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Vol. 62, Issue 1, 58-64, July 2002
1-Induced
Extracellular Matrix with a Novel Inhibitor of the TGF- Type I
Receptor Kinase Activity: SB-431542
Departments of Renal and Urology Research (N.J.L., E.G., A.M., S.B., J.B., C.T., W.M., B.A.O.), Gene Expression Sciences (J.F.), Protein Biochemistry (R.L.), and Medicinal Chemistry (J.H., L.G., J.F.C.), GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Transforming growth factor 
1 (TGF-1) is a potent fibrotic factor
responsible for the synthesis of extracellular matrix. TGF-1 acts
through the TGF- type I and type II receptors to activate
intracellular mediators, such as Smad proteins, the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal-regulated kinase pathway. We expressed the kinase domain of the TGF- type I receptor [activin receptor-like kinase (ALK)5] and the substrate, Smad3, and determined that SB-431542 is a selective inhibitor of Smad3 phosphorylation with an IC50 of 94 nM.
It inhibited TGF-1-induced nuclear Smad3 localization. The p38
mitogen-activated protein kinase inhibitors SB-203580 and SB-202190
also inhibit phosphorylation of Smad3 by ALK5 with IC50
values of 6 and 3 µM, respectively. This suggests that these p38 MAPK
inhibitors must be used at concentrations of less than 10 µM to
selectively address p38 MAPK mechanisms. However, the p38 MAPK
inhibitor SB-242235 did not inhibit ALK5. To evaluate the relative
contribution of Smad signaling and p38 MAPK signaling in
TGF-1-induced matrix production, the effect of SB-431542 was
compared with that of SB-242235 in renal epithelial carcinoma A498
cells. All compounds inhibited TGF-1-induced fibronectin (FN) mRNA,
indicating that FN synthesis is mediated in part via the p38 MAPK
pathway. In contrast, SB-431542, but not the selective p38 MAPK
inhibitor SB-242235, inhibited TGF-1-induced collagen I
1 (col
I1). These data indicate that some matrix markers that are
stimulated by TGF-1 are mediated via the p38 MAPK pathway (i.e.,
FN), whereas others seem to be activated via ALK5 signaling independent
of the p38 MAPK pathway (i.e., col I1).
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Numerous reports describe
TGF-1 as a potent regulator of extracellular matrix. Thus, cells can
be induced to produce extracellular matrix protein and inhibit protease
activity by exogenous TGF-1 (Nakamura et al., 1992
; Ziyadeh et al.,
1994). Transgenic mice that overexpress TGF-1 develop severe
glomerulosclerosis and liver fibrosis (Kopp et al., 1996; Kanzler et
al., 1999). Finally, neutralizing antibodies against TGF-1 can
prevent the accumulation of extracellular matrix in models of renal
disease and lung fibrosis (Border et al., 1990; Sharma et al., 1996;
Ziyadeh et al., 2000).
Several signaling pathways have been implicated in mediating
TGF--induced extracellular matrix production and fibrosis.
Transforming growth factor- signals through two highly conserved
single transmembrane receptors with intracellular serine/threonine
kinase domains. Specifically, the type II receptor phosphorylates
threonine residues in the glycine-serine (GS)-rich domain of the
ligand-occupied type I receptor (ALK5), which results in the activation
of ALK5 (Wrana, 1998). ALK5, in turn, phosphorylates Smad proteins
(Abdollah et al., 1997), which mediate intracellular signaling to the
nucleus. TGF- also activates the p38 mitogen-activated protein
kinase (MAPK) through the TGF- activated kinase, TAK1 (Hanafusa et
al., 1999). Thus, the TGF- receptors can regulate gene
transcription directly by activating the Smad transcription factors,
indirectly via p38 MAPK, or by a combination of both pathways. Other
kinases, such as JNK1 and MKK4, also seem to be involved in TGF-
regulation of fibronectin synthesis (Hocevar et al., 1999).
Furthermore, TGF-1 can activate the extracellular signal-regulated
kinase through a protein synthesis requiring a mechanism that
may involve basic fibroblast growth factor (Finlay et al., 2000). It is
clear that TGF- can interact with several kinase pathways to
influence many components of the extracellular matrix.
Although it has been shown that the p38 MAPK inhibitor SB-203580
can inhibit ALK5 autophosphorylation with an IC50
of 20 µM (Eyers et al., 1998), more selective inhibitors have not
been applied to TGF- regulation of extracellular matrix. We
characterized several compounds for their ability to selectively
inhibit ALK5 or p38 MAPK to delineate the relative contribution of Smad
and p38 MAPK activation in TGF- regulation of extracellular matrix. In this study, therefore, we examine the effects of the selective ALK5
inhibitor SB-431542 (Callahan et al., 2002) and the selective p38 MAPK
inhibitor SB-242235 (Badger et al., 2000) on TGF-1-induced fibronectin, collagen I1, thrombospondin-1, and plasminogen
activator inhibitor-1 mRNA.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Expression of Recombinant Protein.
The kinase domain of
ALK5, amino acids 200 to the C terminus, which lacks the GS region, and
the full-length Smad3 protein were expressed as N-terminal glutathione
S-transferase (GST) fusion proteins in baculovirus
expression system. Proteins were purified with glutathione Sepharose
beads 4B (Amersham Biosciences, Uppsala, Sweden) (Roshak et al.,
2000).
Kinase Assay.
Kinase assays were performed with 65 nM
GST-ALK5 and 184 nM GST-Smad3 in 50 mM HEPES, 5 mM
MgCl2, 1 mM CaCl2, 1 mM
dithiothreitol, and 3 µM ATP. Reactions were incubated with 0.5 µCi
of [33P]
ATP for 3 h at 30°C.
