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Departments of Surgery and Medical Biochemistry, The Ohio State University, Columbus, Ohio 43210; and Department of Surgery, Childrens Hospital, Columbus, Ohio 43205
| Abstract |
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| I. Introduction |
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| II. The Modular Structure of Connective Tissue Growth Factor/Cysteine Rich 61/Nephroblastoma Overexpressed (CCN) Family Members |
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Module 1 is approximately 32% identical with the N-terminal cysteine-rich regions of the six "classic" IGF-binding proteins, IGFBP-1 to -6 (1), and contains a motif (GCGCCXXC) that is involved in binding IGF (17). 125I-labeled IGF-I or -II specifically binds recombinant hCTGF (rhCTGF) (12), although with much lower affinity than classic IGFBPs and more comparable to mac25, a low-affinity IGFBP, also termed IGFBP-7 or IGFBP-related protein (IGFBP-rP)-1 (18). Nov was also reported to bind IGFs (19), but this result has not proven reproducible (20). Recently, the terms IGFBP-8, -9, and -10 were introduced as synonyms for CTGF, nov, and cyr61, respectively (12), although it has since been proposed to use the names IGFBP-rP-2, -3, and -4 until their relationship to the classic IGFBPs has been determined (21). Indeed, a case against classifying the CCN family as IGFBPs has recently been made (22). Whatever the terminology, it remains unclear whether the interaction of IGFs with CCN family members occurs physiologically, whether sequences within module 1 are actually responsible for the observed binding of IGF, and what consequences this interaction has on the respective half-life, bioavailability, or activity of each of the molecules involved. However, there is general agreement that direct, IGF-independent effects of CTGF on the cell cycle are likely to be more significant than its low affinity binding of IGF (12, 22).
Module 2 comprises a Von Willebrand type C domain (VWC) that occurs in Von Willebrand factor as well as various mucins, thrombospondins, and collagens (1). Many proteins that contain VWC modules participate in oligomerization, which may be preceded by a dimerization event (23). Since module 4 of CTGF is a putative dimerization domain, module 2 may mediate the formation of complexes from CTGF dimers. Unlike all other CCN proteins, module 2 in WISP-3 contains only 6 of the 10 cysteines, the functional significance of which has yet to be established (24). Module 3 is a thrombospondin type 1 (TSP1) that contains the local motif WSXCSXXCG (1) and appears to be a cell attachment motif that binds sulfated glycoconjugates (1, 25, 26, 27). While cyr61 and CTGF promote cell adhesion (15, 16), the role of module 3 in this process remains unexplored.
Module 4 is a C-terminal (CT) module that also occurs in the C termini
of a variety of unrelated extracellular mosaic proteins (1). Six of the
10 cysteine residues in the CT module appear to adopt the cystine knot
motif that also occurs in nerve growth factor (NGF), transforming
growth factor-ß (TGF-ß), and platelet-derived growth factor (PDGF)
(1). This complex structure comprises two 2-stranded ß-sheets that
lie face-to-face and are linked by three interlocking disulfide bridges
and has defined a new superfamily of growth regulators (28, 29) to
which members of the CCN family (except orthologs of rCop-1, which lack
module 4; see below) may also belong. Since some of the receptor
binding properties of NGF, TGF-ß, and PDGF reside in variable regions
within the cystine knot (28), the CT module likely contains both
dimerization and receptor-binding domains (1). Although dimerization of
CCN proteins has not been reported, bioactive forms of 10-kDa porcine
CTGF (pCTGF) comprise the C-terminal 102 or 103 residues of the primary
translational product (Fig. 3
) (10) and thus support the proposed role
of module 4 in binding cell surface receptors (1). Module 4 is absent
from rCop and its orthologs (Figs. 1
and 3
), suggesting that they are
functionally distinct from other CCN proteins.
| III. Connective Tissue Growth Factor (CTGF) |
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B. Structure of the CTGF gene and protein
The fisp-12 gene comprises five exons and four introns
and spans 3.1 kb (Ref. 5 ; Table 2
). The
organization and structure of the hCTGF gene are very similar to that
of fisp-12 except that exon 1 encodes one additional amino
acid in the signal peptide (13, 36, 37). There is 80% sequence
identity between CTGF and fisp-12 in the 300 nucleotides
that lie immediately upstream of the mRNA cap site (36), and the
5'-regions of both genes contain a variety of conventional regulatory
elements as well as a unique TGF-ß response element (Fig. 4
). Fisp-12 maps to the A3-B1
region of murine chromosome 10 (5) and hCTGF maps to human chromosome
6q23.1 (38).
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C. CTGF mRNA production
Among the cell types that produce CTGF mRNA are fibroblasts (5, 14, 31, 35, 39, 41, 42), endothelial cells (13, 35, 43), vascular
smooth muscle cells (VSMC) (35, 44), epithelial cells (45, 46, 47),
chondroctyes (48), and glioblastoma cells (37).
Fisp-12/CTGF transcripts have been detected in
multiple tissues of at least four mammalian species (5, 12, 32, 35, 47, 49). Most studies have reported a single CTGF transcript of 2.4 kb,
although glioblastoma cells also contain 3.5-kb and 7.0-kb transcripts
(37). The 2.4-kb transcript is present in unstimulated fibroblasts (35, 39) but is rapidly induced after treatment with TGF-ß or serum and is
superinduced in stimulated fibroblasts in the absence of de
novo protein synthesis (5, 31, 41). These studies collectively
established that CTGF/fisp-12 are encoded by immediate early genes,
although their kinetics of induction are more rapid and sustained than
those of other immediate early genes (41). TGF-ß also increases CTGF
mRNA levels in cultured human or mouse lung mesenchymal cells (34) and
in human chondrocytic cells (48), the latter of which also produce CTGF
mRNA in response to bone morphogenic protein-2, a member of the TGF-ß
family (50). Using an enzyme-linked immunosorbent assay (ELISA),
TGF-ß treatment of human fibroblasts was shown to result in increased
production of the CTGF protein (51). The molecular basis for the action
of TGF-ß on CTGF gene transcription has been atributed to nucleotides
-157 to -145 of the hCTGF promoter (36). This region is a unique
TGF-ß-inducible element (Fig. 4
) that is fully conserved in the
promoter of the fisp-12 gene (5) but is absent from the
other parologs of the gene family (Fig. 4
) as well as from other
immediate early genes. In addition, inhibitors of protein kinase A, but
not of tyrosine kinases or protein kinase C, block TGF-ß-stimulated
CTGF transcription (52). Collectively, the TGF-ß response element and
the involvement of cAMP in CTGF mRNA production represent major
mechanistic differences in CTGF gene transcription as compared with
other CCN family members.
Although considerable attention has been directed toward the TGF-ß
inducibility of CTGF expression and the potential pathophysiological
consequences thereof (53), PDGF, epidermal growth factor (EGF), and
fibroblast growth factor (FGF) also stimulated hCTGF gene expression in
fibroblasts (41). As compared with the effects of TGF-ß on this cell
type, CTGF transcription is less robust in response to these growth
factors (41) and does not result in increased CTGF protein levels (51).
In contrast, pancreatic cancer cells of epithelial origin demonstrate
much stronger production of CTGF mRNA by EGF or TGF-
than TGF-ß,
although the lack of response to TGF-ß was due, at least partly, to
defects in TGF-ß signaling (54). Phenomenologically, the lack of
response to TGF-ß in certain pancreatic cells is similar to that of
skin epithelial cells, which (unlike fibroblasts) do not synthesize
CTGF in response to local TGF-ß administration in vivo
(14). Dexamethasone treatment of cultured 3T3 cells was recently shown
to stimulate CTGF expression while actually down-regulating TGF-ß
mRNA (55). Systemic administration of dexamethasone stimulated CTGF
expression in the heart, kidney, and skin. Basal and
dexamethasone-stimulated CTGF expression was strongly attenuated by
tumor necrosis factor-
(TNF-
) (55), which was independently shown
to suppress basal CTGF mRNA production in bovine aortic endothelial
cells (BAECs), fibroblasts, and VSMCs (35). Finally, increased CTGF
expression in renal epithelial cells in response to injury occurred
without an increase in TGF-ß expression (46). These results show, not
surprisingly, that mechanisms of CTGF gene regulation may be
cell specific and, in addition to the action of TGF-ß, involve a
variety of hormones, growth factors, and cytokines.
D. CTGF production, secretion, and processing
CTGF is present in HUVEC-conditioned medium (13) and undergoes
microsomal processing (5), consistent with the presence of a signal
peptide and its presumed secretion. CTGF mRNA is expressed in BAECs in
which it is present at higher levels during growth than confluence
(43). Similarly, expression of fisp-12 in cycling
fibroblasts is relatively high (15). CTGF produced by human foreskin
fibroblasts or mouse connective tissue cells under normal growth
conditions appears to be cell associated, long lived, and secreted
relatively inefficiently (39). On the other hand, fisp-12
was secreted efficiently from NIH 3T3 cells but was relatively unstable
in the medium (5). Kireeva et al. (15) showed that
fisp-12 was present in the cellular fraction, ECM, and
medium and that inhibition of lysosomal acid hydrolysis increased the
half-life of fisp-12 in the cellular fraction and stabilized
steady-state fisp-12 levels. These data suggest that
membrane-associated fisp-12 may form complexes with
receptors on the surface of fisp-12-producing cells that are
then internalized and degraded (15).
