Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone morphogenetic proteins (BMPs) play critical roles at various stages in endochondral bone formation. In vitro studies have demonstrated that Smad7 regulates transforming growth factor-beta and BMP signals by inhibiting Smad pathways in chondrocytes. However, the in vivo roles of Smad7 during cartilage development are unknown. To investigate distinct effects of Smad7 at different stages during chondrocyte differentiation, we generated a series of conditional transgenic mice that overexpress Smad7 in chondrocytes at various steps of differentiation by using the Cre/loxP system. We generated Col11a2-lacZ(floxed)-Smad7 transgenic mice and mated them with three types of Cre transgenic mice to obtain Smad7(Prx1), Smad7(11Enh), and Smad7(11Prom) conditional transgenic mice. Smad7(Prx1) mice overexpressing Smad7 in condensing mesenchymal cells showed disturbed mesenchymal condensation associated with decreased Sox9 expression, leading to poor cartilage formation. Smad7(11Enh) mice overexpressing Smad7 in round chondrocytes showed decreased chondrocyte proliferation rates. Smad7(11Prom) mice overexpressing Smad7 in flat chondrocytes showed inhibited maturation of chondrocytes toward hypertrophy. Micromass culture of mesenchymal cells showed that BMP-induced cartilaginous nodule formation was down-regulated by overexpression of Smad7, but not Smad6. Overexpression of Smad7, but not Smad6, down-regulated the phosphorylation of p38 MAPKs. Our data provide in vivo evidence for distinct effects of Smad7 at different stages during chondrocyte differentiation and suggest that Smad7 in prechondrogenic cells inhibits chondrocyte differentiation possibly by down-regulating BMP-activated p38 MAPK pathways.
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PMID:Smad7 Inhibits chondrocyte differentiation at multiple steps during endochondral bone formation and down-regulates p38 MAPK pathways. 1864 88

Idiopathic pulmonary fibrosis is a lethal parenchymal lung disease characterized by denudation of the lung epithelium, fibroblast proliferation, and collagen deposition. Cellular changes underlying disease progression involve injury to alveolar epithelial cells, epithelial to mesenchymal transition, proliferation of alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblasts and of fibroblasts resulting in enhanced deposition of extracellular matrix proteins. Hepatocyte growth factor (HGF) inhibits progression of bleomycin-induced pulmonary fibrosis in mice. The mechanism underlying the inhibitory effect of HGF was investigated in an in vitro model. We show that HGF markedly antagonizes basal and transforming growth factor (TGF)-beta-induced expression of myofibroblast markers such as alpha-SMA, collagen type 1, and fibronectin in rat alveolar epithelial cells. HGF also inhibited TGF-beta-induced alpha-SMA expression in primary murine alveolar epithelial cells. Since TGF-beta is known to regulate alpha-SMA expression, the effect of HGF on components of TGF-beta signaling was investigated. HGF induced expression of Smad7, an inhibitor of TGF-beta signaling, in a mitogen-activated protein kinase-dependent manner. HGF also induced the nuclear export of Smad7 and Smad ubiquitin regulatory factor 1 (Smurf1) to the cytoplasm. HGF-dependent decrease in alpha-SMA was abolished with specific siRNAs targeted to Smad7. Thus, induction of Smad7 by HGF serves to limit acquisition of the myofibroblast phenotype in alveolar epithelial cells.
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PMID:Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via Smad7. 1898 20

The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during the progression of epithelial tumors. EMT can be induced by transforming growth factor (TGF)-beta in some tumor cells. Here, we demonstrate the molecular mechanism whereby Snail, a key regulator of EMT, is induced by TGF-beta in tumor cells. Snail induction by TGF-beta was highly dependent on cooperation with active Ras signals, and silencing of Ras abolished Snail induction by TGF-beta in pancreatic cancer Panc-1 cells. Transfection of constitutively active Ras into HeLa cells led to induction of Snail by TGF-beta, while representative direct targets of TGF-beta, including Smad7 and PAI-1, were not affected by Ras signaling. Using mitogen-activated protein kinase inhibitors or Smad3 or Smad2 mutants, we found that phosphorylation at the linker region of Smad2/3 was not required for the induction of Snail by TGF-beta. Taken together, these findings indicate that Ras and TGF-beta-Smad signaling selectively cooperate in the induction of Snail, which occurs in a Smad-dependent manner, but independently of phosphorylation at the linker region of R-Smads by Ras signaling.
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PMID:Role of Ras signaling in the induction of snail by transforming growth factor-beta. 1901 Jul 89

