of c-IAP1 and c-IAP2 on NF-B is through
the B or B-like site(s) located in the promoter or enhancer
regions of the c-IAP1 and c-IAP2 genes.
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NF-B in Development
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
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B was first named by Sen and Baltimore (4)
on the basis of its binding to the enhancer of the immunoglobulin (Ig)
gene in B cells, it was speculated that NF-B acts as a key
transcription factor for the development of the immune system,
especially for B cells (4). Indeed, recent gene knockout
studies provided convincing evidence that a deficiency in B cells
occurred when the genes nfkb1 (p50/p105), nfkb2
(p52/p100), and c-rel were disrupted. B cells from
nfkb1 knockout mice were virtually unresponsive to
lipopolysaccharide stimulation when compared with B cells from control
mice (56)(57). In addition, the total Ig
production and certain kinds of germ-line Ig type switching were
markedly impaired in B cells from nfkb1 knockout mice. In
contrast, the Ig type switching was unaffected in nfkb2
knockout mice, although the absolute number of B cells in peripheral
lymphoid organs decreased and the B cells exhibited a reduced
lipopolysaccharide response (62)(63). In
c-rel gene knockout mice, development of cells from all
hemopoietic lineages appeared normal, although both mature B and T
cells were unresponsive to most mitogenic stimuli (64).
It is becoming more and more evident that NF-B is a key factor not
only for the development and function of B cells, but also for the
development and function of many other cells, including T cells,
thymocytes, dendritic cells, macrophages, and fibroblasts. Targeted
disruption of the relB gene caused varying degrees of thymic
gland atrophy and lymphoid cell depletion in lymph nodes
(65)(66). In addition, T-cell-mediated immune
response and dendritic cell development were strongly impaired. A
double knockout of nfkb1 and nfkb2 demonstrated
an unexpected phenotype. Mice developed osteopetrosis or
Albers-Schoenberg disease as a result of diminished bone resorption
caused by a deficiency in osteoclast lineage development
(67)(68). Additional studies suggested that this
deficiency occurred as a result of a defect either during osteoclast
precursor cell differentiation or during the maturation of osteoclasts.
Obviously, this double knockout experiment could provide a relevant
model to study the etiology of osteoporosis and to develop new
therapeutic strategies for the treatment of this disease. It has been
shown that several cytokines, including TNF, IL-1, IL-6, and GM-CSF,
have osteoclastogenic activity and are increased in osteoblasts and
hematopoietic cells of patients with decreased estrogen concentrations
(67). There is also some evidence to show that occupied
estrogen receptors inhibit IL-6 gene expression by preventing the
binding of NF-B and NF-IL6 transcription factors to their respective
binding sites in the IL-6 gene promoter (69). A similar
mechanism may also be involved in the inhibition of TNF and IL-1
production by estrogen.
NF-B may also play a critical role in embryonic development.
Well-documented evidence from the studies of Drosophila
embryogenesis support this role of NF-B. Dorsal, a fly homolog of
NF-B family members, is vital for the establishment of the embryonic
dorso-ventral axis during development (70). Similarly, in a
mouse gene knockout study, disruption of the relA locus led
to embryonic death at 15–16 days of gestation, accompanied by massive
degeneration of the liver as a result of apoptosis (53). Two
separate groups recently provided additional evidence to show that
NF-B is required for the development of vertebrate embryonic limbs
(71)(72). They found that NF-B genes were
expressed in the progress zone of the developing chick limb bud and
were maintained until the last stage. Inhibition of NF-B activity by
infection with viral vectors that produce transdominant-negative
IB protein caused a highly dysmorphic apical ectodermal ridge,
reduction in overall limb size, loss of distal elements, and arrest of
budding.
The exact role of NF-B family members in the development of cell
lineages and embryonic development remains to be defined. It should be
possible in the near future to answer the specific, key questions that
relate to these issues. For example, which member or combination of
members of the NF-B family is essential for a specific developmental
stage or which gene or gene set is regulated by NF-B for the
differentiation and maturation of a given cell lineage.
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NF-B in Carcinogenesis
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
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B in carcinogenesis is
provided by the observation that activation of NF-B is required in
oncogenic Ras-induced transformation (50). Upon inhibition
of NF-B activation with a superrepressor form of IB, oncogenic
Ras-transformed cells exhibit a loss of cell viability, indicating that
oncogenic Ras requires the cell survival function of NF-B to
overcome the role of the death signal initiated in transformed cells.