Various low mass (1020 kDa) forms of pCTGF were purified from uterine
secretory fluids and shown to commence between modules 2 and 3, at the
beginning of module 3, or between modules 3 and 4 (10, 11) (Fig. 3
).
Native 38-kDa pCTGF undergoes rapid proteolytic processing by uterine
fluids (11) and likely explains the presence of 38-kDa CTGF in uterine
tissues (32) but not in uterine fluids (10, 11). Native low-mass CTGFs
in uterine fluids are extremely stable, and their levels are strongly
correlated with those of CTGF-degrading proteases (11). Although
conditioned medium from serum-stimulated mouse fibroblasts did not
degrade fisp-12 (15), 10- to 12-kDa CTGF, but not 38-kDa
CTGF, was present in conditioned medium from cycling human or mouse
fibroblasts (39). Recently, Western blot analysis demonstrated 12- to
14-kDa C-terminal forms of CTGF in mouse uterine luminal flushings (47)
and 18- and 24-kDa CTGF isoforms in human serum and amniotic,
follicular, peritoneal, and cerebrospinal fluids (40). The presence of
CTGF in sera has been confirmed by ELISA (51). Whereas serum CTGF
levels in normal human subjects were less than 28 ng/ml, those of
patients with biliary atresia were up to 8-fold higher (51). These
results highlight potential diagnostic or prognostic applications of
measuring circulating or secreted CTGF levels.
Collectively, these data suggest that qualitative and quantitative aspects of CTGF secretion may be regulated by numerous factors including stage of cell cycle, growth factor pretreatment, cell type, species and tissue of origin, and protease activity of the pericellular environment. Moreover, the presence of CTGF in a variety of body fluids suggests that they may be important reservoirs of CTGF in vivo.
E. CTGF-heparin interactions
Heparin-affinity chromatography has been used to purify 38-kDa
rhCTGF (14) and 10- to 20-kDa pCTGF (10, 11), the latter of which are
eluted from heparin by 0.8 M NaCl. 35S-labeled
fisp-12 binds to heparin-agarose beads and is eluted by 0.4
M NaCl (15). Although module 3 is a binding motif for
sulfated glycoconjugates (1), residues 247260, 274286, and 305328
of hCTGF bind strongly to heparin (10, 56). Residues 247260 contain a
proposed heparin-binding consensus sequence (XBBXBX) that occurs in a
variety of heparin-binding proteins (57).
As with other heparin-binding growth factors, such as FGFs, heparin-binding EGF-like growth factor, amphiregulin, keratinocyte growth factor, and vascular endothelial growth factor (58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70), the biological activity of CTGF is modulated by heparin (10, 14). The binding of fisp-12 to heparin has been proposed as the basis for the association of fisp-12 with the ECM in cultured cells (15). Heparin-like molecules on the cell surface or in the ECM may constitute a high-capacity, low-affinity binding reservoir for CTGF and thereby regulate its activity, bioavailability, or stability. Indeed, the half-life of fisp-12 in ECM (1 h) is much less than that of cyr61 (4 h) and appears to correlate with the relative affinity of each paralog for heparin (15, 71).
F. Biological properties of CTGF
Native 38-kDa hCTGF is a mitogenic and chemotactic factor for NIH
3T3 cells in vitro (13). Ten-kilodalton forms of pCTGF are
mitogenic for Balb/c 3T3 cells, VSMCs, and endometrial stromal cells,
but not endothelial cells (10, 56). The mitogenic activity of 38-kDa
rhCTGF or 10-kDa pCTGF on fibroblasts is enhanced by EGF, PDGF, basic
FGF (bFGF), or IGF-I and is either enhanced or reduced by heparin
according to the CTGF-heparin ratio (10, 14). In monolayer cultures of
normal rat kidney (NRK) cells, 38-kDa rhCTGF stimulated DNA synthesis
and induced expression of type 1 collagen, fibronectin, and
5
integrin (14), as is characteristic of the effects of TGF-ß. These
various biological effects are elicted by CTGF concentrations of about
120 ng/ml. In vivo, injection of TGF-ß or CTGF into the
dermal/subcuticular area of the skin in neonatal mice produced nodules
comprising mainly connective tissue cells and ECM (14, 72), suggesting
that CTGF plays a role in TGF-ß-mediated formation of granulation
tissue. Recombinant hCTGF is also mitogenic for human lung fibroblasts
(73). However, recombinant 38 kDa fisp-12 did not directly
stimulate DNA synthesis in HUVECs or 3T3 cells at 0.33 µg/ml (15),
although other evidence suggests that endothelial cells do not respond
mitogenically to 10-kDa CTGF, which is nonetheless mitogenic for 3T3
cells and VSMCs (10). At 0.33 µg/ml, the same fisp-12
protein enhanced the mitogenic activity of 10 ng/ml bFGF on HUVECs
and NIH 3T3 cells and promoted attachment of HUVECs, NIH 3T3 cells,
AKR2B cells, and mink lung epithelial cells at 520 µg/ml (15).
These latter effects occurred at 100- to 1000-fold higher
concentrations than were needed for the stimulation of mitosis,
chemotaxis, or ECM production by CTGF in other studies (10, 13, 14).
Nonetheless, a role for CTGF in cell adhesion is further supported by
the localization of CTGF in ECM (15) and by the ability of antisense
CTGF to suppress growth and migration of BAECs in vitro
(43). While 38-kDa CTGF appears to be proteolytically cleaved into low
mass derivatives (11), the relationship (if any) between processing and
activity remains undefined.
Although TGF-ß induces CTGF expression and CTGF mimics some of the effects of TGF-ß in fibroblasts, CTGF-independent pathways of TGF-ß action have been identified in these and other cell types. For example, TGF-ß is a potent inhibitor of the growth of mink lung epithelial cells, whereas CTGF is not (14). In addition, while CTGF and TGF-ß both stimulate DNA synthesis in monolayer cultures of NRK cells, only TGF-ß is able to stimulate anchorage-independent growth (AIG) of the same cells (14, 74). AIG induced by TGF-ß is antagonized by CTGF antibodies or antisense CTGF and is restored by addition of CTGF to TGF-ß-stimulated cells showing that CTGF is involved in the stimulation by TGF-ß of this process (74). Since CTGF was induced by TGF-ß in these cells, it was proposed that both CTGF-dependent and -independent pathways are involved in the stimulation of AIG by TGF-ß (74). The induction of CTGF mRNA and AIG by TGF-ß in NRK cells is inhibited by elevated cAMP levels (52). This effect was reversed by addition of CTGF, but not other growth factors, and was attributed to a CTGF-specific restriction point in late G1 of TGF-ß-activated cells (52).
G. Mechanism of action of CTGF
In addition to contributing to TGF-ß-mediated AIG (see above),
CTGF interacts synergistically with EGF, PDGF, IGF-I, or bFGF (10, 14, 56), suggesting that it activates distinct receptors and/or signaling
pathways to those used by other growth factors. Although 38-kDa hCTGF
was suggested to bind PDGF receptors (13, 75), this possibility was not
supported using a mitogenic form of 10-kDa murine CTGF (39).
Binding studies with 125I-labeled 38-kDa rhCTGF have
demonstrated the presence of specific high- and low-affinity binding
sites and a 280-kDa cross-linked CTGF complex (76). Although there was
no clear evidence for a signal-transducing receptor, these data are
nonetheless potentially very exciting. Alternatively, CTGF may function
primarily as a cell adhesion molecule that regulates cell function
either directly through its association with the ECM or indirectly by
synergizing with other growth factors (15).
| IV. Cyr61 |
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B. Structure of the cyr61 gene and protein
The murine cyr61 gene comprises five exons and four introns that
span 3.1 kb (Table 2
) and contains a serum-response element (SRE) (Fig. 4
) in the 5'-region that mediates serum- or PDGF-induced gene
transcription (6). Induction of cyr61 is similar to that of other
immediate early genes that contain SREs, consistent with its
coordinated expression with c-fos during G0 to
G1 (81), although its transcriptional suppression is
relatively inefficient (6). Although cyr61 expression is induced by
TGF-ß (31), its promoter lacks the novel TGF-ß response element
found in the promoter of CTGF (36) (Fig. 3
). Human cyr61 maps to p22.3
on chromosome 1 (80, 82). The mouse cyr61 gene encodes a 379-residue
protein, which, after signal peptide cleavage, yields a 355-residue
protein containing 38 conserved cysteine residues (31, 78) (Fig. 1
).
The cysteine-free portion of cyr61 is about twice the length of that in
other CCN paralogs (Fig. 1
).