Phosphorylated protein was captured on P-81 paper (Whatman, Maidstone,
England), washed with 0.5% phosphoric acid, and counted by liquid
scintillation. Alternatively, Smad3 or Smad1 protein was also coated
onto FlashPlate Sterile Basic Microplates (PerkinElmer Life Sciences,
Boston, MA). Kinase assays were then performed in FlashPlates with same
assay conditions using either the kinase domain of ALK5 with Smad3 as
substrate or the kinase domain of ALK6 (BMP receptor) with Smad1 as
substrate. Plates were washed three times with phosphate buffer and
counted by TopCount (Packard Bioscience, Meriden, CT).
Cell Culture. A498 renal epithelial carcinoma cell line was obtained from American Type Culture Collection (Manassas, VA) and grown in Earle's minimum essential medium (GlaxoSmithKline, King of Prussia, PA) supplemented with 10% fetal calf serum, penicillin (5 units/ml), and streptomycin (5 ng/ml). Cells were serum-starved for 24 h before treatment. Renal proximal tubule epithelial cells (RPTEC) were obtained from Clonetics Corp. (San Diego, CA) and grown in supplied RPTEC medium.
XTT Viability Assay. A498 cells were seeded at 5,000 to 10,000 cells/well in 96-well plates. The cells were serum-deprived for 24 h and then treated with compounds for 48 h to assess the cellular toxicity. Cell viability is determined by incubating cells for 4 h with XTT labeling and electron coupling reagent according to the manufacturer's directions (Roche Applied Science, Indianapolis, IN). Live cells with active mitochondria produce an orange-colored product, formazan, which is detected using a plate reader at between A450 nm and A500 nm with a reference wavelength greater than 600 nm. The absorbance values correlate with the number of viable cells.
Nuclear Translocation.
RPTEC or MG63 osteoblasts were seeded
at about 30 to 50% confluence on microscope slides. The cells were
serum-starved for 24 h and pretreated for 4 h with the
compounds. The cells were treated with 5 ng/ml TGF-1, BMP-4, or
vehicle for 30 min. The cells were fixed in 4% paraformaldehyde for 15 min, washed three times with PBS, permeabilized for 20 min in 0.5%
Triton X-100 in PBS, and washed three times with PBS. The slides were
blocked for 1 h at room temperature with 10% horse serum in PBS.
Slides were incubated with 1:500 dilution of primary antibody raised against full-length Smad3 (Santa Cruz Biotechnology Inc., Santa Cruz,
CA) at 4°C in 10% horse serum in PBS overnight. The slides were
washed three times with PBS for a total of 30 min. Secondary antibody
conjugated with fluorescein isothiocyanate was added at 1:5000 dilution
in 3% horse serum in PBS for 1 h. Slides were washed three times
in PBS and covered with mounting medium containing 4,6-diamidino-2-phenylindole stain (Vector Laboratories Inc., Burlingame, CA) and coverslipped for viewing. Digital images were captured from 10 fields per condition under identical exposure settings. Average fluorescent intensity was measured for every nucleus
in the field and averaged for the field with Kodak Image analysis
software (Eastman Kodak, Rochester, NY). Mean nuclear fluorescent
intensities were calculated for each condition from the average
intensity generated from each field.
mRNA Analysis.
A498 cells were grown to near confluence in
100-mm dishes, serum-starved for 24 h, and pretreated with
compounds for 4 h followed by a 10 ng/ml addition of TGF-1 (R & D Systems, Inc., Minneapolis, MN). Cells were treated for 6 h
[plasminogen activator inhibitor-1 (PAI-1) and thrombospondin-1
(TSP-1) mRNA] or 24 h [fibronectin (FN) mRNA] after the
addition of TGF-1. Cellular RNA was extracted by acid
phenol/chloroform extraction (Chomczynski and Sacchi, 1987). Total RNA
(10 µg) was resolved by agarose gel electrophoresis and transferred
to nylon membrane (GeneScreen; PerkinElmer Life Sciences, Boston,
MA). Membranes were probed with
32P-labeled cDNA probes (Stratagene, La Jolla,
CA) for FN, TSP-1, PAI-1, and for control ribosomal protein L32
(rpL32). Collagen I1 mRNA was measured by TaqMan real-time RT-PCR
(Applied Biosystems Inc., Foster City, CA).
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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To identify potential inhibitors of ALK5 kinase activity,
compounds were tested for their ability to inhibit ALK5 phosphorylation of Smad3 (Callahan et al., 2002). The kinase domain without the GS
region was cloned and expressed as a GST fusion protein. Expressing the
protein without the GS domain, which has been shown to regulate the
kinase activity (Huse et al., 2001), creates a constitutively active
kinase that is able to phosphorylate GST-Smad3 (Fig.
1). The screening results identified many
inhibitors of p38 MAPK, indicating that the ATP binding site of ALK5
and p38 MAPK bind similar pharmacophores. This was further illustrated
by a report that SB-203580 inhibited the autophosphorylation of ALK5
(Eyers et al., 1998). Based on analysis of structure-activity
relationships, SB-431542 was designed to be a selective ALK5 inhibitor
with little activity against p38 MAPK (compound 14; Callahan et al.,
2002). SB-431542 was identified as a potent ALK5 inhibitor with an
IC50 of 94 nM (Fig.
2). Analogs of the p38 MAPK inhibitor
SB-203580 were also tested (SB-202190 and SB-242235). SB-203580 and
SB-202190 inhibited ALK5 kinase activity with
IC50 values of 6 and 3 µM, respectively (Fig.
2). SB-242235, which was developed as a more selective p38 MAPK
inhibitor (Badger et al., 2000), did not inhibit ALK5 at concentrations
up to 50 µM. Selectivity of SB-431542 was further evaluated against
other type I receptors, such as ALK4 and ALK2. Although SB-431542
inhibited ALK4 with an IC50 of 140 nM, it had no
effect on the kinase activity of ALK2 (Fig.
3). This is consistent with the degree of
homology between these kinases, such that ALK4 is the closest related
kinase to ALK5. These results are further supported by activities
against the full-length receptors transfected in NIH 3T3 cells (Inman
et al., 2002). These data clearly demonstrate that SB-431542 is a
potent and selective inhibitor of ALK5 and ALK4, with slightly higher
selectivity for ALK5.
