Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q16637 (SMA)
 8,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. In response to pancreatic injury and in cell culture, pancreatic stellate cells (PSCs) are transformed ('activated') into highly proliferative myofibroblast-like cells, which express alpha-smooth muscle actin (alpha-SMA), and produce type I collagen and other extracellular matrix components. There is accumulating evidence that activated PSCs play important roles in pancreatic fibrosis and inflammation. 2. The small GTP-binding protein Rho has emerged as an important regulator of the actin cytoskeleton and cell morphology through the downstream effector Rho kinase (ROCK). But, the roles of Rho-ROCK pathway in PSCs are unknown. Here, we examined the effects of (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide (Y-27632) and HA-1077 (fasudil), specific inhibitors of ROCK, on the activation of PSCs. 3. PSCs were isolated from the pancreas of male Wistar rats after perfusion with collagenase P. The actin cytoskeleton was analyzed by phalloidin staining. Expression of RhoA and ROCK was examined by immunostaining and Western blotting. Effects of Y-27632 and HA-1077 on alpha-SMA expression, platelet-derived growth factor-induced proliferation and chemotaxis, and collagen production were assessed. 4. Culture-activated PSCs developed a well-spread cell shape, with extended stress fiber formation. PSCs expressed RhoA, ROCK-1, and ROCK-2. 5. Y-27632 caused disassembly of stress fibers. Y-27632 and HA-1077 inhibited alpha-SMA expression, proliferation, chemotaxis, and type I collagen production in culture-activated PSCs. 6. In addition, Y-27632 and HA-1077 inhibited spontaneous activation of freshly isolated PSCs in culture on plastic. 7. These findings suggest a role of Rho-ROCK pathway in the activation process of PSCs by regulating the actin cytoskeleton, and a potential application of Rho-ROCK pathway inhibitors for the treatment of pancreatic inflammation and fibrosis.
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PMID:Rho kinase inhibitors block activation of pancreatic stellate cells. 1458 Nov 80

We previously developed a robust in vitro model system for vascular smooth muscle cell (VSMC) differentiation from neural crest cell line Monc-1 upon transforming growth factor-beta (TGF-beta) induction. Further studies demonstrated that both Smad and RhoA signaling are critical for TGF-beta-induced VSMC development. To identify downstream targets, we performed Affymetrix cDNA array analysis of Monc-1 cells and identified a gene named response gene to complement 32 (RGC-32) to be important for the VSMC differentiation. RGC-32 expression was increased 5-fold after 2 h and 50-fold after 24 h of TGF-beta induction. Knockdown of RGC-32 expression in Monc-1 cells by small interfering RNA significantly inhibited the expression of multiple smooth muscle marker genes, including SM alpha-actin (alpha-SMA), SM22alpha, and calponin. Of importance, the inhibition of RGC-32 expression correlated with the reduction of alpha-SMA while not inhibiting smooth muscle-unrelated c-fos gene expression, suggesting that RGC-32 is an important protein factor for VSMC differentiation from neural crest cells. Moreover, RGC-32 overexpression significantly enhanced TGF-beta-induced alpha-SMA, SM22alpha, and SM myosin heavy chain promoter activities in both Monc-1 and C3H10T1/2 cells. The induction of VSMC gene promoters by RGC-32 appears to be CArG-dependent. These data suggest that RGC-32 controls VSMC differentiation by regulating marker gene transcription in a CArG-dependent manner. Further studies revealed that both Smad and RhoA signaling are important for RGC-32 activation.
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PMID:Response gene to complement 32, a novel regulator for transforming growth factor-beta-induced smooth muscle differentiation of neural crest cells. 1732 22