C. Cyr61 mRNA production
A single cyr61 transcript of 2.4 kb has been reported in mouse
AKR2B cells, 3T3 fibroblasts, and PSA-1 teratocarcinoma cells (31, 77, 81, 83) and rat H197 embryonic neuronal hippocampal cells (84). A
1.8-kb cef-10 transcript is present in CEFs (79), and two cyr61
transcripts of 2.5 kb and 3.54 kb have been described in human
tissues (80, 82). Although cef-10 mRNA is expressed principally in the
adult lung (79), cyr61 is expressed in multiple adult tissues of the
mouse and human such as heart, uterus, skeletal muscle, and lung (49, 78, 80). Transcript levels in other tissues are variable and likely due
to differences in mRNA detection techniques as well as in the stage of
development or differentiation of the source material. For example,
human cyr61 mRNA expression is higher in the kidney of the fetus than
that of the adult (80). Cyr61 mRNA is present at high levels in mouse
embryos on days 9.514.5, whereas placental expression of cyr61 is
highest on days 17.518.5 (83).
Cyr61 gene expression is stimulated by diverse molecular signals, which
supports its role in a variety of biological processes. In mouse cells,
cyr61 mRNA is rapidly induced by serum, PDGF, FGF, TGF-ß, phorbol
ester, or cholera toxin (31, 77, 78, 81). Serum stimulation of Balb/c
3T3 cells resulted in a rapid increase and sustained high levels of
cyr61 mRNA, which were stabilized by cyclohexamide (78). Similarly,
human cyr61 mRNA is present in proliferating, but not quiescent, skin
fibroblasts (49). In CEFs, transcription of cef-10 is rapidly enhanced
by pp60v-src or serum (79). In human osteoblasts, cyr61
expression is enhanced by EGF, PDGF, and interleukins-1ß, -2, and -6,
as well as by 1
,25-dihydroxyvitamin D3, a mediator of
osteoblast differentiation and function (85). In the rat uterus, cyr61
is estrogen-responsive and strongly induced by tamoxifen (86). In rat
H197 cells, cyr61 is induced within 1 h by bFGF, a stimulator of
neuronal differentiation in this cell type (84). This process appears
to involve both mitogen-activated protein kinase-dependent and
-independent pathways (84).
D. Cyr61 production and secretion
The 41-kDa mouse cyr61 protein is present at very low amounts in
quiescent Balb/c 3T3 cells but reaches peak levels within 2 h of
serum stimulation (78). Cyr61 is differentially distributed in the ECM,
cellular fraction, or cell surface rather than the medium (71, 78). The
extracellular fate and half-life of cyr61 synthesized in response to
mitogenic stimulation were shown to be dependent upon the stage of the
cell cycle and presence of binding moieties in the ECM and on cell
surfaces such as heparin-like molecules from which cyr61 is eluted by
0.60.8 M NaCl (16, 49, 71).
E. Biological properties of cyr61
Recombinant murine cyr61 promotes dose-dependent attachment of
HUVECs or NIH 3T3 cells to plastic surfaces coated with 330 µg/ml
of the protein (16). Similar concentrations of cyr61 also stimulate
dose-dependent chemotaxis of NIH 3T3 cells (16) and human microvascular
endothelial cells (HMVEC) (87). These concentrations of cyr61 were not
mitogenic for NIH 3T3 cells or HUVECs, although they did potentiate the
mitogenic activity of bFGF for these cell types (16, 49). This latter
effect was abolished by cyr61 antiserum and attributed to the
displacement by cyr61 of bFGF from the ECM, thus increasing the
effective concentration of soluble bFGF (16, 49). In mouse limb bud
micromass cultures, cyr61 promoted expression of type II collagen,
incorporation of sulfate, and the production of cartilage nodules (88).
Moreover, cyr61 promoted the adhesion and aggregation of limb bud
mesenchymal cells. Cyr61 was also a weak stimulator of DNA synthesis
and proliferation of limb mesenchymal cells (88). Cyr61 was further
shown to promote chondrogenesis in cell cultures seeded at subthreshold
densities that do not normally undergo chondrogenic differentiation.
These various responses were elicted with 0.35 µg/ml cyr61. Limb
bud micromass cultures showed reduced levels of chondrogenesis when
incubated with neutralizing cyr61 antisera, suggesting that endogenous
cyr61 plays a normal physiological role in chrondrogenic
differentiation (88). Finally, cyr61 has been shown to induce
neovascularization in vivo (87), consistent with its
stimulation of directed migration of HMVECs in vitro (87).
Stable transfection of cyr61 cDNA into RF-1 gastric adenocarcinoma
cells had no effect on in vitro growth rate, yet produced
larger tumors in immunocompromized mouse hosts as compared with a
vector control, a phenomenon that was attributed to cyr61-stimulated
tumor vascularization (87).
F. Mechanism of action of cyr61
A mechanistic framework for the biological properties of cyr61 has
been provided by the finding that cyr61 binds to integrin
vß3, which represents the first (and only)
molecularly defined receptor for any member of the CCN family (89). The
interaction of
vß3 with cyr61 may account
for its promotion of chemotaxis and growth factor-mediated DNA
synthesis as well as cell adhesion since integrins are known to
modulate cell migration and growth factor signaling in other systems
(90). As well as demonstrating a direct interaction between the two
molecules in binding assays in vitro (89), cyr61-mediated
adhesion and migration of cultured endothelial cells were specifically
inhibited by the peptide RGDS and/or antiintegrin
vß3 (87, 89). In addition to its
integrin-binding property, cyr61 appears to be localized to its site of
synthesis by associating with the ECM, possibly by binding to
heparin-like molecules. This interaction may limit the extent of cyr61
diffusion so that its site of action is in close proximity to its site
of synthesis (15).
| V. Nov |
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Putative transciption factor-binding sites are present in the
5'-untranslated region of several nov genes (8, 33, 38, 92)
(Fig. 4
). However, SREs and the TGF-ß response element are absent,
suggesting that transcriptional regulation of nov is distinct from that
of CTGF or cyr61. The activity of the novH promoter is repressed in the
presence of the Wilms tumor suppressor gene WT-1 (94). While WT-1
binding sites are present in the novH promoter (Fig. 4
), WT-1-mediated
repression of novH transcription was experimentally attributed to other
domains in the promoter (94).
The primary translational products of nov orthologs are predicted to
comprise between 343 and 357 amino acids and to contain 38 conserved
cysteine residues (Fig. 1
). The signal peptide in novH appears to
comprise 27 residues (8). In CEFs, an immunoreactive 46-kDa novC
protein was localized to the ECM (93), although the underlying
mechanisms and functional significance remain unclear. NovH produced in
transfected Madin Darby canine kidney cells is a glycosylated protein
that is secreted about 1.5 h after synthesis and requires 0.5
M NaCl for elution from heparin (20). Secreted novH has a
half-life of more than 18 h, which is more than 10 times that of
intracellular novH (20). Levels of the endogenous 46-kDa novH protein
are repressed in 293 kidney cells that constitutively express WT1 (94).
B. Nov mRNA production
A single 2.2-kb novC transcript is usually detected in
MAV1-induced nephroblastomas (7). An exception was a tumor in which
MAV1 integrated within the novC gene itself, resulting in the
production of a 2.0-kb transcript (7). The 2.2-kb novC mRNA
transcript was detected at high levels in the brain and heart of
day 18 chick embryos, with weak signals in muscle and intestine and
nondetectable levels in liver, lung, and yolk sac. In the adult, 2.2-kb
novC mRNA was expressed at high levels in brain and lung, at low levels
in the spleen, and was nondetectable in heart, muscle, and liver (7).
Quiescent cultures of CEFs contain a 2.2-kb novC transcript that is
down-regulated during proliferation, mitogenic stimulation, or
activation of viral oncogenes (95). NovH is normally expressed as a
2.5-kb transcript in human glioma cell lines and Wilms tumors, although
an additional novH mRNA of 1.2 kb was observed in a single Wilms tumor
(8, 37). Unlike novC, this smaller transcript was not the result of
rearrangement of the novH gene (8).
There is little, if any, experimental evidence supporting a role for nov as an immediate early gene. As explained above, there are no motifs in the nov gene promoter that resemble either a SRE or a TGF-ß response element. Serum stimulation of kidney-derived 293 cells or CEFs failed to increase nov mRNA levels within 90 min, even though the genes for CTGF and jun were rapidly activated (93). Moreover, in normal CEFs, nov was expressed in quiescent cells but down-regulated in proliferating cells (95). In contrast to cef-10, expression of p60v-src in CEFs resulted in transcriptional down-regulation of the novC gene (95). NovC expression was also repressed by the viral oncogenes v-erbB, v-mil, and v-crk (95). In addition, mRNA destabilization sequences in the 3'-region are absent from most nov orthologs (except xnov), suggesting that nov RNA degradation is regulated differently from that of CTGF, cyr61, and other immediate early genes.
C. Biological properties of nov
Overexpression of full-length novC cDNA was shown to inhibit the
growth of CEFs grown in soft agar (7). In contrast, transformation of
CEFs occurred after overexpression of an N-terminally truncated form of
novC that initiated at Met99 and was thus comparable to
that expressed after integration of MAV-1 into the novC gene (Fig. 3
)
(7). This truncated form of nov also induced morphological
transformation of rat embryo fibroblasts (8). Within the CCN family,
the ability to function as a protooncogene is thus far unique to nov.
