Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein kinase p38 is activated by mechanical force, but the cellular elements that mediate force-induced p38 phosphorylation are not defined. As alpha-smooth muscle actin (SMA) is an actin isoform associated with force generation in fibroblasts, we asked if SMA participates in the activation of p38 by force. Tensile forces (0.65 pn/mum(2)) generated by magnetic fields were applied to collagen-coated magnetite beads bound to Rat-2 cells. Immunoblotting showed that p38alpha was the predominant p38 isoform. Analysis of bead-associated proteins demonstrated that SMA enrichment of collagen receptor complexes required the alpha2beta1 integrin. SMA was present almost entirely as filaments. Swinholide depolymerized SMA filaments and blocked force-induced p38 phosphorylation and force-induced increases of SMA. Knockdown of SMA (70% reduction) using RNA interference did not affect beta-actin but inhibited force-induced p38 phosphorylation by 50%. Inhibition of Rho kinase blocked SMA filament assembly, force-induced increases of SMA, and force-induced p38 activation. Force application increased SMA content and enhanced the association of phosphorylated p38 with SMA filaments. Blockade of p38 phosphorylation by SB203586 abrogated force-induced increases of SMA. In cells transfected with SMA promoter-beta-galactosidase fusion constructs, co-transfection with constitutively active p38 or MKK6 increased SMA promoter activity by 2.5-3-fold. Dominant negative p38 blocked force-induced activation of the SMA promoter. In SMA negative cells, there was no force-induced p38 phosphorylation. We conclude that force-induced p38 phosphorylation is dependent on an SMA filament-dependent pathway that uses a feed-forward amplification loop to synergize force-induced SMA expression with p38 activation.
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PMID:Smooth muscle actin determines mechanical force-induced p38 activation. 1559 Oct 55

The effects of oxidative stress on collagen and DNA biosynthesis, beta-galactosidase and prolidase activities, and the expression of prolidase, beta1-integrin receptor, FAK, IGF-IR and MAP-kinases (ERK1, ERK2) were evaluated in human dermal fibroblasts. Subconfluent cells were subjected to repetitive stresses with 30 microM t-BHP for 1 hour per day over the course of 5 days. It was found that oxidative stress induced the inhibition of collagen biosynthesis in these cells in a time-dependent manner. Exposure of the cells to 5 stresses contributed to a decrease in collagen and DNA biosynthesis to about 30% and 50% of the control values, respectively. Prolidase activity and expression were only suppressed in fibroblasts subjected to 1 and 3 stresses. In these cells prolidase activity was decreased by about 20%. As a result of 5 stresses, no further inhibition of prolidase activity occurred; however, expression of the enzyme was slightly increased, as demonstrated by Western blot analysis. It was found that these phenomena were neither related to the expression of beta1-integrin receptor nor to that of FAK. However, the exposure of the cells to 3 and 5 stresses contributed to a distinct decrease in IGF-IR and MAP-kinases (ERK1, ERK2) expression, which is probably responsible for the collagen biosynthesis inhibition.
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PMID:Oxidative stress induces IGF-I receptor signaling disturbances in cultured human dermal fibroblasts. A possible mechanism for collagen biosynthesis inhibition. 1564 87

Chronic exposure of many human hepatoma cell lines to a low dose (LD) of doxorubicin induced a senescence-like phenotype (SLP) accompanied by enlargement of cells and increased senescence-associated beta-galactosidase activity. LD doxorubicin-induced SLP was preceded by multinucleation and downregulation of multiple proteins with mitotic checkpoint function, including CENP-A, Mad2, BubR1, and Chk1. LD doxorubicin-treated cells eventually underwent cell death through mitotic catastrophe. When we investigated whether LD doxorubicin-induced cell death shares biochemical characteristics with high dose (HD) doxorubicin-induced apoptosis in Huh-7 cells, we observed that externalization of phosphatidyl serine and release of mitochondrial cytochrome c into the cytosol was associated with both types of cell death. However, propidium iodide exclusion assays showed that membrane integrity was lost in the initial phase of LD doxorubicin-induced cell death through mitotic catastrophe, whereas it was lost during the late phase of HD doxorubicin-induced apoptosis. Furthermore, HD doxorubicin-induced apoptosis but not LD doxorubicin-induced mitotic catastrophe led to transient activation of NF-kappaB and strong, sustained activations of p38, c-Jun N-terminal kinase, and caspases. Collectively, these results indicate that different doses of doxorubicin activate different regulatory mechanisms to induce either apoptosis or cell death through mitotic catastrophe.
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PMID:Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. 1587 Jul 2