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A concern with kinase inhibitors is nonspecific toxicity caused by inhibition of important but unrelated kinases. To assess potential toxicity of these kinase inhibitors, SB-431542, SB-203580, SB-202190, and SB-242235 were examined by XTT assay, which measures mitochondrial activity as an index of cell viability. Exposure of these compounds to A498 renal epithelial carcinoma cells for 48 h resulted in LD50 values of >30, 15, 30, and >30 µM, respectively (data not shown). Therefore, cells can be treated with SB-431542 for up to 48 h at concentrations up to 10 µM without impact on cell viability.
TGF-1 has been shown to cause the translocation of Smad proteins
from the cytoplasm to the nucleus (Hoodless et al., 1996). To evaluate
whether ALK5 activity is required for TGF-1-induced translocation
of Smad3, Smad proteins were visualized in A498 cells by indirect
immunofluorescence using antibodies raised against Smad3. SB-242235 at
a concentration of 20 µM was unable to prevent the TGF--induced
translocation of Smad protein (data not shown). However, SB-431542 at a
concentration of 1 µM significantly reduced the TGF--induced
nuclear accumulation of Smad proteins. To confirm that primary renal
epithelial cells also respond to TGF-1 with increased nuclear Smad,
a dose-response curve using 0, 50, 250, 500, and 700 nM SB-431542 in
primary RPTEC was performed. The IC50 for
inhibiting TGF-1-induced nuclear fluorescence is approximately 50 nM (Fig. 4). BMP-stimulated Smad1 nuclear
fluorescence in MG63 cells was unaffected by SB-431542 (data not
shown). Thus, SB-431542 selectively inhibits TGF-1-induced Smad
translocation without affecting BMP-induced Smads. Furthermore, p38
MAPK activity is not required for TGF-1-induced Smad translocation.
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To evaluate the effect of ALK5 kinase inhibition on TGF-1-induced
matrix production, the effect of SB-431542 on TGF-1-induced collagen I1 and FN mRNA was examined in A498 cells. SB-431542 inhibited TGF-1-induced collagen I1 and PAI-1 mRNA with
IC50 values of 60 and 50 nM, respectively (Fig.
5). In addition, SB-431542 inhibited
TGF-1-induced fibronectin mRNA and protein with
IC50 values of 62 and 22 nM, respectively (Fig.
6). These data demonstrate for the first
time that ALK5 activity is required for TGF-1 regulation of
extracellular matrix markers FN, collagen I1, and PAI-1 mRNA.
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The role of p38 MAPK in mediating TGF-1 regulation of extracellular
matrix was evaluated with the selective p38 MAPK inhibitor SB-242235 in
A498 cells. Although SB-242235 was unable to affect TGF-1-mediated
increase in collagen I1 mRNA levels, it inhibited TGF-1-induced
FN mRNA with an IC50 of 16 nM (Fig.
7). This clearly indicates that TGF-1
regulation of collagen I1 mRNA is independent of p38 MAPK whereas
TGF-1 regulation of FN mRNA is dependent on p38 MAPK activity.
Higher doses of SB-242235 further inhibit FN mRNA and also inhibit
TGF-1-induced TSP-1 mRNA and, to a lesser degree, PAI-1 mRNA (Fig.
8). Moreover, the other p38 MAPK
inhibitors, SB-203580 and SB-202190, also inhibit TGF-1-induced
fibronectin mRNA with IC50 values of 0.5 and 1 µM, respectively (Fig. 9A). However,
these compounds also inhibited collagen I1 mRNA at 10-fold higher
concentrations (Fig. 9B). This clearly shows that these compounds are
less selective than SB-242235 in their ability to distinguish between
fibronectin and collagen I1 activation pathways and, thus, p38 MAPK
dependence.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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TGF-1 is one of the most potent profibrotic cytokines released
and activated after tissue injury (Border and Noble, 1994) and has been
implicated in a variety of human fibrotic diseases, including
glomerulonephritis (Yoshioka et al., 1993), diabetic nephropathy
(Yamamoto et al., 1993), liver cirrhosis (Nagy, 1991), and lung
fibrosis (Anscher, 1993). Several studies support a causal relationship
between TGF-1 and fibrosis. Renal cells can be induced to
produce extracellular matrix protein and inhibit protease activity by
exogenous TGF-1 in vitro (Nakamura et al., 1992; Ziyadeh et al.,
1994). Furthermore, neutralizing antibodies against TGF-1 can
prevent the accumulation of extracellular matrix in nephritic rodents
(Border et al., 1990; Sharma et al., 1996; Ziyadeh et al., 2000) and
bleomycin-treated mice (Giri et al., 1993). Finally, TGF-1
transgenic mice or in vivo transfection of the TGF-1 gene into
normal rats resulted in the rapid development of glomerulosclerosis and
liver fibrosis (Isaka et al., 1993; Imai et al., 1994; Kopp et al.,
1996; Kanzler et al., 1999). Because TGF- is a potent stimulus for
extracellular matrix synthesis, inhibition of ALK5 activity and p38
MAPK may be beneficial in fibrotic disorders. Therefore, we examined
kinase inhibitors for their ability to inhibit the TGF- type I
receptor ALK5.
To identify small molecules able to inhibit ALK5, in vitro kinase
assays were performed with GST fusion proteins of Smad3 and the kinase
domain of ALK5. It must be noted that the kinase assays used the
truncated ALK5 kinase domain that lacks the regulatory GS region. This
is a relatively weak kinase construct, because an incubation of more
than 2 h is required to measure robust phosphorylation signal
compared with other constructs using the hyperphosphorylated GS region
(Huse et al., 2001). In the intact type I receptor, this region must be
phosphorylated for kinase activity (Wrana et al., 1994). The
phosphorylation theoretically causes the displacement of the GS region,
allowing opening of the ATP binding site and thus phosphorylation of
substrate to occur (Huse et al., 2001). By expressing the kinase domain
without this regulatory region fused at the N-terminal to glutathione
S-transferase, however, an active kinase is formed, further
supporting the hypothesis that the GS region is involved in maintaining
the ATP binding site in the inactive state.
