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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adherence of cells to microvascular endothelium is important in a number of processes, including inflammatory responses and metastasis. It has been demonstrated that in human models, cytokines such as TNF, IL-1, IFN-gamma increase the adhesiveness of endothelium for cells of the immune and inflammatory system by stimulating the expression of cell adhesion molecules on endothelial cell surfaces. We and others have shown similar cytokine-induced endothelial adhesiveness for tumor cells in murine and human models. In contrast to the effect of those modulators, transforming growth factor-beta (TGF-beta) has been shown to inhibit the binding of human neutrophils and T lymphocytes to human endothelium, although the mechanism of TGF-beta action remains unknown. Little is known about the effect of TGF-beta on tumor cell-endothelial interaction. In the present study, we demonstrate that TGF-beta inhibits basal and TNF-enhanced binding of murine P815 mastocytoma cells to murine microvascular endothelium (MME). The alterations in MME mediated by TGF-beta, also lead to the inhibition of adherence of murine splenocytes, thymocytes, and human lymphoblastoid cells but do not inhibit adherence of murine B16 melanoma cells. The effect of TGF-beta is transient and inhibition of the endothelial adhesive phenotype is strongest 12 to 24 h after addition of the factor to MME. The TGF-beta-mediated inhibition of P815 basal binding to endothelium is dependent on protein synthesis because cycloheximide reverses the TGF-beta effect. TGF-beta does not appear to activate classical signal transduction pathways. Inhibitors of G proteins do not abolish TGF-beta action, protein kinase C and protein kinase A activators elicit an effect opposite to that of the factor, TGF-beta does not increase intracellular cAMP levels, and finally calcium-mobilizing agents do not mimic, but rather inhibit the effect of TGF-beta. However, TGF-beta-mediated inhibition of both basal binding and TNF-enhanced P815 binding to MME is completely abolished in the presence of the protein phosphatase inhibitor okadaic acid which suggests that TGF-beta may elicit its effect by stimulating protein phosphatase activity.
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PMID:Inhibition of basal and tumor necrosis factor-enhanced binding of murine tumor cells to murine endothelium by transforming growth factor-beta 1. 131 61

Proliferation of wild-type Cloudman S91 melanoma cells is inhibited when insulin is included in the culture medium. Using growth inhibition as a selective marker, we isolated variant cell lines that are either resistant to insulin or dependent upon insulin for growth. We have studied the effects of insulin on proliferation by using combined genetic and biochemical approaches. Through a series of genetic hybridization analyses, we have identified three complementation groups and determined that, in general, insulin-sensitivity is dominant to insulin-resistance. Through analyses of in vitro protein phosphorylation reactions, we have identified a protein of approximately 90 kDa (pp90) whose phosphorylation is a function of at least one of the complementation groups. Although pp90 is not phosphorylated in extracts of insulin-resistant variants, it is phosphorylated in extracts of insulin-sensitive hybrids formed between complementing resistant variants. Insulin itself exhibits little or no regulation over the phosphorylation of pp90; rather, the ability to phosphorylate pp90 correlates with the ability of cells to respond to insulin. Migration in NaDodSO4/polyacrylamide gels, solubility characteristics, and divalent cation requirements indicate that pp90 is distinct from the 95-kDa beta-subunit of the insulin receptor. Both pp90 and its associated phosphoprotein kinase are found in 30,000 X g pellets of sonicated cell lysates, whereas a specific pp90 phosphoprotein phosphatase activity is found in 30,000 X g supernatant fractions. Phosphorylation of pp90 occurs at tyrosine and serine residues. Our evidence indicates that the state of phosphorylation of pp90 is an important determinant in the regulation of cellular proliferation by insulin.
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PMID:Evidence that a 90-kDa phosphoprotein, an associated kinase, and a specific phosphatase are involved in the regulation of Cloudman melanoma cell proliferation by insulin. 298 23

