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1.
Non-Smad signaling pathways 总被引:1,自引:0,他引:1
2.
Andrew Leask 《Arthritis research & therapy》2006,8(4):213-7
The autoimmune disease scleroderma (systemic sclerosis (SSc)) is characterized by extensive tissue fibrosis, causing significant
morbidity. There is no therapy for the fibrosis observed in SSc; indeed, the underlying cause of the scarring observed in
this disease is unknown. Transforming growth factor-β (TGFβ) has long been hypothesized to be a major contributor to pathological
fibrotic diseases, including SSc. Recently, the signaling pathways through which TGFβ activates a fibrotic program have been
elucidated and, as a consequence, several possible points for anti-fibrotic drug intervention in SSc have emerged. 相似文献
3.
Wayde M. Weston Merle B. Potchinsky Cynthia M. Lafferty Linh Ma Robert M. Greene 《In vitro cellular & developmental biology. Animal》1998,34(1):74-78
Summary Signaling pathways utilized by EGF, cAMP, and TGFβ have been demonstrated to play critical roles in normal palate development.
Stimulation of these pathways has been shown in palate cells and numerous other systems to affect cell growth. Because proper
regulation of cell growth is critical to palate development, we speculate that fine regulation of palatal cell growth may
be accomplished through crosstalk between these signaling pathways. We therefore set out to determine the effects of cAMP
and TGFβ on EGF-induced cell proliferation in murine embryonic palate cells. We found that both TGFβ and cAMP inhibited the
proliferative response of cells to treatment with EGF, whereas H89, a serine/threonine protein kinase inhibitor with selectivity
towards cAMP-dependent protein kinase, increased the cells’ proliferative response to EGF. Genestein, a selective inhibitor
of tyrosine kinases, at high doses abrogated the cells’ proliferative response to EGF, confirming that EGF’s ability to induce
cell proliferation is critically dependent upon tyrosine kinase activity. Lower doses of genestein, however, actually enhanced
cellular response to EGF. The data suggest that both the TGFβ- and cAMP-mediated signaling pathways may be involved in modulation
of the effects of EGF on palate cell growth in vivo. 相似文献
4.
Casad ME Yu L Daniels JP Wolf MJ Rockman HA 《Molecular genetics and genomics : MGG》2012,287(4):351-360
Drosophila is a useful model organism in which the genetics of human diseases, including recent advances in identification of the genetics
of heart development and disease in the fly, can be studied. To identify novel genes that cause cardiomyopathy, we performed
a deficiency screen in adult Drosophila. Using optical coherence tomography to phenotype cardiac function in awake adult Drosophila, we identified Df(1)Exel6240 as having cardiomyopathy. Using a number of strategies including customized smaller deletions, screening of mutant alleles,
and transgenic rescue, we identified CG3226 as the causative gene for this deficiency. CG3226 is an uncharacterized gene in
Drosophila possessing homology to the mammalian Siah-interacting protein (SIP) gene. Mammalian SIP functions as an adaptor protein involved
in one of the β-catenin degradation complexes. To investigate the effects of altering β-catenin/Armadillo signaling in the
adult fly, we measured heart function in flies expressing either constitutively active Armadillo or transgenic constructs
that block Armadillo signaling, specifically in the heart. While, increasing Armadillo signaling in the heart did not have
an effect on adult heart function, decreasing Armadillo signaling in the fly heart caused the significant reduction in heart
chamber size. In summary, we show that deletion of CG3226, which has homology to mammalian SIP, causes cardiomyopathy in adult
Drosophila. Alterations in Armadillo signaling during development lead to important changes in the size and function of the adult heart. 相似文献
5.