The dramatic biological differences between the normal and truncated
nov genes have led to suggestions that nov is a growth suppressor gene,
truncation of which results in oncogenic activation. These
interpretations are consistent with the low levels of nov mRNA in
mitogen-stimulated cells and the high levels of nov mRNA in resting
cells (93, 95). Although the truncated nov protein lacked the signal
peptide and the IGF-binding motif in module 1, it is not known how the
loss of one or both of these domains contributes (if at all) to its
transforming properties.
| VI. Elm1/WISP-1 |
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| VII. Heparin-Induced CCN-Like Protein (HICP)/rCop-1/CTGF-3/WISP-2 |
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30% with hCTGF and conservation of all of
the cysteine residues in modules 13 (Fig. 1| VIII. WISP-3 |
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| IX. Other CCN-Like Molecules |
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| X. Regulation of Cellular Functions by the CCN Family |
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In addition, each CCN family member appears to further regulate the cell cycle through their 1) direct mitogenic action (e.g., CTGF); 2) potentiation of the mitogenic activity of other growth factors (e.g., CTGF, cyr61); 3) binding of IGFs (e.g., CTGF); 4) regulation of ECM synthesis (e.g., CTGF, cyr61); 5) regulation of cell attachment and migration (e.g., CTGF, cyr61, elm1); 6) interactions with the ECM (e.g., CTGF, cyr61, nov); 7) oncogenic properties (e.g., nov); and 8) regulation of a cell cycle restriction point (e.g., CTGF). This broad spectrum of biological properties, many of which are interacting and interdependent, demonstrate the complexity by which the cell cycle is likely regulated by the CCN family.
B. Cell adhesion and migration
In vitro studies have shown that CTGF or cyr61 are
chemotactic and promote cell adhesion (13, 15, 16, 87). Elm1 is
expressed in low, but not high, metastatic cell lines and, when
transfected into high-metastatic cell lines, causes them to exhibit
slower rates of tumor growth and decreased incidence of metastasis
(97). Truncated nov stimulates AIG and colony formation in CEFs (7).
Collectively, these data demonstrate broad effects on cell adhesion and
locomotion, which likely reflects the ability of CCN family members to
regulate the composition of the ECM, the net balance between its
synthesis and degradation, as well as to bind directly to ECM
components such as integrins and heparan sulfate proteoglycans (see
below).
C. ECM production
Tissue formation and cell proliferation and differentiation are
dependent upon interactions between cells and the ECM. In processes
such as tissue remodeling and malignancy, ECM components are degraded
by proteases such as collagenase, plasmin, and matrix metalloproteases,
and the ability of cells to interact with the ECM is altered or
abolished. TGF-ß plays a central role in ECM production since it
stimulates synthesis of ECM proteins such as collagen, fibronectin,
laminin, elastin, glycosaminoglycans, and other glycoproteins as well
as synthesis of inhibitors of ECM degradation such as plasminogen
activator inhibitor and tissue inhibitors of metalloproteases (110). In
view of the TGF-ß-inducibility of CTGF and cyr61 gene expression,
these molecules may promote ECM deposition by stimulating synthesis of
ECM components and inhibiting their degradation. While detailed studies
of the regulation of ECM-degrading enzymes and their inhibitors by the
CCN family have yet to be reported, initial studies have shown that
38-kDa CTGF enhances fibronectin, type IV collagen, and integrin
production (14) and that cyr61 stimulates type II collagen production,
albeit in a specialized cell type (88). As discussed below, numerous
fibrotic disorders exhibit substantial ECM involvement and expression
of CTGF. In addition, there is a striking appearance of CTGF in uterine
stromal cells that are undergoing decidualization (47), a highly
regulated process involving increased mitosis and synthesis and
deposition of ECM molecules such as desmin, laminin, and fibronectin
(111). ECM production and remodeling is also a critical component of
development and differentiation during embryogenesis (112).
Collectively, these data suggest that CTGF may exert diverse and
important functions in normal physiology and pathological states via
its net induction of ECM protein deposition and content.
| XI. Biological Processes Involving the CCN Family |
|---|
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|
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Evidence to date supports a role for cyr61 and CTGF in chondrogenesis. The cyr61 protein is present in cartilage and bone in day 1318 mouse embryos (15, 88), and cyr61 mRNA is present in a variety of developing cartilaginous structures in day 8.514.5 embryos (83). A role for cyr61 in normal growth and development of the cartilaginous skeleton is further supported by the ability of cyr61 to stimulate collagen synthesis, sulfate incorporation, and formation of cartilage nodules in mouse limb bud micromass cultures, and adhesion, aggregation, and growth of limb bud mesenchymal cells (88). In the case of CTGF, its mRNA is present in hypertrophic chondroctyes from day 17 mouse embryos, neonatal rabbit growth cartilage tissue and cultured cells, and human chondrocytic cell lines, but not in human osteosarcoma or mouse osteocytic cell lines (48). In cultured rabbit growth cartilage cells, peak levels of CTGF occurred during the early hypertrophic stage. CTGF mRNA levels in these cells were enhanced by treatment with TGF-ß or bone morphogenic protein-2 (48). In addition to its potential role in chondrogenesis, cyr61 may also be involved in hippocampal differentiation, since it is induced in H197 cells by bFGF, which stimulates their differentiation into nonproliferative neuronal cells (84).
Several lines of evidence support a role for nov nephrogenesis. First, novC expression occurs in normal avian kidney cells of the embryo and neonate, yet is barely detectable in adult kidney cells (7). Second, ureteric buds, which give rise to the kidney collecting ducts, fail to demonstrate outgrowth in WT-1-null mice; as discussed above, novH promoter activity is repressed by WT-1, and a reciprocal quantitative gradient of novH and WT1 expression occurs during normal human nephrogenesis (see Ref. 94). Third, novH is localized to differentiating glomerular podocytes where it accumulates and may regulate podocyte structure or function during both pre- and postnatal life (20). Since the composition of the ECM changes during the earliest stages of metanephric induction (113) and ECM components regulate uteric bud morphogenesis, nov may also influence nephrogenesis by binding to the ECM (93).
B. Female reproductive tract function
The actions of ovarian steroids are mediated, in part, by
polypeptide growth factors, which may also contribute to the
uterine-embryo signaling dialogue that initiates implantation and
stimulates embryonic development (114, 115, 116, 117, 118, 119, 120). Also, some growth factors
are secreted into the uterine lumen or localized at the implantation
site, where they may stimulate development of the embryo and placental
membranes (114, 121). CTGF is present in uterine fluids of the pig and
mouse, as well the uterus of the pig, mouse and human (10, 11, 13, 47, 56, 122) suggesting that it is involved in the regulation of uterine
function. In uterine fluids, the levels of low mass CTGFs and CTGF
proteases are highly correlated with each other and show cyclic
variations during the estrous cycle (11). Moreover, there are clear
differences in the levels of CTGF and CTGF protease(s) in uterine
fluids at equivalent stages of the estrous cycle and early pregnancy
suggesting that CTGF production or action is modified in the presence
of the embryo (11, 56). A relationship between CTGF expression and
TGF-ß action during the periimplantation period of the pig is
supported by the presence of both molecules at this time in uterine
and/or embryonic tissues (11, 123, 124, 125). In addition, a direct role of
CTGF on uterine cells is indicated by its stimulation of DNA synthesis
in pig stromal cells in vitro (56).
In mice and women, CTGF is localized primarily to uterine luminal and glandular epithelial cells during the estrous cycle and during the first few days of pregnancy (47, 122). On the day of implantation in mice, epithelial staining for CTGF is strongly reduced and is followed over the next 2 days by profound staining of decidualizing endometrial stromal cells, suggesting that CTGF contributes to the decidualization process or is produced as a result of it (47). Decidualization is a highly regulated differentiation process involving increased vascular permeability, DNA synthesis, and synthesis and deposition of ECM molecules (111, 126, 127, 128). The distribution of uterine CTGF during early pregnancy in the mouse does not entirely correlate with TGF-ß and its receptors, suggesting that TGF-ß-independent synthesis of CTGF may be operative (47). Alternative mechanisms may involve glucocorticoids or estrogen, which stimulate CTGF and cyr61 gene transcription, respectively (55, 86). The nonconcordance of CTGF and TGF-ß may also be related to the initial production of TGF-ß in a latent form (129). Whatever the explanation, these data support a role for uterine CTGF at the time of implantation.
C. Angiogenesis
Angiogenesis, the formation of new capillaries from preexisting
blood vessels, occurs in processes such as tumor growth, diabetic
retinopathy, wound healing, and placental vascularization. It is a
complex process that involves degradation of the capillary basement
membrane, migration and proliferation of endothelial cells, and tube
formation; it is regulated by many factors (130), including cyr61,
which promotes directed migration of HMVECs via
vß3-integrin and induces
neovascularization in the rat cornea (87). Expression patterns of cyr61
support its contribution to angiogenesis in the embryo, placenta,
hypertrophic cartilage, wounds, and tumors (83, 87). Since cell
migration is the only component of angiogenesis to be directly
stimulated by cyr61, indirect effects of cyr61, such as release and
action of the angiogenic factor bFGF from ECM (16, 49), may contribute
to the overall process of neovascularization. These questions and the
role of other CCN family members in angiogenesis will require further
study.