Similarly, NF-B is required for leukemogenesis initiated by Bcr-Abl
chimeric protein (a deregulated tyrosine kinase) (58). The
alternative activation or expression of NF-B is evident in several
human cancers, including breast cancer (73)(74),
non-small cell lung carcinoma (75), thyroid cancer
(76), T- or B-cell lymphocyte leukemia (77), and
several virally-induced tumors (78)(79)(80)(81). Thus, a role for
NF-B in the malignant transformation of cells is highly possible.
Nevertheless, it is unclear whether overactivation or excessive
expression of NF-B in these transformed cells is linked directly to
the transformation or whether NF-B only provides an accessory signal
for the transformation.
Using an estrogen receptor-negative breast cancer cell lines, Sovak et
al. (73) and Nakshatri et al. (74) showed that
NF-B was continuously activated and could be correlated with poor
differentiation and high metastasis of these cancer cells. Aberrant
NF-B activation has also been observed in carcinogen-induced primary
rat mammary tumors and multiple human breast cancer specimens. In human
lung cancer, NF-B p50 and c-Rel were found highly expressed in fresh
human non-small cell lung carcinoma tissues and cell lines
(75). In contrast, the expression of NF-B p52 was very
low or undetectable in these tumors or cell lines. On the other hand,
the constitutive nuclear localization of NF-B p50/p65, the most
abundant heterodimer in signal-induced cells, was found to be required
for the sustained proliferation of Hodgkin lymphoma and was considered
to be a potential diagnostic marker for this disease (77).
Chromosomal alterations of the NF-B or IB gene family have been
noted frequently in several human lymphoid tumors in which
rearrangement of the nfkb2 gene is described more commonly
(82). Rearrangement of the nfkb2 gene causes
deletions of sequences encoding the ankyrin repeat motif of p100.
Consequently, this carboxy-terminal truncated p100 is constitutively
located in the nucleus of cells. Similarly, some groups have identified
rearrangement of the c-rel gene in numerous non-Hodgkin
lymphomas (83). The bcl3 gene, which encodes an
IB-like protein that can regulate transcriptional activity of
NF-B p50 or p52 homodimer, is rearranged at a common chromosomal
breakpoint of chromosome 19q13.1 in most cases of chronic lymphocytic
leukemia with t(14:19) translocation (84). Unlike
rearrangement of the nfkb2 gene, alterations at the
bcl3 locus do not truncate or change the coding sequence,
but rather cause overexpression of bcl3 mRNA.
It is well known that some human tumors result from viral infections.
These tumors include HTLV-1-induced acute leukemia of
CD4+ T cells (78), Epstein-Barr
virus-induced Burkitts and Hodgkin lymphoma (79), hepatitis
B virus-induced hepatocellular carcinoma (80), and
HIV-induced Kaposi sarcoma (81). NF-B can be activated
rapidly by Tax (85), latent membrane protein-1
(86), X protein (87), and Tat protein
(88) encoded by HTLV-1, Epstein-Barr virus, hepatitis B
virus, and HIV, respectively. Therefore, NF-B is thought to be a
common mediator for viral-induced tumorigenesis. Convincing evidence to
support this hypothesis is provided by the observation that mice
treated with antisense oligonucleotides (AS-ODNs) to relA
(NF-B p65) have a reduced incidence of Tax-induced tumors
(89).
The most direct evidence for a role for NF-B in oncogenic
transformation has been derived from the fact that v-Rel, a member of
the Rel/NF-B family of eukaryotic transcription factors, induces
oncogenic transformation in avian lymphoid cells (76).
Recent studies demonstrated that v-Rel also has the capacity of
transforming mammalian cells in vivo (90). Transgenic mice
expressing v-Rel under the control of the lck
T-cell-specific promoter develop T-cell lymphomas. There are two major
DNA-binding complexes found in tumor cells from v-Rel-transgenic mice,
one containing v-Rel homodimers and another containing v-Rel/p50
heterodimers. Additional evidence that supports an oncogenic role of
v-Rel in mammalian cells has been obtained from the study of
overexpression of the Rel/NF-B inhibitor protein, IB, in v-Rel
transgenic mice. Overexpression of IB prolongs the survival of
v-Rel transgenic mice and delays the development of T-cell lymphomas in
this mouse model (91). Furthermore, a functional role for
v-Rel in transformation is also indicated by the observations that a
v-Rel mutant that cannot form homodimers cannot transform cells and
that the addition of a nuclear export signal to v-Rel blocks its
transforming ability (92)(93). Together, these
data provide strong support for the hypothesis that v-Rel contributes
to direct malignant transformation of eukaryotic cells.