Certain similarities seem to exist in the ATP binding pocket between
ALK5 and the serine-threonine kinase, p38 MAPK, because the p38 MAPK
inhibitor, SB-203580, was also able to inhibit ALK5 autophosphorylation
with an IC50 of 20 µM (Eyers et al., 1998). We
have shown that SB-203580 and its analog SB-202190 inhibit ALK5
phosphorylation of Smad3 at 6 and 3 µM, respectively. This class of
imidazoles led to the discovery of a selective ALK5 inhibitor, SB-431542 (Callahan et al., 2002).
We have characterized SB-431542 as a potent (nanomolar) inhibitor of
ALK5 with greater than 100-fold selectivity against p38 MAPK and 25 other kinases (Inman et al., 2002), which can prevent TGF-1-induced
elevation of FN, PAI-1, and collagen I1 mRNA. The selectivity of
SB-431542 seems to be greater for ALK5 than for the closely related
activin type I receptor ALK4 (94 versus 140 nM). This is supported by
findings by Inman et al. (2002), where cells transfected with
constitutively active type I receptors show that SB-431542
preferentially inhibits ALK5 and, to a lesser degree, ALK4, and,
further, ALK7 (Inman et al., 2002). Moreover, this study, as well as
the study by Inman et al. (2002), shows that SB-431542 has no
significant activity against the BMP-activated receptors ALK2, ALK3,
and ALK6 (Inman et al., 2002). Thus, SB-431542 is a useful tool to
evaluate TGF--regulated cellular mechanisms.
Although SB-203580 and SB-202190 are potent p38 MAPK inhibitors
(Beyaert et al., 1996; Feoktistov et al., 1999), they were also able to
inhibit the kinase activity of ALK5 at micromolar concentrations. It
should be noted that earlier reports using SB-203580 to describe the
role of p38 MAPK in TGF- signaling are unlikely to distinguish p38
MAPK from ALK5 activity, due to lack of selectivity at concentrations
greater than 10 µM (Ravanti et al., 1999; Gruden et al., 2000). It is
therefore imperative that SB-203580 and SB-202190 be used at
concentrations of less than 10 µM to avoid nonselective inhibition of
other kinases.
Several studies have shown that TGF- signaling requires both ALK5
and the TGF- type II receptor and is mediated via the cytoplasmic
mediators Smad2 and Smad3. The type II receptor phosphorylates serine
and threonine residues in the GS domain of the ligand-occupied type I
receptor, which results in the activation of the type I receptor
(Wrana, 1998). ALK5 then phosphorylates Ser465
and Ser467 of the conserved C-terminal end of
Smad2 (Abdollah et al., 1997; Souchelnytskyi et al., 1997), and this
phosphorylation of Smad2 is required for its nuclear accumulation and
signaling (Macias-Silva et al., 1996). Smad3 behaves similarly upon
TGF- stimulation. Consistent with these data, SB-431542, but not
SB-242235, prevented the TGF-1-induced nuclear accumulation of Smad
proteins at concentrations similar to those needed to block
TGF-1-induced matrix markers. Because SB-242235 had no effect on
Smad translocation, the p38 MAPK pathway is unlikely to be involved in
modulating nuclear accumulation of Smad proteins.
Because the p38 MAPK selective inhibitor SB-242235 (Badger et al.,
2000), which did not affect ALK5 kinase activity up to 50 µM, did not
significantly affect TGF-1-induced collagen I1 mRNA production,
it is likely that TGF-1 regulation of collagen I1 mRNA is
mediated primarily through ALK5 and Smad activation. However, SB-242235
did inhibit TGF-1-induced FN mRNA and, to a lesser extent, TSP1 and
PAI-1 mRNA. This demonstrates that p38 MAPK activation plays a role in
TGF-1 regulation of FN, TSP-1, and possibly PAI-1 synthesis.
Activation of p38 MAPK leads to activation of transcription factors,
including ATF-2, CREB, and AP-1 (Xing et al., 1998; Zhu and Lobie,
2000; Wilmer et al., 2001), which in turn can bind the respective
response elements found in regulatory sequences of the fibronectin gene
(Srebrow et al., 1993; Nahman et al., 1996; Tamura et al., 1998).
Therefore, TGF-1-induced increase of FN mRNA may be mediated
indirectly via p38 MAPK activation of ATF-2, CREB, and AP-1. It should
be noted that whereas TGF-1 increases collagen I1 and PAI-1 mRNA
rapidly within a few hours, FN mRNA increases are not significant until
more than 16 h. This further suggests that FN mRNA regulation by
TGF-1 is indirect.
In summary, this study shows that SB-431542 is a potent inhibitor of
the TGF- type I receptor ALK5. Although SB-431542 has significant
activity against the closest related kinase (ALK4), it is selective
against 25 other kinases and an excellent tool to evaluate the role of
TGF- and ALK5 in cellular mechanisms. Finally, use of SB-431542 and
the selective p38 MAPK inhibitor SB-242235 also showed that TGF-1
can transcriptionally regulate extracellular matrix genes by several
mechanisms, including the Smad pathway, the p38 MAPK kinase pathway,
and possibly a combination of the two, as well as other kinase
pathways. Thus, TGF-1 seems to regulate collagen I1 mRNA levels
by ALK5 independent of p38 MAPK activation. In contrast, TGF-1
induction of FN mRNA requires p38 MAPK activity. TGF-1 induction of
PAI-1 and TSP-1 mRNA uses at least ALK5 and possibly the p38 MAPK
pathway. It is certain that the Smad proteins interact with other
transcription factors, thereby providing a mechanism for modulation of
TGF-1-responsive genes by other factors and signaling pathways.