Telomerase catalytic subunit (hTERT) has been shown to play a critical role not only in telomere homeostasis but also in cellular survival, DNA repair, and genetic stability. In a previous study, we described that tumor necrosis factor-xalpha (TNFxalpha) induced in the leukemic KG1 cells a senescence state characterized by decreased hTERT activity followed by prolonged growth arrest, increasedx beta-galactosidase activity, telomere shortening, and major chromosomal instability. Interestingly, granulocyte-macrophage colony-stimulating factor (GM-CSF) abrogated all these events. In the present study, we show for the first time that TNFxalpha acts by inhibiting the hTERT gene in both normal CD34x+ cells and fresh leukemic cells. Using KG1 cells as a representative cellular model, we show that TNFxalpha induced sphingomyelin hydrolysis, ceramide production, and c-Jun N-terminal kinase (JNK) activation, all of which are critical components of TNFxalpha signaling, resulting in hTERT gene inhibition. Moreover, we provide evidence that the protective effect of GM-CSF is related to its capacity to interfere with both ceramide generation and ceramide signaling. Negative regulation of the hTERT gene may represent one mechanism by which TNFxalpha interferes with normal hemopoiesis.
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PMID:Tumor necrosis factor-alpha inhibits hTERT gene expression in human myeloid normal and leukemic cells. 1602 May 9

beta-Arrestin is an adaptor protein that has been shown to couple G protein-coupled receptors (GPCRs) to clathrin-coated pits and target them for subsequent internalization. More recently, beta-arrestin 2 has also been shown to be involved in the activation of mitogen-activated protein kinase cascades by G protein-coupled receptors independently of G protein activation. Direct interactions between proteins can be monitored using enzyme complementation between two inactive deletion mutants of beta-galactosidase (beta-gal; Deltaalpha and Deltaomega). In the present study, we have used fusion proteins of the human beta(2)-adrenoceptor (C-terminal beta-gal Deltaalpha) and beta-arrestin 2 (beta-gal Deltaomega) to study directly the pharmacology of this interaction in C2C12 cells expressing the beta(2)-adrenoceptor-beta-gal Deltaalpha fusion protein at low physiological levels (38.2 +/- 2.7 fmol . mg protein(-1)). Isoprenaline, noradrenaline, and adrenaline (-log EC(50) = 5.9, 5.5, and 5.7, respectively) stimulated an association between the beta(2)-adrenoceptor and beta-arrestin 2 at much higher concentrations than required for activation of cAMP accumulation (-log EC(50) = 7.6, 6.3, and 7.7, respectively). This was sensitive to inhibition by the beta(2)-adrenoceptor antagonists propranolol, timolol, and ICI 118551. Both salbutamol and terbutaline behaved as partial agonists of beta-gal complementation. Furthermore, the long-acting beta(2)-agonist salmeterol (-log K(D) for inhibition of [(3)H]CGP12177 binding = 8.7) behaved as an antagonist of isoprenaline-stimulated beta(2)-adrenoceptor-arrestin 2 interactions (-log K(D) = 8.0), whereas acting as a full agonist of cAMP accumulation in the same cells (-log EC(50) = 9.2). These data suggest that salmeterol can discriminate between receptor-G(S) protein and receptor-arrestin 2 complexes (in terms of efficacy and affinity) in a way that is favorable for its long duration of action.
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PMID:Characterization of isoprenaline- and salmeterol-stimulated interactions between beta2-adrenoceptors and beta-arrestin 2 using beta-galactosidase complementation in C2C12 cells. 1605 98