The target genes influenced by NF-B in carcinogenesis have yet to be
defined. The fact that NF-B regulates genes for both cell
carcinogenesis and apoptosis has led to substantial confusion
concerning the role for NF-B on pretransformation or
antitransformation. Additional studies are clearly required to unveil
the molecular basis for the activation and function of NF-B in
transformation.
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NF-B as a Therapeutic Target for Diseases
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
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B plays in controlling the expression of
multiple inflammatory and immune genes involved in toxic shock, acute
phase responses, radiation damage, asthma, rheumatoid arthritis,
atherosclerosis, cancer, and AIDS makes this factor a central and
favorable target for therapeutic intervention of diseases
(1)(2)(3). Most of the biological and biochemical inhibitors of
NF-B presently available act by blocking the signaling pathways that
lead to the activation of NF-B or by compromising the binding
activity of NF-B to target DNA.
The signaling pathway in which IB is phosphorylated, ubiquitinated,
and subsequently degraded by proteasome or other proteases provides
numerous potential target points for interference. Some of these points
may serve as relatively specific targets, such as the TNF/IL-1
receptor, receptor-associating proteins, or IKK complex, whereas others
may be less specific, such as interference with ubiquitin-conjugating
enzymes and proteasome (Fig. 1
). Many antioxidants inhibit NF-B by blocking upstream
signaling that leads to phosphorylation of IB. Antioxidants can
potentially prevent oxidation of redox-sensitive cysteines in kinases
or phosphatases (94). There is evidence to show that
proteasome and calpain inhibitors such as MG132, lactacystin, and
calpastatin are potent inhibitors of NF-B activation. They act by
blocking the degradation of IB (95)(96).
However, it is important to recognize that both proteasome and calpain
are important regulators for normal cellular function and cell cycling
as well. Therefore, the clinical application of general proteasome or
calpain inhibitors would be questionable. Glucocorticoids are
well-known and widely prescribed immunosuppressive and antiinflammatory
drugs. Recent studies have shown that the antiinflammatory effects of
glucocorticoids are achieved either by occupied glucocorticoid
receptor-mediated interference of NF-B DNA-binding activity or by
enhanced synthesis of IB, which would compromise the nuclear
translocation and DNA binding of NF-B (97)(98)(99). Thus,
glucocorticoid therapy may down-regulate the activation of NF-B in
select circumstances. The liberal use of glucocorticoids, however, is
limited because of their well-known side effects on endocrine function
and metabolism.
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NO-generating compounds such as nitroglycerin and nitrofurantoin have
been used for decades for the treatment of cardiovascular diseases
(100). NO is a ubiquitous free radical that promotes
vasodilation and other intracellular and intercellular biological
events. Most radicals are potent activators of NF-B. However, this
is not the case for NO. We have shown that the endogenous induction of
NO inhibits NF-B (101)(102). We assumed that
this inhibition is because of direct S-nitrosylation of NF-B. This
assumption was confirmed recently by Matthews et al. (103),
using electrospray ionization mass spectrometry in which they found
that cysteine 62 (59) of p50 was nitrosylated by NO and that
the nitrosylation of cysteine decreased the NF-B DNA-binding
activity. In addition to its direct modification of NF-B, NO is also
capable of interfering with several signaling pathways that lead to the
activation of NF-B. In fact, in human endothelial cells, Spiecker et
al. (104), Shin et al. (105), De Caterina et al.
(106), and Peng et al. (107) observed that
inhibition of NF-B by NO is through the stabilization of IB
and/or the enhancement of IB synthesis. Our most recent studies
with macrophages and human T cells have shown that both endogenous and
exogenous NO can retard signal-induced IB degradation by
suppressing proteasome activity (Chen et al., unpublished data). It is
also possible that NO functions as a H2O2
scavenger and antioxidant to inhibit activation of NF-B by other
free radicals (95). Therefore, the benefit of NO on
cardiovascular diseases is not only through its vascular relaxation
properties, but also by its ability to decrease NF-B-mediated IL-1,
TNF, intercellular adhesion molecule-1, and vascular cell adhesion
molecule-1 expression. These effects can lead to a reduced risk of
atherosclerosis.