TGF-beta and FAK modulate cell migration, differentiation, proliferation and apoptosis, and TGF-beta promotes FAK transcription in intestinal epithelial cells via Smad-dependent and independent pathways. We utilized a 1320 bp FAK promoter-luciferase construct to characterize basal and TGF-beta-mediated FAK gene transcription in IEC-6 cells. Inhibiting JNK or Akt negated TGF-beta-stimulated promoter activity; ERK inhibition did not block the TGF-beta effect but increased basal activity. Co-transfection with Co-Smad4 enhanced the TGF-beta response while the inhibitory Smad7 abolished it. Serial deletions sequentially removing the four Smad binding elements (SBE) in the 5' untranslated region of the promoter revealed that the two most distal SBE's are positive regulators while SBE3 exerts a negative influence. Mutational deletion of two upstream p53 sites enhanced basal but did not affect TGF-beta-stimulated increases in promoter activity. TGF-beta increased DNA binding of Smad4, phospho-Smad2/3 and Runx1/AML1a to the most distal 435 bp containing 3 SBE and 2 AML1a sites by ChIP assay. However, although point mutation of SBE1 ablated the TGF-beta-mediated rise in SV40-promoter activity, mutation of AML1a sites did not. TGF-beta regulation of FAK transcription reflects a complex interplay between positive and negative non-Smad signals and SBE's, the last independent of p53 or AML1a.
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PMID:TGF-beta1 modulates focal adhesion kinase expression in rat intestinal epithelial IEC-6 cells via stimulatory and inhibitory Smad binding elements. 1905 68

Transforming growth factor (TGF)-beta is a pleiotropic cytokine regulating a variety of cellular processes such as cell growth, differentiation, apoptosis, migration, cell adhesion, and immune response. In the well-understood classical TGF-beta signaling pathway, TGF-beta activates Smad signalling via its two cell surface receptors such as TbetaRII and ALK5/TbetaRI, leading to Smad-mediated transcriptional regulation. In addition, TGF-beta may also activate other signaling pathways like mitogen-activated protein kinase, PI3K, etc. The signaling of TGF-beta is finely regulated at different levels. Inhibitory Smads, including Smad6 and Smad7, are key regulators of TGF-beta/bone morphogenetic protein (BMP) signaling by negative feedback loops. They can form stable complexes with activated type I receptors and thereby blocking the phosphorylation of R-Smads, or recruit ubiquitin E3 ligases, such as Smurf1/2, resulting in the ubiquitination and degradation of the activated type I receptors. Besides, these inhibitory Smad proteins also inhibit TGF-beta/BMP signaling in the nucleus by interacting with transcriptional repressors, such as histone deacetylases, Hoxc-8, and CtBP, or disrupting the formation of the TGF-beta-induced functional Smad-DNA complexes. Smad7 is in turn regulated by different stimuli, including TGF-beta, IFN-gamma, TNF-alpha as well as ultraviolet and TPA, and mediates the crosstalk between TGF-beta and other signaling pathways. Deregulation of Smad7 expression has been associated with various human diseases, such as tissue fibrosis, inflammatory disease as well as carcinogenesis. Overexpression of Smad7 has been shown to antagonize TGF-beta-mediated fibrosis, carcinogenesis, and inflammation, suggesting a therapeutic potential of Smad7 to treat these diseases.
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PMID:Regulation of TGF-beta signaling by Smad7. 1935 40

Angiotensin II is a powerful mediator to induce cardiac remodeling and fibrosis. Transforming growth factor-beta1 (TGF-beta1) and extracellular signal-regulated kinase (ERK) have been implicated in the angiotensin II-induced cardiac fibrosis. However, the signaling pathways for this angiotensin II effect and the interaction between ERK and the TGF-beta1 signaling in this effect have not been well-illustrated. Cardiac fibroblasts were prepared from the ventricles of adult male Sprague-Dawley rats. They were treated with 1 microM angiotensin II in the presence or absence of losartan (angiotensin II AT(1) receptor antagonist), PD123319 (angiotensin II AT(2) receptor antagonist), an anti-TGF-beta1 antibody or PD98059 (ERK inhibitor). The cells were collected for Western blotting and reverse transcription-polymerase chain reaction. Angiotensin II caused a significant increase of the expression of TGF-beta(1), ERK1, phosphorylated-Smad2/3, Smad4 and collagen I. This increase was attenuated by losartan but was not affected by PD123319. An anti-TGF-beta(1) antibody and PD98059 diminished angiotensin II-induced Smad2/3 phosphorylation and the expression of Smad7 and collagen I. Our results suggest that angiotensin II induces collagen I expression through angiotensin II AT(1) receptor-TGF-beta(1)-Smads signaling pathway in cardiac fibroblasts. ERK, by regulating Smads signaling, also participated in the angiotensin II-induced collagen I expression.
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PMID:Angiotensin II increases collagen I expression via transforming growth factor-beta1 and extracellular signal-regulated kinase in cardiac fibroblasts. 1937 81