Reactive oxygen species (ROS) were generated in all oxygen-utilizing organisms. Peroxiredoxin II (Prx II) as one of antioxidant enzymes may play a protective role against the oxidative damage caused by ROS. In order to define the role of Prx II in organismal aging, we evaluated cellular senescence in Prx II(-/-) mouse embryonic fibroblast (MEF). As compared to wild type MEF, cellular senescence was accelerated in Prx II(-/-) MEF. Senescence-associated (SA)-beta-galactosidase (Gal)-positive cell formation was about 30% higher in Prx II(-/-) MEF. N-Acetyl-l-cysteine (NAC) treatment attenuated SA-beta-Gal-positive cell formation. Prx II(-/-) MEF exhibited the higher G2/M (41%) and lower S (1.6%) phase cells as compared to 24% and 7.3% [corrected] in wild type MEF, respectively. A high increase in the p16 and a slight increase in the p21 and p53 levels were detected in PrxII(-/-) MEF cells. The cellular senescence of Prx II(-/-) MEF was correlated with the organismal aging of Prx II(-/-) mouse skin. While extracellular signal-regulated kinase (ERK) and p38 activation was detected in Prx II(-/-) MEF, ERK and c-Jun N-terminal kinase (JNK) activation was detected in Prx II(-/-) skin. These results suggest that Prx II may function as an enzymatic antioxidant to prevent cellular senescence and skin aging.
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PMID:Inhibitory role of peroxiredoxin II (Prx II) on cellular senescence. 1610 12

Upregulation of plasminogen activator inhibitor type 1 (PAI-1) expression is a critical mechanism through which transforming growth factor-beta1 (TGF-beta1) accelerates intimal growth. The aim of this study was to identify signaling pathways through which TGF-beta1 upregulates PAI-1 expression in endothelial cells (EC) and test interventions for blocking these pathways. We transduced cultured bovine EC with an adenoviral vector containing the PAI-1 promoter fused to a beta-galactosidase reporter gene. We used these cells, along with vectors expressing potential modifiers of TGF-beta1 signaling and pharmacologic antagonists of mitogen-activated protein kinase (MAPK) pathways to identify key mediators of basal and TGF-beta1-regulated PAI-1 expression. Basal activity of the PAI-1 promoter was directly correlated with Ras activation and was blocked by a dominant negative (DN) type I TGF-beta receptor. TGF-beta1-stimulated activity of the PAI-1 promoter did not require Ras activation, and was lessened or eliminated by expression of either DN type I or type II TGF-beta receptors and by inhibition of either of two MAPKs: MEK and p38. Our results suggest unanticipated pathways of TGF-beta1 signaling in EC and point to new strategies to limit TGF-beta1-induced vascular disease.
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PMID:Identification of intracellular pathways through which TGF-beta1 upregulates PAI-1 expression in endothelial cells. 1613 37

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.
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PMID:Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. 1617 Mar 53

Spreds (Sprouty-related proteins with an Ena/Vasodilator-stimulated phosphoprotein homology-1 domain) are a new protein family inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway. Different RNA and protein studies already revealed an almost ubiquitous Spred-2 expression pattern. But until now, only few data were available on the in situ Spred-2 promoter activity. Here, we show a detailed in situ analysis of a mouse strain with a trapped Spred-2 gene, bringing a beta-galactosidase and neomycin fusion gene (beta-geo) under the control of the endogenous Spred-2 promoter. This allowed us to monitor Spred-2 promoter activity in practically every organ and their corresponding sub-compartments. X-Gal staining of newborn and adult mice revealed a nearly congruent Spred-2 promoter activity pattern. Our detailed data provide information for further studies of the still enigmatic physiological functions of Spred-2 in various organs by identifying the tissues with strong Spred-2 promoter activity.
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PMID:Tissue-specific Spred-2 promoter activity characterized by a gene trap approach. 1637 60

Epidemiological, animal, and cell culture studies have identified boron as a chemopreventative agent in prostate cancer. The present objective was to identify boron-induced changes in the DU-145 human prostate cancer cell line. We show that prolonged exposure to pharmacologically-relevant levels of boric acid, the naturally occurring form of boron circulating in human plasma, induces the following morphological changes in cells: increases in granularity and intracellular vesicle content, enhanced cell spreading and decreased cell volume. Documented increases in beta-galactosidase activity suggest that boric acid induces conversion to a senescent-like cellular phenotype. Boric acid also causes a dose-dependent reduction in cyclins A-E, as well as MAPK proteins, suggesting their contribution to proliferative inhibition. Furthermore, treated cells display reduced adhesion, migration and invasion potential, along with F-actin changes indicative of reduced metastatic potential. Finally, the observation of media acidosis in treated cells correlated with an accumulation of lysosome-associated membrane protein type 2 (LAMP-2)-negative acidic compartments. The challenge of future studies will be to identify the underlying mechanism responsible for the observed cellular responses to this natural blood constituent.
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PMID:Cellular changes in boric acid-treated DU-145 prostate cancer cells. 1649 20


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