D. Wound repair
Many studies have established that growth factors, including
TGF-ß, are involved in wound healing (see Ref. 131). Collectively,
CTGF and cyr61 exhibit numerous biological properties that are of
potential importance in the wound healing response, including
stimulation of cell proliferation, cell adhesion, chemotaxis,
angiogenesis, production of ECM components, and augmentation of bFGF
activity. Early studies showed that cyr61 gene expression was induced
during the first hour of liver regeneration in the mouse after partial
hepatectomy (132). These results are consistent with the role of cyr61
as an immediate early gene and demonstrate that cyr61 is
transcriptionally activated as a response to injury. In tissue from
within subcutaneously implanted Schilling chambers in rats (133), CTGF
expression peaked on day 9 of injury after peak expression of TGF-ß
on day 3 (41). The coordinate expression of the two factors was
interpreted as a component of a growth factor cascade in which TGF-ß
initiated regeneration and repair and stimulated the production of
CTGF, which was required later in the wound healing process (41).
Somewhat different kinetics of gene transcription have been reported in
full thickness wounds in which CTGF and TGF-ß both exhibited peak
expression 1224 h after injury (55, 134). Although dexamethasone was
shown to stimulate CTGF gene expression in uninjured tissue, it did not
affect CTGF mRNA levels in wounded tissues and was attributed to the
presence of TNF-
, which inhibits CTGF gene expression (35, 55).
Finally, scrape wounding BSC-1 renal epithelial cells resulted in
stimulation of CTGF gene expression, which reached peak levels 4 h
after injury (46). CTGF was induced both in cells at the wound and some
distance from it, suggesting that an inductive signal was communicated
to distant cells from the initial wound site, although there were no
changes in expression levels of TGF-ß, PDGF, or bFGF (46).
E. Fibrotic disorders
Many fibrotic disorders are typified by excessive connective
tissue and ECM formation and exhibit marked overexpression of TGF-ß,
which is fibrogenic and strongly linked to the pathogenesis of these
diseases (135, 136, 137). In view of the biological activities of CTGF and
the link between CTGF production and TGF-ß action, studies have
recently been initiated to examine the role of CTGF in fibrotic
disorders of the skin, kidney, lung, and blood vessels. Subcutaneous
injection of TGF-ß into neonatal mice, which causes a rapid increase
in the amount of granulation tissue comprising connective tissue cells
and abundant ECM, was shown to result in enhanced levels of CTGF mRNA
in connective tissue fibroblasts but not in epithelial cells or
endothelial cells (14, 72). Injection of 38-kDa rhCTGF caused a very
similar fibrotic reaction as TGF-ß in terms of histological findings,
time course, and area affected (14). This fibrotic response was
specific to TGF-ß and CTGF and not mimicked by EGF, PDGF, or bFGF
(14, 72).
Overexpression of CTGF mRNA occurs in a variety of fibrotic skin disorders including 1) systemic sclerosis in which CTGF expression is temporally associated with the sclerotic phase and is highest in the fibroblasts of the deep dermis (42); 2) localized sclerosis in which CTGF-positive fibroblasts are scattered throughout the lesion (138); 3) keloids in which CTGF-positive fibroblasts are present throughout the lesion but concentrated in the expanding peripheral regions (138); and 4) scar tissue, eosinic fasciitis, nodular fasciitis, and Dupuytrens contracture in which CTGF was partially expressed in some of the fibroblasts (138).
In kidney fibrosis, CTGF expression is increased in inflammatory glomerular and tubulointerstitial lesions, as compared with normal kidney or noninflammatory glomerular lesions (139). Extracapillary proliferative lesions, capsular adhesions, and periglomerular fibrosis were characterized by a pronounced increase in epithelial expression of CTGF. CTGF expression was also somewhat increased in mesangial proliferative lesions of diabetic and IgA nephropathies (139). In a rat model of glomerulonephritis, CTGF mRNA was up-regulated in parietal epithelial cells and podocytes, where it was expressed in areas of crescentic extracapillary proliferation, periglomerular fibrosis, and in interstitial foci (140). Cultured mesangial cells and podocytes demonstrated enhanced CTGF mRNA in response to TGF-ß (140) or under hyperglycemic conditions (141), the latter of which causes ECM deposition and induction of TGF-ß1 (142).
In bleomycin-induced fibroproliferative lung disease in mice, which is characterized by up-regulation of TGF-ß mRNA (143, 144), bleomycin treatment of sensitive mice resulted in a 2- to 3-fold increase in lung CTGF mRNA levels and collagen synthesis as compared with resistant mice (34). CTGF is present at higher levels in bronchoalveolar lavage fluid from patients with fibrosing alveolitis as compared with normal individuals, and lung fibroblasts from patients with scleroderma-associated fibrotic lung produce more CTGF in response to TGF-ß than control cells (145). An autocrine role for CTGF in lung growth is supported by the expression of CTGF mRNA in murine lung (5) and in cultures of human or mouse lung mesenchymal cells in which it is rapidly induced by TGF-ß (34) and its stimulation of mitosis and collagen synthesis in fibroblasts (73, 145).
CTGF mRNA is expressed in atherosclerotic vessels at 50- to 100-fold the level of that in normal arteries (44). In advanced atherosclerotic lesions, CTGF was localized to VSMCs and endothelial cells primarily at sites of ECM accumulation and fibrosis, including the shoulders of fibrous caps (44, 139, 146). VSMCs respond mitogenically to CTGF (10) and produce CTGF mRNA in response to TGF-ß (44, 146), consistent with the presence of a CTGF autocrine loop that is initiated by TGF-ß. Although the potential involvement of CTGF in stimulating intimal thickening is highly deleterious, it has been argued that CTGF-stimulated ECM production may actually stabilize the fibrous cap and reduce the chance of plaque rupture (146). Finally, the association between HICP expression and growth arrest in VSMCs (98) suggests that attenuation of HICP may contribute to hyperplastic VSMC diseases such as athero- and arteriosclerosis.
The profibrotic properties of CTGF suggest that it is an attractive therapeutic target in a variety of fibrotic disorders, especially as it operates downstream of TGF-ß (53, 136). Intervention at the level of CTGF would still allow certain beneficial non-CTGF-dependent effects of TGF-ß (e.g., antiinflammatory) to persist while negating its fibrogenic action. Over the next few years we can expect to see a careful evaluation of all components of the CTGF pathwayits gene, mRNA, transcription factors, protein, receptor, and second messengerswith the goal of finding optimal molecular targets for the control of CTGF-mediated fibrosis.
F. Inflammation
In addition to inflammatory kidney disease (see above), CTGF is
overexpressed in inflammatory bowel diseases (IBD) such as Crohns
disease and ulcerative colitis (147). IBD demonstrated high levels of
CTGF, TGF-ß, collagen type I, fibronectin, and integrin
5. CTGF
was overexpressed in regions of inflammation and in noninflamed regions
that were stenosed and was present in the vicinity of TGF-ß-producing
cells (147). CTGF was thus proposed to promote mesenchymal tissue
repair and remodeling after the acute inflammatory phase and to
stimulate chronic matrix deposition leading to fibrosis and stenosis
(147).
G. Tumor growth
Several lines of evidence support a role for CCN molecules in
tumorigenesis, the most compelling of which is the oncogenic property
of N-terminally truncated nov (7). The tumorigenicity of a gastric
adenocarcinoma cell line was increased when transfected with cyr61, the
angiogenic properties of which support its role in tumor growth and
vascularization (87). Consistent with its profibrotic properties, CTGF
is overexpressed in breast cancer, pancreatic cancer, and melanomas
exhibiting significant involvement of connective tissue cells
(desmoplasia) (54, 148, 149). Similarly, WISP-1 and WISP-2 are strongly
expressed in the fibrovascular stroma of breast tumors from Wnt-1
transgenic mice (24). CTGF is expressed in sarcoma and chondrosarcoma
cells (39, 48), while cyr61 is expressed in rhabdomyosarcoma and cell
lines derived from malignant melanoma, breast and colon adenocarcinoma,
and bladder papilloma (87, 150). Tumors of the nervous system express
CTGF, nov, and cyr61 in a complex and mainly noncorrelative pattern
(37, 82).
Elevated expression of novC mRNA was a consistent finding in all MAV1- and MAV2-induced avian nephroblastomas (7, 93). While novC was expressed most highly in differentiated tumors (7), its levels are more correlated with tumor age than histological status (93). In Wilms tumors, novH is mainly overexpressed in tumors of predominantly stromal origin (8) and is positively correlated with heterotypic muscle differentiation (20). Nov expression is inversely correlated with the levels of WT-1 mRNA in some (8, 93), but not all (20), studies. Since WT-1 and several viral oncogenes repress nov expression in vitro (94, 95), these variable results demonstrate that the relationship between nov expression and tumorigenesis is complex and that nov transcription mechanisms in both normal and tumor cells requires further study. Despite its apparent role as a growth arrest gene in transfected cells (7), the potential role of nov in growth arrest may be cell type specific or secondary to other biological functions in tumors, thereby accounting for its overexpression in some nephroblastomas (7, 93). Nonetheless, the absence of the IGF binding motif in oncogenic nov and the coexpression of nov and IGF-II in some avian renal tumors and Wilms tumors suggest a possible link between nov and IGF in nephroblastoma (93).