Esmeralda N Blaney Davidson Elly L Vitters Wim B van den Berg Peter M van der Kraan 《Arthritis research & therapy》2006,8(3):R65-8
Cartilage damage in osteoarthritis (OA) is considered an imbalance between catabolic and anabolic factors, favoring the catabolic
side. We assessed whether adenoviral overexpression of transforming growth factor-β (TGFβ) enhanced cartilage repair and whether
TGFβ-induced fibrosis was blocked by local expression of the intracellular TGFβ inhibitor Smad7. We inflicted cartilage damage
by injection of interleukin-1 (IL-1) into murine knee joints. After 2 days, we injected an adenovirus encoding TGFβ. On day
4, we measured proteoglycan (PG) synthesis and content. To examine whether we could block TGFβ-induced fibrosis and stimulate
cartilage repair simultaneously, we injected Ad-TGFβ and Ad-Smad7. This was performed both after IL-1-induced damage and in
a model of primary OA. In addition to PG in cartilage, synovial fibrosis was measured by determining the synovial width and
the number of procollagen I-expressing cells. Adenoviral overexpression of TGFβ restored the IL-1-induced reduction in PG
content and increased PG synthesis. TGFβ-induced an elevation in PG content in cartilage of the OA model. TGFβ-induced synovial
fibrosis was strongly diminished by simultaneous synovial overexpression of Smad7 in the synovial lining. Of great interest,
overexpression of Smad7 did not reduce the repair-stimulating effect of TGFβ on cartilage. Adenoviral overexpression of TGFβ
stimulated repair of IL-1- and OA-damaged cartilage. TGFβ-induced synovial fibrosis was blocked by locally inhibiting TGFβ
signaling in the synovial lining by simultaneously transfecting it with an adenovirus overexpressing Smad7. 相似文献
6.
7.
Tissue fibrosis and vascular disease are hallmarks of systemic sclerosis (SSc). Transforming growth factor β (TGFβ) is a key-player
in fibroblast activation and tissue fibrosis in SSc. In contrast to fibrosis, evidence for a role of TGFβ in vascular disease
of SSc is scarce. Using a transgenic mouse model with fibroblast-specific expression of a kinase-deficient TGFβ receptor type
II, Derrett-Smith and colleagues demonstrate that aberrant TGFβ signaling in fibroblasts might result in activation of vascular
smooth muscle cells and architectural changes of the vessel wall of the aorta. 相似文献
8.
9.
Age-related progression of cardiovascular disease is by far the largest health problem in the US and involves vascular damage,
progressive vascular fibrosis and the accumulation of lipid-rich atherosclerotic lesions. Advanced lesions can restrict flow
to key organs and can trigger occlusive thrombosis resulting in a stroke or myocardial infarction. Transforming growth factor-beta
(TGF-β) is a major orchestrator of the fibroproliferative response to tissue damage. In the early stages of repair, TGF-β
is released from platelets and activated from matrix reservoirs; it then stimulates the chemotaxis of repair cells, modulates
immunity and inflammation and induces matrix production. At later stages, it negatively regulates fibrosis through its strong
antiproliferative and apoptotic effects on fibrotic cells. In advanced lesions, TGF-β might be important in arterial calcification,
commonly referred to as “hardening of the arteries”. Because TGF-β can signal through multiple pathways, namely the SMADs,
a MAPK pathway and the Rho/ROCK pathways, selective defects in TGF-β signaling can disrupt otherwise coordinated pathways
of tissue regeneration. TGF-β is known to control cell proliferation, cell migration, matrix synthesis, wound contraction,
calcification and the immune response, all being major components of the atherosclerotic process. However, many of the effects
of TGF-β are essential to normal tissue repair and thus, TGF-β is often thought to be “atheroprotective”. The present review
attempts to parse systematically the known effects of TGF-β on both the major risk factors for atherosclerosis and to isolate
the role of TGF-β in the many component pathways involved in atherogenesis. 相似文献
10.
Yoshiya Asano Kyoko Koishi Tony Frugier Ian S. McLennan 《Cellular and molecular neurobiology》2009,29(5):621-633
The transforming growth factor betas (TGFβs) are context-dependent regulators of neurons in vitro, but their physiological
functions in the brain are unclear. Haploinsufficiency of either Tgfβ1 or Tgfβ2 leads to age-related deterioration of neurons,
but the development of the brain is normal in the full absence of either of these genes. However, some individuals with mis-sense
mutations of TGFβ receptors are mentally retarded, suggesting that the TGFβ isoforms can compensate for each other during
brain development. This possibility was tested by generating mice (NSE × PTR) with neuron-specific expression of a dominant-negative
inhibitor of TGFβ signaling. The NSE × PTR mice with a FVBxC57Bl/6 genetic background were viable and developed normally despite
strong neuronal expression of the inhibitor of TGFβ signaling. Their cerebella were of normal size and contained normal numbers
of neurons. When the genetic background of the mice was changed to C57BL/6, the phenotype of the mice became neonatal lethal,
with the neonates exhibiting various malformations. The malformations correlated with sites of non-neuronal expression of
the transgenes and included facial dysmorphogenesis, incomplete closure of the ventral body wall and absence of intestinal
motility. The C57BL/6 Tgfbm1–3 alleles, which modulate the phenotype of Tgfβ1−/− mice, were not major determinants of the NSE × PTR phenotype. The data suggest that the development of the cerebellum is
insensitive to the level of TGFβ signaling, although this may be dependent on the genetic background. 相似文献
11.