A homotransplantable tumour (LY) and cell lines (LY-PPB6 and LY-H12) were established from a spontaneous malignant peripheral nerve sheath tumour (PNST) of the uterine cervix of an F344 rat. Primary and LY tumours consisted of oval or spindle-shaped cells arranged in a flatfield or streaming fashion, and indistinct nuclear palisades were seen. Immunohistochemically, neoplastic cells reacted to vimentin, S-100 protein, neuron-specific enolase (NSE), myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) in varying degrees, indicating neurogenic derivation. LY-PPB6-induced tumours in syngeneic rats developed cellular whorling patterns reacting particularly strongly to S-100 protein, NSE, MBP and GFAP. Nerve growth factor (NGF) mRNA expression was shown in LY-PPB6 cells by the reverse transcription-polymerase chain reaction (RT-PCR). By contrast, LY-H12 had a normal chromosomal number of 42, and did not produce tumours when injected into syngeneic rats. LY-H12 cells reacted to vimentin and alpha-smooth muscle actin (alpha-SMA), and the alpha-SMA-positive cell number was increased dose-dependently by the addition of transforming growth factor (TGF)-beta1, indicating a myofibroblastic nature. LY-PPB6 cells were neoplastic with properties of PNS cells, whereas LY-H12 cells were non-neoplastic stromal cells showing myofibroblastic differentiation. As TGF-beta1 mRNA expression was shown in both LY-PPB6 and LY-H12 cells by the RT-PCR, the myofibroblastic phenotype of LY-H12 cells may be mediated by paracrine or autocrine signalling in tumour tissues. LY-PPB6 and LY-H12 may prove useful for studies on the pathobiological nature of neoplastic cells and interactions between neoplastic and stromal cells in PNSTs.
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PMID:Neoplastic and non-neoplastic cell lines from a malignant peripheral nerve sheath tumour of the cervix of a rat. 1753 54

Spinal muscular atrophy (SMA) is the most common genetic disease resulting in infant mortality due to severe loss of alpha-motor neurons. SMA is caused by mutations or deletions of the ubiquitously expressed survival motor neuron (SMN) gene. However, why alpha-motor neurons of SMA patients are specifically affected is not clear. We demonstrate here that Smn knockdown in PC12 cells alters the expression pattern of profilin II, resulting in an increase in the neuronal-specific profilin IIa isoform. Moreover, the depletion of Smn, a known interacting partner of profilin IIa, further contributes to the increased profilin IIa availability. Altogether, this leads to an increased formation of ROCK/profilin IIa complex and an inappropriate activation of the RhoA/ROCK pathway, resulting in altered cytoskeletal integrity and a subsequent defect in neuritogenesis. This study represents the first description of a mechanism underlying SMA pathogenesis and highlights new targets for therapeutic intervention for this devastating disorder.
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PMID:Smn depletion alters profilin II expression and leads to upregulation of the RhoA/ROCK pathway and defects in neuronal integrity. 1787 96

Proliferative vitroretinopathy (PVR) is caused by retinal pigment epithelial (RPE) cell proliferation and transformation into fibrotic cells that produce extracellular matrix (ECM) components. Transforming growth factor beta1 (TGF-beta1) is known to play an important role in PVR pathogenesis. To determine how TGF-beta1 mediates the pathogenic changes in RPE cells, we characterized the effects of TGF-beta1 on the morphology, ECM accumulation, and stress fiber formation of ARPE-19 cells, a human RPE cell line. We then elucidated the signaling pathways that mediate these effects. Serum-starved ARPE-19 cells were incubated with 10 ng/ml TGF-beta1 and their morphological changes were examined by phase-contrast microscopy. Actin reorganization was examined by immunochemistry and confocal microscopy. Protein phosphorylation was analyzed by Western blot analysis. TGF-beta1 treatment induced cytoskeleton reorganization, alpha-SMA expression, increased the phosphorylation of ERK, Smad2/3, and AKT, and activated RhoA and Rac1. Cytoskeletal rearrangement was prevented by pretreatment with a Rho inhibitor and by expression of a dominant negative form of Rho. TGF-beta1 also increased LIM kinase and cofilin phosphorylation and the Rho inhibitor blocked this effect. We propose that TGF-beta1 induces human RPE cells to undergo cytoskeletal actin rearrangement via Rho GTPase-dependent pathways that modulate LIM kinase and cofilin activity. This inhibits actin depolymerization and induces the cytoskeletal rearrangements in RPE cells that result in the characteristic features of PVR.
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PMID:Rho plays a key role in TGF-beta1-induced cytoskeletal rearrangement in human retinal pigment epithelium. 1831 80