The inverse relationship between nov expression and phenotype of some nephroblastomas is shared with other CCN family members in other tumors. For example, elm1 expression is inversely correlated with the incidence of metastasis and growth of melanoma cells (96, 97). In addition, inverse correlations have been reported between malignant phenotype and the level of CTGF expression in fibroblast and endothelial cell tumors (151), and the level of cyr61 expression in neuroblastoma (83) and prostate cancer (152). On the other hand, rCop-1 is underexpressed in transformed cells and is a negative regulator of the growth of transformed, but not normal, cells (99). Colon tumors demonstrate underexpression of WISP-2 and overexpression of WISP-1 and -3 while in breast tumor models both WISP-1 and -2 are involved in the Wnt signaling pathway that leads to cell transformation (24). Collectively, the individual CCN family members appear to be over-, under-, or randomly expressed in a variety of tumors, and it is currently impossible to establish a unifying hypothesis for the CCN family in tumor growth.
| XII. Perspectives and Future Directions |
|---|
|
|
|---|
Many additional questions remain unanswered. Are there other members of the CCN family? Do CCN proteins physiologically bind IGFs and, if so, what are the consequences? Are there unique signal-transducing receptors for CCN proteins? What signaling pathways are activated when CCN proteins bind to cell surfaces? What are the identities of CTGF proteases and how are they regulated? What are the biological consequences of the absence of module 4 in rCop-1 and the absence of the cysteine residues in module 2 of WISP-3? Why is nov overexpressed in some nephroblastomas if it is a growth arrest gene? How does cyr61 promote angiogenesis? What other disease states involve the CCN family? What is the relationship between the CCN family and endocrine function? With recent interest in the field, rapid progress in answering some of these questions can be expected in the near future.
In conclusion, the CCN family comprises highly related modular proteins that have wide ranging properties that impact cellular functions such as growth, differentiation, adhesion, and locomotion. The biological properties and actions of CCN proteins are probably complex and likely reflect a dynamic equilibrium of their constituent modules with soluble, cell surface, or ECM-binding proteins. Since these conditions are hard to define molecularly and difficult, if not impossible, to reproduce in vitro, the challenge ahead is to understand the biological roles of the CCN family in normal and pathological processes as a function of the composition of the pericellular environment in vivo.
| Acknowledgments |
|---|
| Footnotes |
|---|
1 This work was supported by NIH Grant HD-30334, US Department of
Agriculture Grant 9803693, and FibroGen, Inc. (in which D.R.B. has an
equity interest). ![]()
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F. Tosetti, D. M. Noonan, and A. Albini Choking hypoxia-inducible factor 1alpha: a novel mechanism for connective tissue growth factor inhibition of angiogenesis. J Natl Cancer Inst, July 19, 2006; 98(14): 946 - 948. [Full Text] [PDF] |
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R Gao and D R Brigstock A novel integrin {alpha}5{beta}1 binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells Gut, June 1, 2006; 55(6): 856 - 862. [Abstract] [Full Text] [PDF] |
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M. De Falco, S. Staibano, F. P. D'Armiento, M. Mascolo, G. Salvatore, A. Busiello, I. F. Carbone, F. Pollio, and A. Di Lieto Preoperative Treatment of Uterine Leiomyomas: Clinical Findings and Expression of Transforming Growth Factor-{beta}3 and Connective Tissue Growth Factor Reproductive Sciences, May 1, 2006; 13(4): 297 - 303. [Abstract] [PDF] |
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T. Aikawa, J. Gunn, S. M. Spong, S. J. Klaus, and M. Korc Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer Mol. Cancer Ther., May 1, 2006; 5(5): 1108 - 1116. [Abstract] [Full Text] [PDF] |
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S. Zheng and A. Chen Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor Am J Physiol Gastrointest Liver Physiol, May 1, 2006; 290(5): G883 - G893. [Abstract] [Full Text] [PDF] |
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Z.-Y. Tong and D. R Brigstock Intrinsic biological activity of the thrombospondin structural homology repeat in connective tissue growth factor. J. Endocrinol., March 1, 2006; 188(3): R1 - R8. [Abstract] [Full Text] [PDF] |
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K. Ask, G. E. M. Martin, M. Kolb, and J. Gauldie Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls. Proceedings of the ATS, January 1, 2006; 3(4): 389 - 393. [Abstract] [Full Text] [PDF] |
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S. Kondo, N. Tanaka, S. Kubota, Y. Mukudai, G. Yosimichi, T. Sugahara, and M. Takigawa Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells Mol. Cancer Ther., January 1, 2006; 5(1): 129 - 137. [Abstract] [Full Text] [PDF] |
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F. Yang, J. A. Tuxhorn, S. J. Ressler, S. J. McAlhany, T. D. Dang, and D. R. Rowley Stromal Expression of Connective Tissue Growth Factor Promotes Angiogenesis and Prostate Cancer Tumorigenesis Cancer Res., October 1, 2005; 65(19): 8887 - 8895. [Abstract] [Full Text] [PDF] |
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W. C. Duncan, S. G. Hillier, E. Gay, J. Bell, and H. M. Fraser Connective Tissue Growth Factor Expression in the Human Corpus Luteum: Paracrine Regulation by Human Chorionic Gonadotropin J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5366 - 5376. [Abstract] [Full Text] [PDF] |
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M.-T. Lin, C.-Y. Zuon, C.-C. Chang, S.-T. Chen, C.-P. Chen, B.-R. Lin, M.-Y. Wang, Y.-M. Jeng, K.-J. Chang, P.-H. Lee, et al. Cyr61 Induces Gastric Cancer Cell Motility/Invasion via Activation of the Integrin/Nuclear Factor-{kappa}B/Cyclooxygenase-2 Signaling Pathway Clin. Cancer Res., August 15, 2005; 11(16): 5809 - 5820. [Abstract] [Full Text] [PDF] |
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Z. He, K. J. Way, E. Arikawa, E. Chou, D. M. Opland, A. Clermont, K. Isshiki, R. C. W. Ma, J. A. Scott, F. J. Schoen, et al. Differential Regulation of Angiotensin II-induced Expression of Connective Tissue Growth Factor by Protein Kinase C Isoforms in the Myocardium J. Biol. Chem., April 22, 2005; 280(16): 15719 - 15726. [Abstract] [Full Text] [PDF] |
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C. G. Lin, C.-C. Chen, S.-J. Leu, T. M. Grzeszkiewicz, and L. F. Lau Integrin-dependent Functions of the Angiogenic Inducer NOV (CCN3): IMPLICATION IN WOUND HEALING J. Biol. Chem., March 4, 2005; 280(9): 8229 - 8237. [Abstract] [Full Text] [PDF] |
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S. Banerjee, K. Sengupta, N. K. Saxena, K. Dhar, and S. K. Banerjee Epidermal Growth Factor Induces WISP-2/CCN5 Expression in Estrogen Receptor-{alpha}-Positive Breast Tumor Cells through Multiple Molecular Cross-talks Mol. Cancer Res., March 1, 2005; 3(3): 151 - 162. [Abstract] [Full Text] [PDF] |
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Y. Mukudai, S. Kubota, T. Eguchi, S. Kondo, K. Nakao, and M. Takigawa Regulation of Chicken ccn2 Gene by Interaction between RNA cis-Element and Putative trans-Factor during Differentiation of Chondrocytes J. Biol. Chem., February 4, 2005; 280(5): 3166 - 3177. [Abstract] [Full Text] [PDF] |
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W. E. Kutz, Y. Gong, and M. L. Warman WISP3, the Gene Responsible for the Human Skeletal Disease Progressive Pseudorheumatoid Dysplasia, Is Not Essential for Skeletal Function in Mice Mol. Cell. Biol., January 1, 2005; 25(1): 414 - 421. [Abstract] [Full Text] [PDF] |
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W. Chien, T. Kumagai, C. W. Miller, J. C. Desmond, J. M. Frank, J. W. Said, and H. P. Koeffler Cyr61 Suppresses Growth of Human Endometrial Cancer Cells J. Biol. Chem., December 17, 2004; 279(51): 53087 - 53096. [Abstract] [Full Text] [PDF] |
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D. F. Higgins, M. P. Biju, Y. Akai, A. Wutz, R. S. Johnson, and V. H. Haase Hypoxic induction of Ctgf is directly mediated by Hif-1 Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1223 - F1232. [Abstract] [Full Text] [PDF] |