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Acknowledgments |
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We thank Drs. David Brooks and Caroline Hill for critical discussions.
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Footnotes |
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Received November 28, 2001; Accepted March 21, 2002
Address correspondence to: Nicholas J. Laping, Ph.D., Renal and Urology Research, UW2521, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406. E-mail: nicholas_j_laping{at}sbphrd.com
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Abbreviations |
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TGF-1, transforming growth factor 1;
GS, glycine-serine;
ALK, activin receptor-like kinase;
MAPK, mitogen-activated protein kinase;
SB-203580, 4-[4'-fluorophenyl]-2-[4'-methylsulfinylphenyl]-5-[4'-pyridyl]
imidazole;
SB-431542, 4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide;
SB-242235, 4-[4-(4-flurophenyl)-1-(4-piperidinyl)-1H-imidazol-5-yl]-2-methoxypyrimidine;
GST, glutathione S-transferase;
RPTEC, renal proximal
tubule epithelial cells;
XTT, 2,3-bis[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolium-5-carboxyaniline;
BMP, bone morphogenetic protein;
PBS, phosphate-buffered saline;
PAI-1, plasminogen activator inhibitor-1;
TSP-1, thrombospondin-1;
FN, fibronectin;
rpL32, ribosomal protein L32;
RT-PCR, reverse
transcription-polymerase chain reaction;
SB-202190, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7.
Mol Pharmacol
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 Y.-q. Xiao, K. Liu, J.-f. Shen, G.-T. Xu, and W. Ye SB-431542 Inhibition of Scar Formation after Filtration Surgery and Its Potential Mechanism Invest. Ophthalmol. Vis. Sci., April 1, 2009; 50(4): 1698 - 1706. [Abstract] [Full Text] [PDF]
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 P. Sucosky, K. Balachandran, A. Elhammali, H. Jo, and A. P. Yoganathan Altered Shear Stress Stimulates Upregulation of Endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-{beta}1-Dependent Pathway Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 254 - 260. [Abstract] [Full Text] [PDF]
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Y. Wang, J. Fortin, P. Lamba, M. Bonomi, L. Persani, M. S. Roberson, and D. J. Bernard Activator Protein-1 and Smad Proteins Synergistically Regulate Human Follicle-Stimulating Hormone {beta}-Promoter Activity Endocrinology, November 1, 2008; 149(11): 5577 - 5591. [Abstract] [Full Text] [PDF]
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 Z. Wu, W. Zhang, G. Chen, L. Cheng, J. Liao, N. Jia, Y. Gao, H. Dai, J. Yuan, L. Cheng, et al. Combinatorial Signals of Activin/Nodal and Bone Morphogenic Protein Regulate the Early Lineage Segregation of Human Embryonic Stem Cells J. Biol. Chem., September 5, 2008; 283(36): 24991 - 25002. [Abstract] [Full Text] [PDF]
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F. Meng, X. Cheng, L. Yang, N. Hou, X. Yang, and A. Meng Accelerated re-epithelialization in Dpr2-deficient mice is associated with enhanced response to TGF{beta} signaling J. Cell Sci., September 1, 2008; 121(17): 2904 - 2912. [Abstract] [Full Text] [PDF]
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 M. F. Walsh, D. R. Ampasala, J. Hatfield, R. Vander Heide, S. Suer, A. K. Rishi, and M. D. Basson Transforming Growth Factor-{beta} Stimulates Intestinal Epithelial Focal Adhesion Kinase Synthesis via Smad- and p38-Dependent Mechanisms Am. J. Pathol., August 1, 2008; 173(2): 385 - 399. [Abstract] [Full Text] [PDF]
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 D. Romero, M. Iglesias, C. P.H. Vary, and M. Quintanilla Functional blockade of Smad4 leads to a decrease in {beta}-catenin levels and signaling activity in human pancreatic carcinoma cells Carcinogenesis, May 1, 2008; 29(5): 1070 - 1076. [Abstract] [Full Text] [PDF]
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 M. Oka, C. Iwata, H. I. Suzuki, K. Kiyono, Y. Morishita, T. Watabe, A. Komuro, M. R. Kano, and K. Miyazono Inhibition of endogenous TGF-{beta} signaling enhances lymphangiogenesis Blood, May 1, 2008; 111(9): 4571 - 4579. [Abstract] [Full Text] [PDF]
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H. Dadlani, M. L. Ballinger, N. Osman, R. Getachew, and P. J. Little Smad and p38 MAP Kinase-mediated Signaling of Proteoglycan Synthesis in Vascular Smooth Muscle J. Biol. Chem., March 21, 2008; 283(12): 7844 - 7852. [Abstract] [Full Text] [PDF]
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 S. Bharathy, W. Xie, J. M. Yingling, and M. Reiss Cancer-Associated Transforming Growth Factor {beta} Type II Receptor Gene Mutant Causes Activation of Bone Morphogenic Protein-Smads and Invasive Phenotype Cancer Res., March 15, 2008; 68(6): 1656 - 1666. [Abstract] [Full Text] [PDF]
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S. Velasco, P. Alvarez-Munoz, M. Pericacho, P. t. Dijke, C. Bernabeu, J. M. Lopez-Novoa, and A. Rodriguez-Barbero L- and S-endoglin differentially modulate TGF{beta}1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts J. Cell Sci., March 15, 2008; 121(6): 913 - 919. [Abstract] [Full Text] [PDF]
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 R. B. Gilchrist, M. Lane, and J. G. Thompson Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality Hum. Reprod. Update, March 1, 2008; 14(2): 159 - 177. [Abstract] [Full Text] [PDF]