PTEN/MMAC1 is a tumor suppressor gene located on chromosome 10q23. Inherited PTEN/MMAC1 mutations are associated with a cancer predisposition syndrome known as Cowden's disease. Somatic mutation of PTEN has been found in a number of malignancies, including glioblastoma, melanoma, and carcinoma of the prostate and endometrium. The protein product (PTEN) encodes a dual-specificity protein phosphatase and in addition can dephosphorylate certain lipid substrates. Herein, we show that PTEN protein induces a G1 block when reconstituted in PTEN-null cells. A PTEN mutant associated with Cowden's disease (PTEN;G129E) has protein phosphatase activity yet is defective in dephosphorylating inositol 1,3,4,5-tetrakisphosphate in vitro and fails to arrest cells in G1. These data suggest a link between induction of a cell-cycle block by PTEN and its ability to dephosphorylate, in vivo, phosphatidylinositol 3,4,5-trisphosphate. In keeping with this notion, PTEN can inhibit the phosphatidylinositol 3,4, 5-trisphosphate-dependent Akt kinase, a downstream target of phosphatidylinositol 3-kinase, and constitutively active, but not wild-type, Akt overrides a PTEN G1 arrest. Finally, tumor cells lacking PTEN contain high levels of activated Akt, suggesting that PTEN is necessary for the appropriate regulation of the phosphatidylinositol 3-kinase/Akt pathway.
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PMID:Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. 1005 3

The feasibility of chemically-induced premature chromosome condensation (PCC) was tested in two human fibroblast and two human malignant melanoma cell lines. To induce PCCs, calyculin A, a potent protein phosphatase inhibitor, was used at a final concentration of 80 nM. Attached cells and cells put into suspension by trypsinization were incubated with calyculin A at 37 degrees C for 1 hour. Calyculin A was able to induce PCCs in all the phases of the cell cycle with the tumour cell lines giving the highest PCC frequency. No systematic differences were observed between attached cells and cells put into suspension by trypsinization. However, a cytotoxic effect that led to the loss of 50% to 80% of the treated cells was observed. The cytotoxic effect was more severe in the fibroblast than in the tumour cell lines. The appearance of deformed, fragile and fragmented nuclei with no particular chromatin condensation would explain to some extent this cytotoxic effect. A better understanding of the mechanism of action of calyculin A would help generalizing its use to study interphase chromosome aberrations.
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PMID:Differential induction of premature chromosome condensation by calyculin A in human fibroblast and tumor cell lines. 1036 32

We described the occurrence of 4 transcripts differentially displayed between syngeneic murine B16F10 (metastatic melanoma) and Melan-a (immortalised melanocytes) cell lines. We now report that one such transcript, which is B16F10-specific, represents a protein phosphatase-2A B' regulatory subunit. No expression of this transcript was detected in the weakly metastatic B16F1 by Northern blotting. Moreover, the transcript was not expressed by spontaneously immortalised, non-tumorigenic, melanocytes (Melan-Ab and Melan-a2), nor was it expressed by ras-transformed, tumourigenic melanocytes (Melan-Ab-LTR-ras). Cloning of the 5'-end region of this transcript (termed band 8A) from B16F10 cells revealed an intracisternal A-particle insertion, including the long terminal repeat region, which could account for the observed high expression in B16F10 cells. Single cell clones of B16F10 manifested an experimental metastasis capacity, which correlated with band 8A expression with the lowest expressors being least metastatic. The human homologue of the B' regulatory subunit, B56gamma, is expressed preferentially at the mRNA level in human melanoma cell lines compared with normal epidermal melanocytes. In situ hybridisation studies on human clinical samples detected high expression of this gene in a number of malignant melanomas. Our results imply strongly that this protein phosphatase-2A regulatory subunit may have a role in melanoma tumour progression.
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PMID:Identification by differential display of a protein phosphatase-2A regulatory subunit preferentially expressed in malignant melanoma cells. 1041 69