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M. Hermansson, Y. Sawaji, M. Bolton, S. Alexander, A. Wallace, S. Begum, R. Wait, and J. Saklatvala Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin {beta}A (Activin A), a Regulatory Molecule for Chondrocytes J. Biol. Chem., October 15, 2004; 279(42): 43514 - 43521. [Abstract] [Full Text] [PDF] |
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N. Chen, S.-J. Leu, V. Todorovic, S. C.-T. Lam, and L. F. Lau Identification of a Novel Integrin {alpha}v{beta}3 Binding Site in CCN1 (CYR61) Critical for Pro-angiogenic Activities in Vascular Endothelial Cells J. Biol. Chem., October 15, 2004; 279(42): 44166 - 44176. [Abstract] [Full Text] [PDF] |
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S.-J. Leu, N. Chen, C.-C. Chen, V. Todorovic, T. Bai, V. Juric, Y. Liu, G. Yan, S. C.-T. Lam, and L. F. Lau Targeted Mutagenesis of the Angiogenic Protein CCN1 (CYR61): SELECTIVE INACTIVATION OF INTEGRIN {alpha}6{beta}1-HEPARAN SULFATE PROTEOGLYCAN CORECEPTOR-MEDIATED CELLULAR FUNCTIONS J. Biol. Chem., October 15, 2004; 279(42): 44177 - 44187. [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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F. K. Askari, R. Dick, M. Mao, and G. J. Brewer Tetrathiomolybdate Therapy Protects Against Concanavalin A and Carbon Tetrachloride Hepatic Damage in Mice Exp Biol Med, September 1, 2004; 229(8): 857 - 863. [Abstract] [Full Text] [PDF] |
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D. M. French, R. J. Kaul, A. L. D'Souza, C. W. Crowley, M. Bao, G. D. Frantz, E. H. Filvaroff, and L. Desnoyers WISP-1 Is an Osteoblastic Regulator Expressed During Skeletal Development and Fracture Repair Am. J. Pathol., September 1, 2004; 165(3): 855 - 867. [Abstract] [Full Text] [PDF] |
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C. T. Fu, J. F. Bechberger, M. A. Ozog, B. Perbal, and C. C. Naus CCN3 (NOV) Interacts with Connexin43 in C6 Glioma Cells: POSSIBLE MECHANISM OF CONNEXIN-MEDIATED GROWTH SUPPRESSION J. Biol. Chem., August 27, 2004; 279(35): 36943 - 36950. [Abstract] [Full Text] [PDF] |
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H. Yokoi, M. Mukoyama, T. Nagae, K. Mori, T. Suganami, K. Sawai, T. Yoshioka, M. Koshikawa, T. Nishida, M. Takigawa, et al. Reduction in Connective Tissue Growth Factor by Antisense Treatment Ameliorates Renal Tubulointerstitial Fibrosis J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1430 - 1440. [Abstract] [Full Text] [PDF] |
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S. Sakamoto, M. Yokoyama, X. Zhang, K. Prakash, K. Nagao, T. Hatanaka, R. H. Getzenberg, and Y. Kakehi Increased Expression of CYR61, an Extracellular Matrix Signaling Protein, in Human Benign Prostatic Hyperplasia and Its Regulation by Lysophosphatidic Acid Endocrinology, June 1, 2004; 145(6): 2929 - 2940. [Abstract] [Full Text] [PDF] |
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Y. Absenger, H. Hess-Stumpp, B. Kreft, J. Kratzschmar, B. Haendler, N. Schutze, P.-A. Regidor, and E. Winterhager Cyr61, a deregulated gene in endometriosis Mol. Hum. Reprod., June 1, 2004; 10(6): 399 - 407. [Abstract] [Full Text] [PDF] |
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E. M. Tam, C. J. Morrison, Y. I. Wu, M. S. Stack, and C. M. Overall Membrane protease proteomics: Isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates PNAS, May 4, 2004; 101(18): 6917 - 6922. [Abstract] [Full Text] [PDF] |
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P. C. Trackman and A. Kantarci CONNECTIVE TISSUE METABOLISM AND GINGIVAL OVERGROWTH Critical Reviews in Oral Biology & Medicine, May 1, 2004; 15(3): 165 - 175. [Abstract] [Full Text] [PDF] |
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A W Rachfal, M H Luquette, and D R Brigstock Expression of connective tissue growth factor (CCN2) in desmoplastic small round cell tumour J. Clin. Pathol., April 1, 2004; 57(4): 422 - 425. [Abstract] [Full Text] [PDF] |
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D. Xie, D. Yin, H.-J. Wang, G.-T. Liu, R. Elashoff, K. Black, and H. P. Koeffler Levels of Expression of CYR61 and CTGF Are Prognostic for Tumor Progression and Survival of Individuals with Gliomas Clin. Cancer Res., March 15, 2004; 10(6): 2072 - 2081. [Abstract] [Full Text] [PDF] |
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R. Gao and D. R. Brigstock Connective Tissue Growth Factor (CCN2) Induces Adhesion of Rat Activated Hepatic Stellate Cells by Binding of Its C-terminal Domain to Integrin {alpha}v{beta}3 and Heparan Sulfate Proteoglycan J. Biol. Chem., March 5, 2004; 279(10): 8848 - 8855. [Abstract] [Full Text] [PDF] |
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C.-C. Chang, J.-Y. Shih, Y.-M. Jeng, J.-L. Su, B.-Z. Lin, S.-T. Chen, Y.-P. Chau, P.-C. Yang, and M.-L. Kuo Connective Tissue Growth Factor and Its Role in Lung Adenocarcinoma Invasion and Metastasis J Natl Cancer Inst, March 3, 2004; 96(5): 364 - 375. [Abstract] [Full Text] [PDF] |
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S. Croci, L. Landuzzi, A. Astolfi, G. Nicoletti, A. Rosolen, F. Sartori, M. Y. Follo, N. Oliver, C. De Giovanni, P. Nanni, et al. Inhibition of Connective Tissue Growth Factor (CTGF/CCN2) Expression Decreases the Survival and Myogenic Differentiation of Human Rhabdomyosarcoma Cells Cancer Res., March 1, 2004; 64(5): 1730 - 1736. [Abstract] [Full Text] [PDF] |
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M. Minato, S. Kubota, H. Kawaki, T. Nishida, A. Miyauchi, H. Hanagata, T. Nakanishi, T. Takano-Yamamoto, and M. Takigawa Module-Specific Antibodies against Human Connective Tissue Growth Factor: Utility for Structural and Functional Analysis of the Factor as Related to Chondrocytes J. Biochem., March 1, 2004; 135(3): 347 - 354. [Abstract] [Full Text] [PDF] |
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H. R. Mason, A. C. Lake, J. E. Wubben, R. A. Nowak, and J. J. Castellot Jr The growth arrest-specific gene CCN5 is deficient in human leiomyomas and inhibits the proliferation and motility of cultured human uterine smooth muscle cells Mol. Hum. Reprod., March 1, 2004; 10(3): 181 - 187. [Abstract] [Full Text] [PDF] |
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H. R. Mason, D. Grove-Strawser, B. S. Rubin, R. A. Nowak, and J. J. Castellot Jr. Estrogen Induces CCN5 Expression in the Rat Uterus in Vivo Endocrinology, February 1, 2004; 145(2): 976 - 982. [Abstract] [Full Text] [PDF] |
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S. Sakamoto, M. Yokoyama, K. Prakash, J.-I. Tsuruha, S. Masamoto, R. H. Getzenberg, and Y. Kakehi Development of Quantitative Detection Assays for CYR61 as a New Marker for Benign Prostatic Hyperplasia J Biomol Screen, December 1, 2003; 8(6): 701 - 711. [Abstract] [PDF] |
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P. Bonniaud, P. J. Margetts, M. Kolb, T. Haberberger, M. Kelly, J. Robertson, and J. Gauldie Adenoviral Gene Transfer of Connective Tissue Growth Factor in the Lung Induces Transient Fibrosis Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 770 - 778. [Abstract] [Full Text] [PDF] |
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G. Weston, A. C. Trajstman, C. E. Gargett, U. Manuelpillai, B. J. Vollenhoven, and P. A.W. Rogers Fibroids display an anti-angiogenic gene expression profile when compared with adjacent myometrium Mol. Hum. Reprod., September 1, 2003; 9(9): 541 - 549. [Abstract] [Full Text] [PDF] |
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Y. Liang, C. Li, V. M. Guzman, A. J. Evinger III, C. E. Protzman, A. H.-P. Krauss, and D. F. Woodward Comparison of Prostaglandin F2{alpha}, Bimatoprost (Prostamide), and Butaprost (EP2 Agonist) on Cyr61 and Connective Tissue Growth Factor Gene Expression J. Biol. Chem., July 11, 2003; 278(29): 27267 - 27277. [Abstract] [Full Text] [PDF] |
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J. M. Schober, L. F. Lau, T. P. Ugarova, and S. C.-T. Lam Identification of a Novel Integrin {alpha}M{beta}2 Binding Site in CCN1 (CYR61), a Matricellular Protein Expressed in Healing Wounds and Atherosclerotic Lesions J. Biol. Chem., July 3, 2003; 278(28): 25808 - 25815. [Abstract] [Full Text] [PDF] |
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S. WERNER and R. GROSE Regulation of Wound Healing by Growth Factors and Cytokines Physiol Rev, July 1, 2003; 83(3): 835 - 870. [Abstract] [Full Text] [PDF] |
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P. Finckenberg, K. Inkinen, J. Ahonen, S. Merasto, M. Louhelainen, H. Vapaatalo, D. Muller, D. Ganten, F. Luft, and E. Mervaala Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways Am. J. Pathol., July 1, 2003; 163(1): 355 - 366. [Abstract] [Full Text] [PDF] |