Several studies indicate that cancer-associated fibroblasts play a critical role in cancer cell invasion and metastasis, the hallmarks of malignancy. To better understand the mechanisms underlying such effects, we established a heterotypic model of human fibroblasts (primary colon fibroblasts and immortalized human dermal fibroblasts) in co-culture with human colon cancer cells (HCT-8/E11), using three-dimensional collagen type-I and Matrigel matrices. We report that TGF-beta is the unique and dominant factor to provide pro-invasive signals to HCT-8/E11 colon cancer cells from TGF-beta-treated human fibroblasts in three-dimensional collagen type I and Matrigel matrices. These effects are not mimicked or reversed by EGF or bFGF, and are associated with the TGF-beta-mediated induction of myofibroblast differentiation and functional markers, such as alpha-SMA, the haptotactic matrix molecule TNC, collagen type 1 maturation enzyme P4H, serine protease FAP, and myofibroblast contractility. Accordingly, TGF-beta induced a strong activation of RhoA and stress fiber formation in fibroblasts, with no impact on Rac1-GTP levels. In contrast, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. Taken together, our data imply that TGF-beta and EGF exert invasive growth-promoting actions in human colon tumors through a differential and cumulative impact on the stromal and cancer cell compartments. Our data predict that inhibitors directed at this reciprocal molecular and cellular crosstalk will have therapeutic applications for targeting the invasive growth of human primary tumors and their metastatic spread.
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PMID:Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. 1842 81

In previous studies, we have demonstrated that RhoA/B-dependent signaling regulates TGFbeta-induced rapid actin reorganization in Swiss 3T3 fibroblasts. Here we report that TGFbeta regulates long-term actin remodeling by increasing the steady-state mRNA levels of the RhoB gene in mouse Swiss 3T3 fibroblasts and human hepatoma HepG2 cells. We show that this regulation is specific for the RhoB gene and is facilitated by enhanced activity of the RhoB promoter. Adenovirus-mediated gene transfer of Smad2 and Smad3 in Swiss 3T3 fibroblasts induced transcription of the endogenous RhoB gene but not the RhoA gene. Interestingly, in JEG-3 choriocarcinoma cells that lack endogenous Smad3, TGFbeta-induced transcriptional up-regulation of the RhoB gene was not observed, but it was restored by adenoviral Smad3 overexpression. In addition, Smad2 and Smad3 triggered activation of RhoA and RhoB GTPases and long-term actin reorganization in Swiss 3T3 fibroblasts. Finally, Smad3, and to a lesser extent Smad2, induced transcription of the alpha-smooth muscle actin (alpha-SMA) gene, and enhanced the incorporation of alpha-SMA into microfilaments in Swiss 3T3 fibroblasts. These data reveal a novel mechanism of cross-talk between the classical TGFbeta/Smad pathway and Rho GTPases, regulating the rapid and the long-term actin reorganization that may control the fibroblast-myofibroblast differentiation program.
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PMID:A novel mechanism of TGFbeta-induced actin reorganization mediated by Smad proteins and Rho GTPases. 1863 Nov 73