Transdominant IB mutants have been widely used in various
experimental systems. The IB mutated at Ser32/Ser36 or
Lys21/Lys22 is much more resistant to ubiquitination and degradation by
the proteasome, but it is still able to associate with and sequester
NF-B. Specific inhibition of NF-B by transfection and expression
of this IB mutant has been achieved in studies of oncogenic Ras
and Bcr-Abl-induced transformation and apoptosis and numerous other
experiments (50)(51)(58). Yet the
therapeutic use of this approach remains to be defined. A more rational
and promising strategy to block NF-B activation and its role in
disease initiation is the development of oligonucleotide-based
interventions. From a therapeutic perspective, this approach
potentially targets a specific point in the signaling pathway to
inhibit NF-B without influencing other cellular biological
functions. There are two types of oligonucleotides presently being
tested. One type is an antisense oligonucleotide (AS-ODN) that binds to
a selected mRNA by Watson-Crick base pairing to ablate translation of
selected gene products. Compelling evidence for the usefulness of this
approach has been obtained from an experiment involving
2,4,6-trinitrobenzene sulfonic acid-induced inflammatory colitis
(108). Local administration of p65 antisense
phosphorothioate oligonucleotides abrogated clinical and histological
signs of trinitrobenzene sulfonic acid-induced colitis. Similarly,
treatment of rheumatoid synoviocytes or fibroblasts with p65 AS-ODN
decreased IL-1ß-induced cyclooxygenase-2 protein expression and
prostaglandin E2 production
(109)(110). A second type of oligonucleotide
used to intervene in the function of NF-B is a decoy of
double-stranded ODNs containing a NF-B-binding element. This decoy
acts as a competitor to block the binding of NF-B to promoter
regions of target genes, thus inhibiting gene transactivation. The
first evidence for the potential of this NF-B decoy was obtained
from the study of HIV-LTR transactivation in Epstein-Barr
virus-transformed B cells. Treatment of cells with NF-B decoy DNA
strongly inhibited HIV-LTR activity (111). Recently, this
decoy strategy was used successfully in studies of NF-B-mediated
lymphocyte cytokine production, IgE isotype switching, and
ischemia-reperfusion myocardial infarction (112)(113)(114).
The reports describing the use of NF-B AS-ODNs or decoys are very
promising. However, a wide variety of unexpected sequence-independent
effects have come to light and consequently compromise rational drug
design and anticipated single gene elimination.
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Determination of NF-B Activation and Its Function
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
|---|
B may be used as a diagnostic index to guide therapeutic
strategies for certain diseases. Several methods to determine NF-B
activation or its function have been widely used in research
laboratories, such as the electrophoretic mobility shift assay (EMSA),
in situ hybridization, Western blot, and the reporter gene assay.
Because NF-B is translocated into nuclei after the degradation of
its inhibitor, IB, the amount of NF-B proteins in nuclear
extracts may authentically reflect the activation status of NF-B.
EMSA is a traditional and simple method used to determine the inducible
and constitutive NF-B in nuclei. To do this, a total nuclear extract
is incubated with a -32P-labeled double-stranded
ODN containing a consensus B-site, usually GGGAATTCCC. The protein
bound to the B probe can be resolved by 5% sodium dodecyl
sulfate-polyacrylamide gel electrophoresis and autoradiography. If
specific antibodies are included during the incubation of nuclear
extract with the B probe, the member composition of the NF-B
complex can also be identified using this approach.
In combination with histopathological and cytological studies of tumor
tissue and inflammatory tissue, nuclear translocation of NF-B can
also be quantified by use of fluorescence-labeled antibodies against
different NF-B family members in tissue sections. There are several
major advantages of this approach to determine nuclear translocation of
NF-B. First, the tissue or cell morphology is well preserved, and it
provides precise localization of various NF-B members. Second, use
of this method avoids the problem of radioactive materials and false
stress signals, which may happen when nuclear extracts and
32P-labeled probes are used in EMSA. Third, one can
accurately identify the population of cells expressing NF-B members.
For cell suspension samples such as blood cells, both patch clamp and
flow cytometric methods have been used to determine the translocation
of NF-B through nuclear pore complex and DNA binding, respectively.
During nuclear translocation, NF-B may plug the nuclear pore complex
channel and thus interrupt ion flow through the channel. The reduction
in the ion conductance of the channel can be recorded by patch clamp
detection (115). By the use of a flow cytometer equipped
with double optical filters that allow detection of propidium
iodide-stained nuclei and fluorescein isothiocyanate-stained NF-B,
the translocation of NF-B into nuclei can also be identified in
mononuclear cells and neutrophils without preseparation of cell
populations (116). However, the requirement for technical
expertise and specific equipment compromises the potential application
of these two methods in clinical laboratories.