The cytokines of the TGFβ superfamily are highly conserved in evolution and elicit a diverse range of cellular responses in
all metazoa. In Drosophila, the signaling pathways of the two TGFβ subfamilies, Activins and Bone Morphogenetic Proteins (BMPs), have been well studied.
To address the question of whether the findings from Drosophila are representative of insects in general, we analyzed the components of TGFβ-signaling present in the genome of the beetle
Tribolium castaneum. We were able to identify orthologs of the BMPs Decapentaplegic and Glass bottom boat, of the Activins Activinβ and Dawdle,
as well as orthologs of the less well-known ligands Myoglianin and Maverick, together with orthologs of all TGFβ receptors
and cytoplasmic signal transducers present in Drosophila. This indicates that the diversity of TGFβ signaling components is generally well conserved between Drosophila and Tribolium. However, the genome of the beetle—and of the bee Apis mellifera—lacks an ortholog of the Drosophila BMP Screw but does contain a vertebrate-like BMP10 homolog which is not found in Drosophila. Concerning BMP inhibitors, Tribolium displays an even more vertebrate-like ensemble of components. We found two orthologs of the vertebrate DAN family, Dan and
Gremlin, and show embryonic expression of a vertebrate-like BAMBI ortholog, all of which are absent in Drosophila. This suggests that Tribolium might have retained a more ancestral composition of TGFβ signaling components and that TGFβ signaling underwent considerable
change in the Drosophila lineage. Tribolium is an excellent model to study the function of these ancestral signaling components in insects.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
12.
Peter M van der Kraan Esmeralda N Blaney Davidson Wim B van den Berg 《Arthritis research & therapy》2010,12(1):201
Transforming growth factor beta (TGFβ) is a growth factor with many faces. In our osteoarthritis (OA) research we have found
that TGFβ can be protective as well as deleterious for articular cartilage. We postulate that the dual effects of TGFβ on
chondrocytes can be explained by the fact that TGFβ can signal via different receptors and related Smad signaling routes.
On chondrocytes, TGFβ not only signals via the canonical type I receptor ALK5 but also via the ALK1 receptor. Notably, signaling
via ALK5 (Smad2/3 route) results in markedly different chondrocyte responses than ALK1 signaling (Smad1/5/8), and we postulate
that the balance between ALK5 and ALK1 expression on chondrocytes will determine the overall effect of TGFβ on these cells.
Importantly, signaling via ALK1, but not ALK5, stimulates MMP-13 expression by chondrocytes. In cartilage of ageing mice and
in experimental OA models we have found that the ALK1/ALK5 ratio is significantly increased, favoring TGFβ signaling via the
Smad1/5/8 route, changes in chondrocyte differentiation and MMP-13 expression. Moreover, human OA cartilage showed a significant
correlation between ALK1 and MMP-13 expression. In this paper we summarize concepts in OA, its link with ageing and disturbed
growth factor responses, and a potential role of TGFβ signaling in OA development. 相似文献
13.
Lisa?L?Maduzia Andrew?F?Roberts Huang?Wang Xia?Lin Lena?J?Chin Cole?M?Zimmerman Stephen?Cohen Xin-Hua?Feng Richard?W?Padgett
Background
In C. elegans there are two well-defined TGFβ-like signaling pathways. The Sma/Mab pathway affects body size morphogenesis, male tail development and spicule formation while the Daf pathway regulates entry into and exit out of the dauer state. To identify additional factors that modulate TGFβ signaling in the Sma/Mab pathway, we have undertaken a genetic screen for small animals and have identified kin-29. 相似文献14.