Thromboxane A(2) (TxA(2)) is involved in smooth muscle contraction and atherosclerotic vascular diseases. Accumulating evidence suggests a pivotal role for mesenchymal stem cells (MSCs) in vascular remodeling. In the present study, we demonstrate for the first time that the TxA(2) mimetic U46619 induces differentiation of human adipose tissue-derived MSCs (hADSCs) to smooth muscle-like cells, as demonstrated by increased expression of smooth muscle-specific contractile proteins such as alpha-smooth muscle actin (alpha-SMA), calponin, smoothelin, and smooth muscle-myosin heavy chain. Using an in vitro collagen gel lattice contraction assay, we showed that U46619-induced expression of the contractile proteins was associated with increased contractility of the cells. U46619 increased the intracellular Ca(2+) concentration in hADSCs and pretreatment of the cells with the thromboxane receptor antagonist SQ29548 or the calmodulin (CaM) inhibitor W13 abrogated the U46619-induced alpha-SMA expression and contractility, suggesting a pivotal role of Ca(2+)/CaM in the U46619-stimulated smooth muscle differentiation of hADSCs. In addition, U46619 elicited activation of RhoA in hADSCs, and pretreatment of the cells with the Rho kinase-specific inhibitor Y27632 or overexpression of the dominant-negative mutants of RhoA and Rho kinase blocked U46619-stimulated alpha-SMA expression and contractility. Furthermore, U46619 induced phosphorylation of myosin light chain (MLC) through CaM/MLC kinase- and Rho kinase-dependent pathways, and the MLC kinase inhibitor ML-7 abrogated U46619-induced alpha-SMA expression and contractility. These results suggest that U46619 induces differentiation of hADSCs to contractile smooth muscle-like cells through CaM/MLCK- and RhoA-Rho kinase-dependent actin polymerization.
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PMID:Thromboxane a(2) induces differentiation of human mesenchymal stem cells to smooth muscle-like cells. 1884 63

Spinal muscular atrophy (SMA) is the most common human genetic disease resulting in infant mortality. SMA is caused by mutations or deletions in the ubiquitously expressed survival motor neuron 1 (SMN1) gene. Why SMA specifically affects motor neurons remains poorly understood. We have shown that Smn deficient PC12 cells have increased levels of the neuronal profilin IIa protein, leading to an inappropriate activation of the RhoA/ROCK pathway. This suggests that mis-regulation of neuronal actin dynamics is central to SMA pathogenesis. Here, we demonstrate an increase in profilin IIa and a decrease in plastin 3 protein levels in a SMA mouse model. Furthermore, knock-out of profilin II upregulates plastin 3 expression in a Smn-dependent manner. However, the depletion of profilin II and the restoration of plastin 3 are not sufficient to rescue the SMA phenotype. Our study suggests that additional regulators of actin dynamics must also contribute to SMA pathogenesis.
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PMID:SMN, profilin IIa and plastin 3: a link between the deregulation of actin dynamics and SMA pathogenesis. 1949 69

Elevated intraocular pressure arising from impaired aqueous humor drainage through the trabecular pathway is a major risk factor for glaucoma. To understand the molecular basis for Rho GTPase-mediated resistance to aqueous humor drainage, we investigated the possible interrelationship between actomyosin contractile properties and extracellular matrix (ECM) synthesis in human trabecular meshwork (TM) cells expressing a constitutively active form of RhoA (RhoAV14). TM cells expressing RhoAV14 exhibited significant increases in fibronectin, tenascin C, laminin, alpha-smooth muscle actin (alpha-SMA) levels, and matrix assembly in association with increased actin stress fibers and myosin light-chain phosphorylation. RhoAV14-induced changes in ECM synthesis and actin cytoskeletal reorganization were mimicked by lysophosphatidic acid and TGF-beta(2), known to increase resistance to aqueous humor outflow and activate Rho/Rho kinase signaling. RhoAV14, lysophosphatidic acid, and TGF-beta(2) stimulated significant increases in Erk1/2 phosphorylation, paralleled by profound increases in fibronectin, serum response factor (SRF), and alpha-SMA expression. Treatment of RhoA-activated TM cells with inhibitors of Rho kinase or Erk, on the other hand, decreased fibronectin and alpha-SMA levels. Although suppression of SRF expression (both endogenous and RhoA, TGF-beta(2)-stimulated) via the use of short hairpin RNA decreased alpha-SMA levels, fibronectin was unaffected. Conversely, fibronectin induced alpha-SMA expression in an SRF-dependent manner. Collectively, data on RhoA-induced changes in actomyosin contractile activity, ECM synthesis/assembly, and Erk activation, along with fibronectin-induced alpha-SMA expression in TM cells, reveal a potential molecular interplay between actomyosin cytoskeletal tension and ECM synthesis/assembly. This interaction could be significant for the homeostasis of aqueous humor drainage through the pressure-sensitive trabecular pathway.
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PMID:Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells. 1994 66


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