The functional characteristic of NF-B can be determined
experimentally by assaying the expressing B-dependent reporter
genes. Traditionally, a reporter construct containing chloramphenicol
acetyltransferase or luciferase reporter genes under the control of
B elements is transfected into cells. Upon stimulation, the reporter
gene activity in cells can be detected by ELISA, thin-layer
chromatography, a luminometer, or a scintillation counter. For clinical
purposes, the transactivational activity of NF-B can be measured
indirectly by determining the production of cytokines, cell adhesion
molecules, and enzymes whose genes are dependent on NF-B
transcription factor.
|
Conclusion |
|---|
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
|---|
B activation can be a powerful
therapeutic strategy for reducing tissue damage as a consequence of the
releases of inflammatory mediators. In addition, controlled regulation
of NF-B activation has the potential to increase the sensitivity of
tumor cells to antitumor therapy. However, a complete and persistent
blockage of NF-B activation will lead to immune deficiencies and the
apoptosis of healthy cells. Studies are underway to develop NF-B
member-specific and cell type-specific drugs that can inhibit the
activation of NF-B only in target cells. Because of the key role
that this factor plays in the expression of proinflammatory genes and
its importance to the function of the immune system, intense research
is presently being carried out to further delineate the role and
function of this important nuclear factor in health and pathogenesis.
|
Footnotes |
|---|
1 Nonstandard abbreviations: NF-B, nuclear factor-B; IKK, IB kinase; NIK, NF-B-inducing kinase; IL, interleukin; CSF, colony-stimulating factor; GM, granulocyte-macrophage; IAP, mammalian inhibitor of apoptosis; Ig, immunoglobulin; AS-ODN, antisense oligonucleotide; ODN, oligonucleotide; and EMSA, electrophoretic mobility shift assay.
|
References |
|---|
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TopAbstractIntroductionKinase Cascade for the...NF-{kappa}B and Cell ApoptosisNF-{kappa}B in DevelopmentNF-{kappa}B in CarcinogenesisNF-{kappa}B as a Therapeutic...Determination of NF-{kappa}B...ConclusionReferences |
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 S. Guerra, L. A. Lopez-Fernandez, R. Conde, A. Pascual-Montano, K. Harshman, and M. Esteban Microarray Analysis Reveals Characteristic Changes of Host Cell Gene Expression in Response to Attenuated Modified Vaccinia Virus Ankara Infection of Human HeLa Cells J. Virol., June 1, 2004; 78(11): 5820 - 5834. [Abstract] [Full Text] [PDF]
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B. Jiang, S. Xu, X. Hou, D. R. Pimentel, and R. A. Cohen Angiotensin II Differentially Regulates Interleukin-1-{beta}-inducible NO Synthase (iNOS) and Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression: ROLE OF p38 MAPK J. Biol. Chem., May 7, 2004; 279(19): 20363 - 20368. [Abstract] [Full Text] [PDF]
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 S. A. McCracken, E. Gallery, and J. M. Morris Pregnancy-Specific Down-Regulation of NF-{kappa}B Expression in T Cells in Humans Is Essential for the Maintenance of the Cytokine Profile Required for Pregnancy Success J. Immunol., April 1, 2004; 172(7): 4583 - 4591. [Abstract] [Full Text] [PDF]
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 T. Y. Ma, G. K. Iwamoto, N. T. Hoa, V. Akotia, A. Pedram, M. A. Boivin, and H. M. Said TNF-{alpha}-induced increase in intestinal epithelial tight junction permeability requires NF-{kappa}B activation Am J Physiol Gastrointest Liver Physiol, March 1, 2004; 286(3): G367 - G376. [Abstract] [Full Text] [PDF]
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 Y. Zhao, S. Joshi-Barve, S. Barve, and L. H. Chen Eicosapentaenoic Acid Prevents LPS-Induced TNF-{alpha} Expression by Preventing NF-{kappa}B Activation J. Am. Coll. Nutr., February 1, 2004; 23(1): 71 - 78. [Abstract] [Full Text] [PDF]