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R. Mishra and M. S. Simonson Oleate Induces a Myofibroblast-Like Phenotype in Mesangial Cells Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 541 - 547. [Abstract] [Full Text] [PDF]
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 F. J Diaz, K. Sugiura, and J. J Eppig Regulation of Pcsk6 Expression During the Preantral to Antral Follicle Transition in Mice: Opposing Roles of FSH and Oocytes Biol Reprod, January 1, 2008; 78(1): 176 - 183. [Abstract] [Full Text] [PDF]
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J. Xu, B. Yao, X. Fan, M. M. Langworthy, M.-Z. Zhang, and R. C. Harris Characterization of a putative intrarenal serotonergic system Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1468 - F1475. [Abstract] [Full Text] [PDF]
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 M. C. Waghabi, M. Keramidas, C. M. Calvet, M. Meuser, M. d. N. C. Soeiro, L. Mendonca-Lima, T. C. Araujo-Jorge, J.-J. Feige, and S. Bailly SB-431542, a Transforming Growth Factor {beta} Inhibitor, Impairs Trypanosoma cruzi Infection in Cardiomyocytes and Parasite Cycle Completion Antimicrob. Agents Chemother., August 1, 2007; 51(8): 2905 - 2910. [Abstract] [Full Text] [PDF]
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Q. Xu, J. T. Norman, S. Shrivastav, J. Lucio-Cazana, and J. B. Kopp In vitro models of TGF-beta-induced fibrosis suitable for high-throughput screening of antifibrotic agents Am J Physiol Renal Physiol, August 1, 2007; 293(2): F631 - F640. [Abstract] [Full Text] [PDF]
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P. Dai, T. Nakagami, H. Tanaka, T. Hitomi, and T. Takamatsu Cx43 Mediates TGF-beta Signaling through Competitive Smads Binding to Microtubules Mol. Biol. Cell, June 1, 2007; 18(6): 2264 - 2273. [Abstract] [Full Text] [PDF]
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A.-C. Poncelet, H. W. Schnaper, R. Tan, Y. Liu, and C. E. Runyan Cell Phenotype-specific Down-regulation of Smad3 Involves Decreased Gene Activation as Well as Protein Degradation J. Biol. Chem., May 25, 2007; 282(21): 15534 - 15540. [Abstract] [Full Text] [PDF]
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O. Scherner, S. K. Meurer, L. Tihaa, A. M. Gressner, and R. Weiskirchen Endoglin Differentially Modulates Antagonistic Transforming Growth Factor-beta1 and BMP-7 Signaling J. Biol. Chem., May 11, 2007; 282(19): 13934 - 13943. [Abstract] [Full Text] [PDF]
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R. A. Dragovic, L. J. Ritter, S. J. Schulz, F. Amato, J. G. Thompson, D. T. Armstrong, and R. B. Gilchrist Oocyte-Secreted Factor Activation of SMAD 2/3 Signaling Enables Initiation of Mouse Cumulus Cell Expansion Biol Reprod, May 1, 2007; 76(5): 848 - 857. [Abstract] [Full Text] [PDF]
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R. Diwakar, A. L. Pearson, P. Colville-Nash, N. J. Brunskill, and M. E. C. Dockrell The role played by endocytosis in albumin-induced secretion of TGF-beta1 by proximal tubular epithelial cells Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1464 - F1470. [Abstract] [Full Text] [PDF]
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F. J. Diaz, K. Wigglesworth, and J. J. Eppig Oocytes determine cumulus cell lineage in mouse ovarian follicles J. Cell Sci., April 15, 2007; 120(8): 1330 - 1340. [Abstract] [Full Text] [PDF]
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 S.-H. Jeon, B.-C. Chae, H.-A Kim, G.-Y. Seo, D.-W. Seo, G.-T. Chun, N.-S. Kim, S.-W. Yie, W.-H. Byeon, S.-H. Eom, et al. Mechanisms underlying TGF-{beta}1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis J. Leukoc. Biol., February 1, 2007; 81(2): 557 - 566. [Abstract] [Full Text] [PDF]
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K. Ogawa, A. Saito, H. Matsui, H. Suzuki, S. Ohtsuka, D. Shimosato, Y. Morishita, T. Watabe, H. Niwa, and K. Miyazono Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells J. Cell Sci., January 1, 2007; 120(1): 55 - 65. [Abstract] [Full Text] [PDF]
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E. S. Jeon, H. J. Moon, M. J. Lee, H. Y. Song, Y. M. Kim, Y. C. Bae, J. S. Jung, and J. H. Kim Sphingosylphosphorylcholine induces differentiation of human mesenchymal stem cells into smooth-muscle-like cells through a TGF-{beta}-dependent mechanism J. Cell Sci., December 1, 2006; 119(23): 4994 - 5005. [Abstract] [Full Text] [PDF]
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B. M. Zhao and F. M. Hoffmann Inhibition of Transforming Growth Factor-beta1-induced Signaling and Epithelial-to-Mesenchymal Transition by the Smad-binding Peptide Aptamer Trx-SARA Mol. Biol. Cell, September 1, 2006; 17(9): 3819 - 3831. [Abstract] [Full Text] [PDF]
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S. McMahon, M. Charbonneau, S. Grandmont, D. E. Richard, and C. M. Dubois Transforming Growth Factor beta1 Induces Hypoxia-inducible Factor-1 Stabilization through Selective Inhibition of PHD2 Expression J. Biol. Chem., August 25, 2006; 281(34): 24171 - 24181. [Abstract] [Full Text] [PDF]
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 T. Oida, L. Xu, H. L. Weiner, A. Kitani, and W. Strober TGF-beta-Mediated Suppression by CD4+CD25+ T Cells Is Facilitated by CTLA-4 Signaling J. Immunol., August 15, 2006; 177(4): 2331 - 2339. [Abstract] [Full Text] [PDF]