Angiotensin II (Ang II) stimulation has been shown to regulate proliferation of skin fibroblasts and the production of extracellular matrix, which are very important processes in skin wound healing and fibrosis; however, there is little knowledge about the mechanisms involved in this process. We investigated the molecular aspects of this system with regards to Ang II in human dermal fibroblasts (HDF) and its potential role in fibrosis. Fibroblasts derived from human skin were subjected to examine differential relative gene and protein expression after transfection with specific reporter expression vectors and Ang II in vitro. In growth-arrested HDFs, Ang II treatment for 20 min caused acute activation of Smad2 phosphorylation, Smad overexpression and Smad-dependent gene transcription. The angiotensin type 1 (AT1) antagonist losartan diminished Ang II-induced Smad activation. The blockade of endogenous transforming growth factor-beta1 did modify the activation of Smad caused by Ang II. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 diminished Ang II-induced Smad2 phosphorylation. Transient transfection with Smad7, which interferes with receptor-mediated activation of Smad2, diminished Ang II-induced connective tissue growth factor promoter activation, gene and protein expression and fibronectin, type I procollagen and type III procollagen overexpression, showing that Smad activation is involved in Ang II-induced dermal fibrosis. Our results show that Ang II activation of Smad2 occurs via the AT1 receptor, but not the AT2 receptor. Activation of Smad2 required p38 MAPK but not p42/p44 MAPK or the epidermal growth factor receptor.
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PMID:Angiotensin II activates connective tissue growth factor and induces extracellular matrix changes involving Smad/activation and p38 mitogen-activated protein kinase signalling pathways in human dermal fibroblasts. 1939

Immunological tolerance is one of the fundamental aspects of the immune system. The CD4(+)CD25(+) regulatory T (Treg) cells have emerged as key players in the development of tolerance to self and foreign antigens. However, little is known about the endogenous factors and mechanisms controlling their suppressive capacity on immune response. In this study, we observed that docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, diminished, in a dose-dependent manner, the capacity of Treg cells to inhibit the CD4(+)CD25(-) effector T-cell proliferation. DHA not only reduced the migration of Treg cells toward chemokines but also downregulated the mRNA expression of CCR-4 and CXCR-4 in Treg cells. DHA also curtailed ERK1/2 and Akt phosphorylation and downregulated the Smad7 levels in these cells. Contradictorily, DHA upregulated the mRNA expression of Foxp3, CTLA-4, TGF-beta, and IL-10; nonetheless, this fatty acid increased the expression of p27(KIP1) mRNA, known to be involved in Treg cell unresponsiveness. In Foxp3-immunoprepitated nuclear proteins, DHA upregulated histone desacetylase 7 levels that would again participate in the unresposnsiveness of these cells. Finally, a DHA-enriched diet also diminished, ex vivo, the suppressive capacity of Treg cells. Altogether, these results suggest that DHA, by diminishing Treg cell functions, may play a key role in health and disease.
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PMID:Docosahexaenoic acid reduces suppressive and migratory functions of CD4+CD25+ regulatory T-cells. 1956 60

Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g.kg(-1).day(-1) by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-beta, Smad2, alpha-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-kappaB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox), p22(phox)), PAI-1, TGF-beta, connective tissue growth factor, alpha-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-kappaB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.
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PMID:Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. 1965 15

Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)-mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II-induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-beta1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II-induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II-induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-beta-dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-beta gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal-regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-beta-independent, Ang II type 1 receptor-mediated extracellular signal-regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II-mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II-induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II-mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-beta-dependent and -independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy.
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PMID:Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: the role of Smad3. 1966 56


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