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E. Hagi-Pavli, P. M. Farthing, and S. Kapas Stimulation of adhesion molecule expression in human endothelial cells (HUVEC) by adrenomedullin and corticotrophin Am J Physiol Cell Physiol, February 1, 2004; 286(2): C239 - C246. [Abstract] [Full Text]
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B. Jiang, S. Xu, X. Hou, D. R. Pimentel, P. Brecher, and R. A. Cohen Temporal Control of NF-{kappa}B Activation by ERK Differentially Regulates Interleukin-1{beta}-induced Gene Expression J. Biol. Chem., January 9, 2004; 279(2): 1323 - 1329. [Abstract] [Full Text] [PDF]
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 A. S. Karban, T. Okazaki, C. I.M. Panhuysen, T. Gallegos, J. J. Potter, J. E. Bailey-Wilson, M. S. Silverberg, R. H. Duerr, J. H. Cho, P. K. Gregersen, et al. Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis Hum. Mol. Genet., January 1, 2004; 13(1): 35 - 45. [Abstract] [Full Text] [PDF]
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 K. Yamamoto, T. Shioi, K. Uchiyama, T. Miyamoto, S. Sasayama, and A. Matsumori Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice J. Am. Coll. Cardiol., December 3, 2003; 42(11): 2000 - 2006. [Abstract] [Full Text] [PDF]
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F. Lebron, R. Vassallo, V. Puri, and A. H. Limper Pneumocystis carinii Cell Wall {beta}-Glucans Initiate Macrophage Inflammatory Responses through NF-{kappa}B Activation J. Biol. Chem., June 27, 2003; 278(27): 25001 - 25008. [Abstract] [Full Text] [PDF]
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M. E. Poynter, C. G. Irvin, and Y. M. W. Janssen-Heininger A Prominent Role for Airway Epithelial NF-{kappa}B Activation in Lipopolysaccharide-Induced Airway Inflammation J. Immunol., June 15, 2003; 170(12): 6257 - 6265. [Abstract] [Full Text] [PDF]
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G. Alexander, H. Carlsen, and R. Blomhoff Strong In Vivo Activation of NF-{kappa}B in Mouse Lenses by Classic Stressors Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2683 - 2688. [Abstract] [Full Text] [PDF]
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 S. Gupta, N. H. Purcell, A. Lin, and S. Sen Activation of nuclear factor-{kappa}B is necessary for myotrophin-induced cardiac hypertrophy J. Cell Biol., December 23, 2002; 159(6): 1019 - 1028. [Abstract] [Full Text] [PDF]
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 B. Jiang, S. Xu, P. Brecher, and R. A. Cohen Growth Factors Enhance Interleukin-1{beta}-Induced Persistent Activation of Nuclear Factor-{kappa}B in Rat Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1811 - 1816. [Abstract] [Full Text] [PDF]
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 P. Cameron, D. Bingham, A. Paul, M. Pavelka, S. Cameron, D. Rotondo, and R. Plevin Essential Role for Verotoxin in Sustained Stress-Activated Protein Kinase and Nuclear Factor Kappa B Signaling, Stimulated by Escherichia coli O157:H7 in Vero Cells Infect. Immun., October 1, 2002; 70(10): 5370 - 5380. [Abstract] [Full Text] [PDF]
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O. Lopez-Franco, Y. Suzuki, G. Sanjuan, J. Blanco, P. Hernandez-Vargas, Y. Yo, J. Kopp, J. Egido, and C. Gomez-Guerrero Nuclear Factor-{kappa}B Inhibitors as Potential Novel Anti-Inflammatory Agents for the Treatment of Immune Glomerulonephritis Am. J. Pathol., October 1, 2002; 161(4): 1497 - 1505. [Abstract] [Full Text] [PDF]
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 M. T Gewaltig and G. Kojda Vasoprotection by nitric oxide: mechanisms and therapeutic potential Cardiovasc Res, August 1, 2002; 55(2): 250 - 260. [Abstract] [Full Text] [PDF]
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M. P. Russo, B. L. Bennett, A. M. Manning, D. A. Brenner, and C. Jobin Differential requirement for NF-kappa B-inducing kinase in the induction of NF-kappa B by IL-1beta , TNF-alpha , and Fas Am J Physiol Cell Physiol, July 1, 2002; 283(1): C347 - C357. [Abstract] [Full Text] [PDF]