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T. Quan, T. He, Y. Shao, L. Lin, S. Kang, J. J. Voorhees, and G. J. Fisher Elevated Cysteine-Rich 61 Mediates Aberrant Collagen Homeostasis in Chronologically Aged and Photoaged Human Skin Am. J. Pathol., August 1, 2006; 169(2): 482 - 490. [Abstract] [Full Text] [PDF]
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A. J. Ottaviano, L. Sun, V. Ananthanarayanan, and H. G. Munshi Extracellular Matrix-Mediated Membrane-Type 1 Matrix Metalloproteinase Expression in Pancreatic Ductal Cells Is Regulated by Transforming Growth Factor-{beta}1. Cancer Res., July 15, 2006; 66(14): 7032 - 7040. [Abstract] [Full Text] [PDF]
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E. Natarajan, J. D. Omobono II, Z. Guo, S. Hopkinson, A. J.F. Lazar, T. Brenn, J. C. Jones, and J. G. Rheinwald A Keratinocyte Hypermotility/Growth-Arrest Response Involving Laminin 5 and p16INK4A Activated in Wound Healing and Senescence Am. J. Pathol., June 1, 2006; 168(6): 1821 - 1837. [Abstract] [Full Text] [PDF]
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 M. Jinnin, H. Ihn, and K. Tamaki Characterization of SIS3, a Novel Specific Inhibitor of Smad3, and Its Effect on Transforming Growth Factor-beta1-Induced Extracellular Matrix Expression Mol. Pharmacol., February 1, 2006; 69(2): 597 - 607. [Abstract] [Full Text] [PDF]
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C. Boxall, S. T. Holgate, and D. E. Davies The contribution of transforming growth factor-{beta} and epidermal growth factor signalling to airway remodelling in chronic asthma Eur. Respir. J., January 1, 2006; 27(1): 208 - 229. [Abstract] [Full Text] [PDF]
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 P. R. A. Johnson, J. K. Burgess, Q. Ge, M. Poniris, S. Boustany, S. M. Twigg, and J. L. Black Connective Tissue Growth Factor Induces Extracellular Matrix in Asthmatic Airway Smooth Muscle Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 32 - 41. [Abstract] [Full Text] [PDF]
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B. Schmierer and C. S. Hill Kinetic Analysis of Smad Nucleocytoplasmic Shuttling Reveals a Mechanism for Transforming Growth Factor {beta}-Dependent Nuclear Accumulation of Smads Mol. Cell. Biol., November 15, 2005; 25(22): 9845 - 9858. [Abstract] [Full Text] [PDF]
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E. Sugaru, M. Sakai, K. Horigome, T. Tokunaga, M. Kitoh, W. E. Hume, R. Nagata, T. Nakagawa, and M. Taiji SMP-534 inhibits TGF-{beta}-induced ECM production in fibroblast cells and reduces mesangial matrix accumulation in experimental glomerulonephritis Am J Physiol Renal Physiol, November 1, 2005; 289(5): F998 - F1004. [Abstract] [Full Text] [PDF]
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L. Levy and C. S. Hill Smad4 Dependency Defines Two Classes of Transforming Growth Factor {beta} (TGF-{beta}) Target Genes and Distinguishes TGF-{beta}-Induced Epithelial-Mesenchymal Transition from Its Antiproliferative and Migratory Responses Mol. Cell. Biol., September 15, 2005; 25(18): 8108 - 8125. [Abstract] [Full Text] [PDF]
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A. Suzuki, G.-i. Kusakai, Y. Shimojo, J. Chen, T. Ogura, M. Kobayashi, and H. Esumi Involvement of Transforming Growth Factor-{beta}1 Signaling in Hypoxia-induced Tolerance to Glucose Starvation J. Biol. Chem., September 9, 2005; 280(36): 31557 - 31563. [Abstract] [Full Text] [PDF]
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 S. S. Khandekar, B. Feng, T. Yi, S. Chen, N. Laping, and N. Bramson A Liquid Chromatography/Mass Spectrometry-Based Method for the Selection of ATP Competitive Kinase Inhibitors J Biomol Screen, August 1, 2005; 10(5): 447 - 455. [Abstract] [PDF]
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C. Baldwin, V. G. Nolan, D. F. Wyszynski, Q.-L. Ma, P. Sebastiani, S. H. Embury, A. Bisbee, J. Farrell, L. Farrer, and M. H. Steinberg Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis Blood, July 1, 2005; 106(1): 372 - 375. [Abstract] [Full Text] [PDF]
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 E. T. Grygielko, W. M. Martin, C. Tweed, P. Thornton, J. Harling, D. P. Brooks, and N. J. Laping Inhibition of Gene Markers of Fibrosis with a Novel Inhibitor of Transforming Growth Factor-{beta} Type I Receptor Kinase in Puromycin-Induced Nephritis J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 943 - 951. [Abstract] [Full Text] [PDF]
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C. H. Stuelten, S. D. Byfield, P. R. Arany, T. S. Karpova, W. G. Stetler-Stevenson, and A. B. Roberts Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-{alpha} and TGF-{beta} J. Cell Sci., May 15, 2005; 118(10): 2143 - 2153. [Abstract] [Full Text] [PDF]
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C. P. Denton, G. E. Lindahl, K. Khan, X. Shiwen, V. H. Ong, N. J. Gaspar, K. Lazaridis, D. R. Edwards, A. Leask, M. Eastwood, et al. Activation of Key Profibrotic Mechanisms in Transgenic Fibroblasts Expressing Kinase-deficient Type II Transforming Growth Factor-{beta} Receptor (T{beta}RII{Delta}k) J. Biol. Chem., April 22, 2005; 280(16): 16053 - 16065. [Abstract] [Full Text] [PDF]
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K. S. Jones, S. Akel, C. Petrow-Sadowski, Y. Huang, D. C. Bertolette, and F. W. Ruscetti Induction of Human T Cell Leukemia Virus Type I Receptors on Quiescent Naive T Lymphocytes by TGF-{beta} J. Immunol., April 1, 2005; 174(7): 4262 - 4270. [Abstract] [Full Text] [PDF]