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C. G. Lin, S.-J. Leu, N. Chen, C. M. Tebeau, S.-X. Lin, C.-Y. Yeung, and L. F. Lau CCN3 (NOV) Is a Novel Angiogenic Regulator of the CCN Protein Family J. Biol. Chem., June 20, 2003; 278(26): 24200 - 24208. [Abstract] [Full Text] [PDF] |
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K. Sawai, K. Mori, M. Mukoyama, A. Sugawara, T. Suganami, M. Koshikawa, K. Yahata, H. Makino, T. Nagae, Y. Fujinaga, et al. Angiogenic Protein Cyr61 is Expressed by Podocytes in Anti-Thy-1 Glomerulonephritis J. Am. Soc. Nephrol., May 1, 2003; 14(5): 1154 - 1163. [Abstract] [Full Text] [PDF] |
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K. H. Kim, Y. K. Min, J.-H. Baik, L. F. Lau, B. Chaqour, and K. C. Chung Expression of Angiogenic Factor Cyr61 during Neuronal Cell Death via the Activation of c-Jun N-terminal Kinase and Serum Response Factor J. Biol. Chem., April 11, 2003; 278(16): 13847 - 13854. [Abstract] [Full Text] [PDF] |
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A. Leask, A. Holmes, C. M. Black, and D. J. Abraham Connective Tissue Growth Factor Gene Regulation. REQUIREMENTS FOR ITS INDUCTION BY TRANSFORMING GROWTH FACTOR-beta 2 IN FIBROBLASTS J. Biol. Chem., April 4, 2003; 278(15): 13008 - 13015. [Abstract] [Full Text] [PDF] |
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B Perbal, D R Brigstock, and L F Lau Report on the second international workshop on the CCN family of genes Mol. Pathol., April 1, 2003; 56(2): 80 - 85. [Abstract] [Full Text] [PDF] |
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D R Brigstock, R Goldschmeding, K-i Katsube, S C-T Lam, L F Lau, K Lyons, C Naus, B Perbal, B Riser, M Takigawa, et al. Proposal for a unified CCN nomenclature Mol. Pathol., April 1, 2003; 56(2): 127 - 128. [Abstract] [Full Text] [PDF] |
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H. Thibout, C. Martinerie, C. Creminon, F. Godeau, P. Boudou, Y. Le Bouc, and M. Laurent Characterization of Human NOV in Biological Fluids: An Enzyme Immunoassay for the Quantification of Human NOV in Sera from Patients with Diseases of the Adrenal Gland and of the Nervous System J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 327 - 336. [Abstract] [Full Text] [PDF] |
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A. C. Lake, A. Bialik, K. Walsh, and J. J. Castellot Jr CCN5 Is a Growth Arrest-Specific Gene That Regulates Smooth Muscle Cell Proliferation and Motility Am. J. Pathol., January 1, 2003; 162(1): 219 - 231. [Abstract] [Full Text] [PDF] |
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F.-E Mo, A. G. Muntean, C.-C. Chen, D. B. Stolz, S. C. Watkins, and L. F. Lau CYR61 (CCN1) Is Essential for Placental Development and Vascular Integrity Mol. Cell. Biol., December 15, 2002; 22(24): 8709 - 8720. [Abstract] [Full Text] [PDF] |
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Y.-P. Cheon, Q. Li, X. Xu, F. J. DeMayo, I. C. Bagchi, and M. K. Bagchi A Genomic Approach to Identify Novel Progesterone Receptor Regulated Pathways in the Uterus during Implantation Mol. Endocrinol., December 1, 2002; 16(12): 2853 - 2871. [Abstract] [Full Text] [PDF] |
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S.-J. Leu, S. C.-T. Lam, and L. F. Lau Pro-angiogenic Activities of CYR61 (CCN1) Mediated through Integrins alpha vbeta 3 and alpha 6beta 1 in Human Umbilical Vein Endothelial Cells J. Biol. Chem., November 22, 2002; 277(48): 46248 - 46255. [Abstract] [Full Text] [PDF] |
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J. K. G. Crean, D. Finlay, M. Murphy, C. Moss, C. Godson, F. Martin, and H. R. Brady The Role of p42/44 MAPK and Protein Kinase B in Connective Tissue Growth Factor Induced Extracellular Matrix Protein Production, Cell Migration, and Actin Cytoskeletal Rearrangement in Human Mesangial Cells J. Biol. Chem., November 8, 2002; 277(46): 44187 - 44194. [Abstract] [Full Text] [PDF] |
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J. Lafont, M. Laurent, H. Thibout, F. Lallemand, Y. Le Bouc, A. Atfi, and C. Martinerie The Expression of novH in Adrenocortical Cells Is Down-regulated by TGFbeta 1 through c-Jun in a Smad-independent Manner J. Biol. Chem., October 18, 2002; 277(43): 41220 - 41229. [Abstract] [Full Text] [PDF] |
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B. Chaqour, C. Whitbeck, J.-S. Han, E. Macarak, P. Horan, P. Chichester, and R. Levin Cyr61 and CTGF are molecular markers of bladder wall remodeling after outlet obstruction Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E765 - E774. [Abstract] [Full Text] [PDF] |
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C. R. Harlow, L. Davidson, K. H. Burns, C. Yan, M. M. Matzuk, and S. G. Hillier FSH and TGF-{beta} Superfamily Members Regulate Granulosa Cell Connective Tissue Growth Factor Gene Expression in Vitro and in Vivo Endocrinology, September 1, 2002; 143(9): 3316 - 3325. [Abstract] [Full Text] [PDF] |
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K. J. Way, K. Isshiki, K. Suzuma, T. Yokota, D. Zvagelsky, F. J. Schoen, G. E. Sandusky, P. A. Pechous, C. J. Vlahos, H. Wakasaki, et al. Expression of Connective Tissue Growth Factor Is Increased in Injured Myocardium Associated With Protein Kinase C {beta}2 Activation and Diabetes Diabetes, September 1, 2002; 51(9): 2709 - 2718. [Abstract] [Full Text] [PDF] |
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K. Sakamoto, S. Yamaguchi, R. Ando, A. Miyawaki, Y. Kabasawa, M. Takagi, C. L. Li, B. Perbal, and K.-i. Katsube The Nephroblastoma Overexpressed Gene (NOV/ccn3) Protein Associates with Notch1 Extracellular Domain and Inhibits Myoblast Differentiation via Notch Signaling Pathway J. Biol. Chem., August 9, 2002; 277(33): 29399 - 29405. [Abstract] [Full Text] [PDF] |
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C L Li, V Martinez, B He, A Lombet, and B Perbal A role for CCN3 (NOV) in calcium signalling Mol. Pathol., August 1, 2002; 55(4): 250 - 261. [Abstract] [Full Text] [PDF] |
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E E-D A Moussad, M A E Rageh, A K Wilson, R D Geisert, and D R Brigstock Temporal and spatial expression of connective tissue growth factor (CCN2; CTGF) and transforming growth factor {beta} type 1 (TGF-{beta}1) at the utero-placental interface during early pregnancy in the pig Mol. Pathol., June 1, 2002; 55(3): 186 - 192. [Abstract] [Full Text] [PDF] |
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J. M. Schober, N. Chen, T. M. Grzeszkiewicz, I. Jovanovic, E. E. Emeson, T. P. Ugarova, R. D. Ye, L. F. Lau, and S. C.-T. Lam Identification of integrin alpha Mbeta 2 as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions Blood, May 29, 2002; 99(12): 4457 - 4465. [Abstract] [Full Text] [PDF] |
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S. Kondo, S. Kubota, T. Shimo, T. Nishida, G. Yosimichi, T. Eguchi, T. Sugahara, and M. Takigawa Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases Carcinogenesis, May 1, 2002; 23(5): 769 - 776. [Abstract] [Full Text] [PDF] |
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T. M. Grzeszkiewicz, V. Lindner, N. Chen, S. C.-T. Lam, and L. F. Lau The Angiogenic Factor Cysteine-Rich 61 (CYR61, CCN1) Supports Vascular Smooth Muscle Cell Adhesion and Stimulates Chemotaxis through Integrin {alpha}6{beta}1 and Cell Surface Heparan Sulfate Proteoglycans Endocrinology, April 1, 2002; 143(4): 1441 - 1450. [Abstract] [Full Text] [PDF] |
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M. C. Manara, B. Perbal, S. Benini, R. Strammiello, V. Cerisano, S. Perdichizzi, M. Serra, A. Astolfi, F. Bertoni, J. Alami, et al. The Expression of ccn3(nov) Gene in Musculoskeletal Tumors Am. J. Pathol., March 1, 2002; 160(3): 849 - 859. [Abstract] [Full Text] [PDF] |
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J. Liu, V.-M. Kosma, T. Vanttinen, C. Hyden-Granskog, and R. Voutilainen Gonadotrophins inhibit the expression of insulin-like growth factor binding protein-related protein-2 mRNA in cultured human granulosa-luteal cells Mol. Hum. Reprod., February 1, 2002; 8(2): 136 - 141. [Abstract] [Full Text] [PDF] |
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F. Su, M. Overholtzer, D. Besser, and A. J. Levine WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase Genes & Dev., January 1, 2002; 16(1): 46 - 57. [Abstract] [Full Text] [PDF] |
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C.-C. Chen, F.-E Mo, and L. F. Lau The Angiogenic Factor Cyr61 Activates a Genetic Program for Wound Healing in Human Skin Fibroblasts J. Biol. Chem., December 7, 2001; 276(50): 47329 - 47337. [Abstract] [Full Text] [PDF] |
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