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D.-w. Jeong, M.-H. Yoo, T. S. Kim, J.-H. Kim, and I. Y. Kim Protection of Mice from Allergen-induced Asthma by Selenite. PREVENTION OF EOSINOPHIL INFILTRATION BY INHIBITION OF NF-kappa B ACTIVATION J. Biol. Chem., May 10, 2002; 277(20): 17871 - 17876. [Abstract] [Full Text] [PDF]
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Y. K. Gruijthuijsen, P. Casarosa, S. J. F. Kaptein, J. L. V. Broers, R. Leurs, C. A. Bruggeman, M. J. Smit, and C. Vink The Rat Cytomegalovirus R33-Encoded G Protein-Coupled Receptor Signals in a Constitutive Fashion J. Virol., February 1, 2002; 76(3): 1328 - 1338. [Abstract] [Full Text] [PDF]
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 E. W. Uhl, S. Giguere, T. J. Jack, and T. Hodge Increased Pulmonary Activation of Nuclear Factor-{kappa}B (NF-{kappa}B) in Foals Inoculated with Rhodococcus equi is Associated with Increased Expression of Inflammatory Cytokines Vet. Pathol., January 1, 2002; 39(1): 132 - 136. [Abstract] [Full Text] [PDF]
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B. Jiang, P. Brecher, and R. A. Cohen Persistent Activation of Nuclear Factor-{kappa}B by Interleukin-1{beta} and Subsequent Inducible NO Synthase Expression Requires Extracellular Signal-Regulated Kinase Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1915 - 1920. [Abstract] [Full Text] [PDF]
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G. Valen, Z.-q. Yan, and G.o. K. Hansson Nuclear factor kappa-B and the heart J. Am. Coll. Cardiol., August 1, 2001; 38(2): 307 - 314. [Abstract] [Full Text] [PDF]
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 G. K. RANGAN, Y. WANG, and D. C. H. HARRIS Pharmacologic Modulators of Nitric Oxide Exacerbate Tubulointerstitial Inflammation in Proteinuric Rats J. Am. Soc. Nephrol., August 1, 2001; 12(8): 1696 - 1705. [Abstract] [Full Text] [PDF]
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F. Chen, V. Castranova, and X. Shi New Insights into the Role of Nuclear Factor-{kappa}B in Cell Growth Regulation Am. J. Pathol., August 1, 2001; 159(2): 387 - 397. [Abstract] [Full Text]
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C. M. Fleming, H. He, A. Ciota, D. Perkins, and P. W. Finn Administration of Pentoxifylline During Allergen Sensitization Dissociates Pulmonary Allergic Inflammation from Airway Hyperresponsiveness J. Immunol., August 1, 2001; 167(3): 1703 - 1711. [Abstract] [Full Text] [PDF]
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 M. Adib-Conquy, K. Asehnoune, P. Moine, and J.-M. Cavaillon Long-term-impaired expression of nuclear factor-{kappa}B and I{kappa}B{alpha} in peripheral blood mononuclear cells of trauma patients J. Leukoc. Biol., July 1, 2001; 70(1): 30 - 38. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, J. Blanco, and J. Egido Systemic Infusion of Angiotensin II into Normal Rats Activates Nuclear Factor-{{kappa}}B and AP-1 in the Kidney : Role of AT1 and AT2 Receptors Am. J. Pathol., May 1, 2001; 158(5): 1743 - 1756. [Abstract] [Full Text] [PDF]
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 E. Ho, N. Quan, Y.-H. Tsai, W. Lai, and T. M. Bray Dietary Zinc Supplementation Inhibits NF {{kappa}}B Activation and Protects Against Chemically Induced Diabetes in CD1 Mice Experimental Biology and Medicine, February 1, 2001; 226(2): 103 - 111. [Abstract] [Full Text]
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 H.-M. Shen, Z. Zhang, Q.-F. Zhang, and C.-N. Ong Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L10 - L17. [Abstract] [Full Text] [PDF]
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Y.-H. Li, Z.-Q. Yan, J. S. Jensen, K. Tullus, and A. Brauner Activation of Nuclear Factor kappa B and Induction of Inducible Nitric Oxide Synthase by Ureaplasma urealyticum in Macrophages Infect. Immun., December 1, 2000; 68(12): 7087 - 7093. [Abstract] [Full Text] [PDF]