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S. Tsukada, J. K. Westwick, K. Ikejima, N. Sato, and R. A. Rippe SMAD and p38 MAPK Signaling Pathways Independently Regulate {alpha}1(I) Collagen Gene Expression in Unstimulated and Transforming Growth Factor-{beta}-stimulated Hepatic Stellate Cells J. Biol. Chem., March 18, 2005; 280(11): 10055 - 10064. [Abstract] [Full Text] [PDF]
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 D. James, A. J. Levine, D. Besser, and A. Hemmati-Brivanlou TGF{beta}/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells Development, March 15, 2005; 132(6): 1273 - 1282. [Abstract] [Full Text] [PDF]
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R. S. Muraoka-Cook, N. Dumont, and C. L. Arteaga Dual Role of Transforming Growth Factor ss in Mammary Tumorigenesis and Metastatic Progression Clin. Cancer Res., January 15, 2005; 11(2): 937s - 943s. [Abstract] [Full Text] [PDF]
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 S. Wang, M. C. Wilkes, E. B. Leof, and R. Hirschberg Imatinib mesylate blocks a non-Smad TGF-{beta} pathway and reduces renal fibrogenesis in vivo FASEB J, January 1, 2005; 19(1): 1 - 11. [Abstract] [Full Text] [PDF]
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 S.S. Prime, M. Davies, M. Pring, and I.C. Paterson THE ROLE OF TGF-{beta} IN EPITHELIAL MALIGNANCY AND ITS RELEVANCE TO THE PATHOGENESIS OF ORAL CANCER (PART II) Critical Reviews in Oral Biology & Medicine, November 1, 2004; 15(6): 337 - 347. [Abstract] [Full Text] [PDF]
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A. M. Ramirez, S. Takagawa, M. Sekosan, H. A. Jaffe, J. Varga, and J. Roman Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model Am. J. Pathol., October 1, 2004; 165(4): 1223 - 1232. [Abstract] [Full Text] [PDF]
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B. Sauer, R. Vogler, H. von Wenckstern, M. Fujii, M. B. Anzano, A. B. Glick, M. Schafer-Korting, A. B. Roberts, and B. Kleuser Involvement of Smad Signaling in Sphingosine 1-Phosphate-mediated Biological Responses of Keratinocytes J. Biol. Chem., September 10, 2004; 279(37): 38471 - 38479. [Abstract] [Full Text] [PDF]
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F. J. Nicolas, K. De Bosscher, B. Schmierer, and C. S. Hill Analysis of Smad nucleocytoplasmic shuttling in living cells J. Cell Sci., August 15, 2004; 117(18): 4113 - 4125. [Abstract] [Full Text] [PDF]
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M. C. Birchenall-Roberts, T. Fu, O.-s. Bang, M. Dambach, J. H. Resau, C. L. Sadowski, D. C. Bertolette, H.-J. Lee, S.-J. Kim, and F. W. Ruscetti Tuberous Sclerosis Complex 2 Gene Product Interacts with Human SMAD Proteins: A MOLECULAR LINK OF TWO TUMOR SUPPRESSOR PATHWAYS J. Biol. Chem., June 11, 2004; 279(24): 25605 - 25613. [Abstract] [Full Text] [PDF]
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 M. D. Hjelmeland, A. B. Hjelmeland, S. Sathornsumetee, E. D. Reese, M. H. Herbstreith, N. J. Laping, H. S. Friedman, D. D. Bigner, X.-F. Wang, and J. N. Rich SB-431542, a small molecule transforming growth factor-{beta}-receptor antagonist, inhibits human glioma cell line proliferation and motility Mol. Cancer Ther., June 1, 2004; 3(6): 737 - 745. [Abstract] [Full Text] [PDF]
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S. DaCosta Byfield, C. Major, N. J. Laping, and A. B. Roberts SB-505124 Is a Selective Inhibitor of Transforming Growth Factor-{beta} Type I Receptors ALK4, ALK5, and ALK7 Mol. Pharmacol., March 1, 2004; 65(3): 744 - 752. [Abstract] [Full Text] [PDF]
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 B. Guo, D. Koya, M. Isono, T. Sugimoto, A. Kashiwagi, and M. Haneda Peroxisome Proliferator-Activated Receptor-{gamma} Ligands Inhibit TGF-{beta}1-Induced Fibronectin Expression in Glomerular Mesangial Cells Diabetes, January 1, 2004; 53(1): 200 - 208. [Abstract] [Full Text] [PDF]
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H. Ungefroren, W. Lenschow, W.-B. Chen, F. Faendrich, and H. Kalthoff Regulation of Biglycan Gene Expression by Transforming Growth Factor-beta Requires MKK6-p38 Mitogen-activated Protein Kinase Signaling Downstream of Smad Signaling J. Biol. Chem., March 21, 2003; 278(13): 11041 - 11049. [Abstract] [Full Text] [PDF]
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K. Howe, J. Gauldie, and D. M. McKay TGF-beta effects on epithelial ion transport and barrier: reduced Cl- secretion blocked by a p38 MAPK inhibitor Am J Physiol Cell Physiol, December 1, 2002; 283(6): C1667 - C1674. [Abstract] [Full Text] [PDF]
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K. Singh, O. A. Batuman, H. O. Akman, M. H. Kedees, V. Vakil, and M. M. Hussain Differential, Tissue-specific, Transcriptional Regulation of Apolipoprotein B Secretion by Transforming Growth Factor beta J. Biol. Chem., October 11, 2002; 277(42): 39515 - 39524. [Abstract] [Full Text] [PDF]
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G. J. Inman, F. J. Nicolas, J. F. Callahan, J. D. Harling, L. M. Gaster, A. D. Reith, N. J. Laping, and C. S. Hill SB-431542 Is a Potent and Specific Inhibitor of Transforming Growth Factor-beta Superfamily Type I Activin Receptor-Like Kinase (ALK) Receptors ALK4, ALK5, and ALK7 Mol. Pharmacol., July 1, 2002; 62(1): 65 - 74. [Abstract] [Full Text] [PDF]
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, SB-202190; 
, SB-242235; 
,
SB-203580; 
, SB-431542.
); B, TGF-