Alan M. Holmes Markella Ponticos Xu Shi-wen Christopher P. Denton David J. Abraham 《Journal of cell communication and signaling》2011,5(3):173-177
The ability of TGFβ1 to act as a potent pro-fibrotic mediator is well established, potently inducing the expression of fibrogenic
genes including type I collagen (COL1A2) and CCN2. Previously we have shown elevated expression of the TGFβ accessory receptor,
endoglin on Systemic Sclerosis (SSc) dermal fibroblasts. Here we sought to assess the cell surface expression of the TGFβ
receptor complex on SSc dermal fibroblasts (SDF), and investigate their role in maintaining the elevated expression of CCN2.
SDF exhibited elevated expression of the TGFβ accessory receptors betaglycan/TGFβRIII and endoglin, but not type I or type
II receptors. To determine the effect of altered receptor repertoire on TGFβ responses, we investigated the effect of exogenous
TGFβ on expression of two pro-fibrotic genes. SDF exhibited higher basal expression of COL1A2 and CCN2 compared to healthy
controls. TGFβ induced a marked increase in the expression of these genes in normal dermal fibroblasts, whereas SDF exhibited
only a modest increase. We next sought to determine if higher basal expression in SDF was a result of autocrine expression
of TGFβ. Surprisingly basal expression was not affected by a pan-neutralizing TGFβ antibody. To explore if altered accessory
receptor expression alone could account for these changes, we determined their effects on CCN2 promoter activity. Endoglin
inhibited CCN2 promoter activity in response to TGFβ. TGFβRIII alone or in combination with endoglin was sufficient to enhance
basal CCN2 promoter activity. Thus TGFβ accessory receptors may play a significant role in the altered expression of fibrogenic
genes in SDF. 相似文献
15.
Di Guglielmo GM 《Journal of cell communication and signaling》2010,4(4):185-186
Lung fibrosis is often treated with corticosteroids to reduce the inflammatory response, however, no effective treatment options
exist for the underlying disease. An important player in the fibrotic cascade is the cytokine, transforming growth factor
beta (TGFβ). TGFβ is converted from an inactive procytokine complex to active TGFβ by enzymes such as thrombospondin-1 (TSP-1).
It is therefore presumed that TSP-1 deficient mice would fare better to bleomycin-induced pulmonary fibrosis because TGFβ
would not be efficiently converted to the active form. Interestingly, a recent article by Ezzie and colleagues shows that
TSP-1 deficiency does not protect mice from systemic bleomycin challenge. Indeed, they find the opposite, as TSP-1-null mice
appear to exhibit greater lung fibrosis than wild type mice, although similar TGFβ signaling was observed in the lungs of
both mouse strains. 相似文献
16.
Charlotte E. Konikoff Robert G. Wisotzkey Michael J. Stinchfield Stuart J. Newfeld 《Journal of molecular evolution》2010,70(4):303-312
The canonical Wnt pathway is one of the oldest and most functionally diverse of animal intercellular signaling pathways. Though
much is known about loss-of-function phenotypes for Wnt pathway components in several model organisms, the question of how
this pathway achieved its current repertoire of functions has not been addressed. Our phylogenetic analyses of 11 multigene
families from five species belonging to distinct phyla, as well as additional analyses employing the 12 Drosophila genomes,
suggest frequent gene duplications affecting ligands and receptors as well as co-evolution of new ligand–receptor pairs likely
facilitated the expansion of this pathway’s capabilities. Further, several examples of recent gene loss are visible in Drosophila
when compared to family members in other phyla. By comparison the TGFβ signaling pathway is characterized by ancient gene
duplications of ligands, receptors, and signal transducers with recent duplication events restricted to the vertebrate lineage.
Overall, the data suggest that two distinct molecular evolutionary mechanisms can create a functionally diverse developmental
signaling pathway. These are the recent dynamic generation of new genes and ligand–receptor interactions as seen in the Wnt
pathway and the conservative adaptation of ancient pre-existing genes to new roles as seen in the TGFβ pathway. From a practical
perspective, the former mechanism limits the investigator’s ability to transfer knowledge of specific pathway functions across
species while the latter facilitates knowledge transfer. 相似文献
17.