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T. A. Blinman, I. Gukovsky, M. Mouria, V. Zaninovic, E. Livingston, S. J. Pandol, and A. S. Gukovskaya Activation of pancreatic acinar cells on isolation from tissue: cytokine upregulation via p38 MAP kinase Am J Physiol Cell Physiol, December 1, 2000; 279(6): C1993 - C2003. [Abstract] [Full Text] [PDF]
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F. Chen, L. M. Demers, V. Vallyathan, Y. Lu, V. Castranova, and X. Shi Impairment of NF-kappa B activation and modulation of gene expression by calpastatin Am J Physiol Cell Physiol, September 1, 2000; 279(3): C709 - C716. [Abstract] [Full Text] [PDF]
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M. D. S. Jean, C. Debbasch, M. Rahmani, F. Brignole, G. Feldmann, J.-M. Warnet, and C. Baudouin Fas- and Interferon {gamma}-Induced Apoptosis in Chang Conjunctival Cells: Further Investigations Invest. Ophthalmol. Vis. Sci., August 1, 2000; 41(9): 2531 - 2543. [Abstract] [Full Text]
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E. R. Fields, B. J. Seufzer, E. M. Oltz, and S. Miyamoto A Switch in Distinct I{kappa}B{alpha} Degradation Mechanisms Mediates Constitutive NF-{kappa}B Activation in Mature B Cells J. Immunol., May 1, 2000; 164(9): 4762 - 4767. [Abstract] [Full Text] [PDF]
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F. Arnalich, E. Garcia-Palomero, J. Lopez, M. Jimenez, R. Madero, J. Renart, J. J. Vazquez, and C. Montiel Predictive Value of Nuclear Factor kappa B Activity and Plasma Cytokine Levels in Patients with Sepsis Infect. Immun., April 1, 2000; 68(4): 1942 - 1945. [Abstract] [Full Text] [PDF]
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M. F. Romano, A. Lamberti, R. Bisogni, C. Garbi, A. M. Pagnano, P. Auletta, P. Tassone, M. C. Turco, and S. Venuta Amifostine Inhibits Hematopoietic Progenitor Cell Apoptosis by Activating NF-kappa B/Rel Transcription Factors Blood, December 15, 1999; 94(12): 4060 - 4066. [Abstract] [Full Text] [PDF]
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F. Chen, L. M. Demers, V. Vallyathan, Y. Lu, V. Castranova, and X. Shi Involvement of 5'-Flanking kappa B-like Sites within bcl-x Gene in Silica-induced Bcl-x Expression J. Biol. Chem., December 10, 1999; 274(50): 35591 - 35595. [Abstract] [Full Text] [PDF]
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E. Ho and T. M. Bray Antioxidants, NF{kappa}B Activation, and Diabetogenesis Experimental Biology and Medicine, December 1, 1999; 222(3): 205 - 213. [Abstract] [Full Text]
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F. Chen, Y. Lu, V. Castranova, Y. Rojanasakul, K. Miyahara, Y. Shizuta, V. Vallyathan, X. Shi, and L. M. Demers Nitric Oxide Inhibits HIV Tat-Induced NF-{kappa}B Activation Am. J. Pathol., July 1, 1999; 155(1): 275 - 284. [Abstract] [Full Text] [PDF]
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M. W. Anthonsen, A. Solhaug, and B. Johansen Functional Coupling between Secretory and Cytosolic Phospholipase A2 Modulates Tumor Necrosis Factor-alpha - and Interleukin-1beta -induced NF-kappa B Activation J. Biol. Chem., August 3, 2001; 276(32): 30527 - 30536. [Abstract] [Full Text] [PDF]
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P. Casarosa, R. A. Bakker, D. Verzijl, M. Navis, H. Timmerman, R. Leurs, and M. J. Smit Constitutive Signaling of the Human Cytomegalovirus-encoded Chemokine Receptor US28 J. Biol. Chem., January 5, 2001; 276(2): 1133 - 1137. [Abstract] [Full Text] [PDF]
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F. Chen, Y. Lu, Z. Zhang, V. Vallyathan, M. Ding, V. Castranova, and X. Shi Opposite Effect of NF-kappa B and c-Jun N-terminal Kinase on p53-independent GADD45 Induction by Arsenite J. Biol. Chem., March 30, 2001; 276(14): 11414 - 11419. [Abstract] [Full Text] [PDF]
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S. Van Huffel, F. Delaei, K. Heyninck, D. De Valck, and R. Beyaert Identification of a Novel A20-binding Inhibitor of Nuclear Factor-kappa B Activation Termed ABIN-2 J. Biol. Chem., August 3, 2001; 276(32): 30216 - 30223. [Abstract] [Full Text] [PDF]
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inhibition.