Caveolin-1 (Cav-1) isoforms, including Cav-1α and Cav-1β, were identified as integral membrane proteins and the major components
of caveolae. Cav-1 proteins are highly conserved during evolution from {itCaenorhabditis elegans} to human and are capable
of interacting with many signaling molecules through their caveolin scaffolding domains to regulate the activities of multiple
signaling pathways. Thus, Cav-1 plays crucial roles in the regulation of cellular proliferation, differentiation and apoptosis
in a cell-specific and contextual manner. In addition, Cav-1 is essential for embryonic development of vertebrates owing to
its regulation of BMP, Wnt, TGF-β and other key signaling molecules. Moreover, Cav-1 is mainly expressed in terminally differentiated
cells and its abnormal expression is often associated with human diseases, such as tumor progression, cardiovascular diseases,
fibrosis, lung regeneration, and diseases related to virus. In this review, we will further discuss the potential of Cav-1
as a target for disease therapy and multiple drug resistance. 相似文献
18.
O'Sullivan JA Zloza A Kohlhapp FJ Moore TV Lacek AT Dulin NO Guevara-Patiño JA 《Cancer immunology, immunotherapy : CII》2011,60(11):1543-1551
While the effects of TCR affinity and TGFβ on CD8+ T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFβ-mediated
suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities
in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions
prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses
by CD8+ T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFβ. Susceptibility to TGFβ-mediated suppression
is associated with downregulation of RGS3, a recently recognized negative regulator of TGFβ signaling, but not expression
of TGFβ receptors I/II. These results suggest a novel tolerance mechanism whereby CD8+ T cells are discriminately regulated by TGFβ according to the affinity of the ligand on which they were initially primed.
In addition, because of the major role played by TGFβ in tumor-induced immune suppression, these results identify the affinity
of the priming ligand as a primary concern in CD8+ T-cell-mediated cancer immunotherapeutic strategies. 相似文献
19.
Introduction
Transforming growth factor beta (TGFβ) plays a central role in morphogenesis, growth, and cell differentiation. This cytokine is particularly important in cartilage where it regulates cell proliferation and extracellular matrix synthesis. While the action of TGFβ on chondrocyte metabolism has been extensively catalogued, the modulation of specific genes that function as mediators of TGFβ signalling is poorly defined. In the current study, elements of the Smad component of the TGFβ intracellular signalling system and TGFβ receptors were characterised in human chondrocytes upon TGFβ1 treatment. 相似文献20.
Summary In an accompanying report (Moreno-Cuevas, J. E.; Sirbasku, D. A., In Vitro Cell. Dev. Biol.; 2000), we demonstrated 80-fold
estrogen mitogenic effects with MTW9/PL2 rat mammary tumor cells in cultures supplemented with charcoaldextran-treated serum.
All sera tested contained an estrogen reversible inhibitor(s). The purpose of this report is to extend those observations
to additional sex steroid-responsive human and rodent cell lines. Every line tested showed a biphasic response to hormone-depleted
serum. Concentrations of ≤10% (v/v) promoted substantive growth. At higher concentrations, serum was progressively inhibitory.
With estrogen receptor-positive (ER+) human breast cancer cells, rat pituitary tumor cells, and Syrian hamster kidney tumor cells, 50% (v/v) serum caused significant
inhibition, which was reversed by very low physiologic concentrations of estrogens. This same pattern was observed with the
steroid hormone-responsive LNCaP human prostatic carcinoma cells. Because steroid hormone mitogenic effects are now easily
demonstrable using our new methods, the identification of positive results has nullified our original endocrine estromedin
hypothesis. We also evaluated autocrine/paracrine growth factor models of estrogen-responsive growth. We asked if insulin-like
growth factors I and II, insulin, transforming growth factor alpha, or epidermal growth factor substituted for the positive
effects of estrogens. Growth factors did not reverse the serum-caused inhibition. We asked also if transforming growth factor
beta (TGFβ) substituted for the serum-borne inhibitor. TGFβ did not substitute. Altogether, our results are most consistent
with the concept of a unique serum-borne inhibitor as has been proposed in the estrocolyone model. However, the aspect of
the estrocolyone model related to steroid hormone mechanism of action requires more evaluation. The effects of sex steroids
at picomolar concentrations may reflect mediation via inhibitor “activated” intracellular signaling pathways. 相似文献