Cytostatin, which is isolated from a microbial cultured broth as a low molecular weight inhibitor of cell adhesion to extracellular matrix (ECM), has anti-metastatic activity against B16 melanoma cells in vivo. In this study, we examined a target of cytostatin inhibiting cell adhesion to ECM. Cytostatin inhibited tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin upon B16 cell adhesion to fibronectin. While the amount of FAK was not affected by cytostatin, electrophoretically slow-migrating paxillin appeared. Alkaline phosphatase treatment diminished cytostatin-induced slow-migrating paxillin. Furthermore, cytostatin increased intracellular serine/threonine-phosphorylated proteins and was found to be a selective inhibitor of protein phosphatase 2A (PP2A). Cytostatin inhibited PP2A with an IC(50) of 0.09 microgram/ml in a non-competitive manner against a substrate, p-nitrophenyl phosphate, but it had no apparent effect on other protein phosphatases including PP1, PP2B and alkaline phosphatase even at 100 microgram/ml. On the contrary, dephosphocytostatin, a cytostatin analogue, without inhibitory effect on PP2A did not affect B16 cell adhesion including FAK and paxillin. These results indicate that cytostatin inhibits cell adhesion through modification of focal contact proteins such as paxillin by inhibiting a PP2A type protein serine/threonine phosphatase. This is the first report that describes a drug with anti-metastatic ability that inhibits PP2A selectively.
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PMID:Cytostatin, an inhibitor of cell adhesion to extracellular matrix, selectively inhibits protein phosphatase 2A. 1055 74

Both F10 and BL6 sublines of B16 mouse melanoma cells are metastatic after intravenous injection, but only BL6 cells are metastatic after subcutaneous injection. Retrotransposon insertion was found to produce an N-terminally truncated form (Deltagamma1) of the B56gamma1 regulatory subunit isoform of protein phosphatase (PP) 2A in BL6 cells, but not in F10 cells. We found an interaction of paxillin with PP2A C and B56gamma subunits by co-immunoprecipitation. B56gamma1 co-localized with paxillin at focal adhesions, suggesting a role for this isoform in targeting PP2A to paxillin. In this regard, Deltagamma1 behaved similarly to B56gamma1. However, the Deltagamma1-containing PP2A heterotrimer was insufficient for the dephosphorylation of paxillin. Transfection with Deltagamma1 enhanced paxillin phosphorylation on serine residues and recruitment into focal adhesions, and cell spreading with an actin network. In addition, Deltagamma1 rendered F10 cells as highly metastatic as BL6 cells. These results suggest that mutations in PP2A regulatory subunits may cause malignant progression.
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PMID:A truncated isoform of the PP2A B56 subunit promotes cell motility through paxillin phosphorylation. 1067 25

The phosphatase 2A (PP2A) is one of the major cellular serine-threonine phosphatases. It was recently shown that the gene encoding for the beta isoform of its subunit A, PPP2R1B, is altered in human lung and colorectal carcinomas, suggesting a role in human tumorigenesis. Here, we report the detection of mutations in breast, lung carcinomas and melanomas in the genes of both alpha (PPP2R1A) and beta isoforms. Mutations affecting PPP2R1B were found in four breast carcinomas, while mutations in PPP2R1A were found in carcinomas of the breast and of the lung and in one melanoma. Most of the mutations affecting PPP2R1B were exons deletions, suggesting abnormal splicing. These splicing abnormalities were detected in tumor samples in the absence of the normal splicing product, and were not found in several normal controls. In one case, a homozygous deletion present in tumor DNA, and not in the matched normal control was demonstrated. Mutations affecting the PPP2R1A gene were nucleotide substitutions changing highly conserved amino acids and one frame-shift. Although the frequency of alterations is low, the inclusion of both isoforms of subunit A in the genes mutated in human cancer and the addition of breast cancer to the list of neoplasms in which PPP2R1B is altered, strengthen the potential role of PP2A in human tumorogenesis.
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PMID:Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. 1071 7

The authors previously showed that monocytes treated with calcium ionophore (CI) acquire characteristics of mature dendritic cells (DC) in part through a calcineurin-dependent pathway. In this study, the authors evaluated the ability of granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-2 (IL-2), and interleukin-12 (IL-12) alone or in combination with CI to induce DC characteristics in peripheral blood monocytes. Monocytes obtained by leukapheresis and countercurrent centrifugal elutriation were cultured with calcium, cytokines, or both, profiled by flow cytometry, and assessed for antigen uptake and sensitization of autologous CD8+ T cells to antigen. Monocytes treated with the combination of GM-CSF, IL-2, and IL-12 resulted in immunophenotypic and antigen uptake profiles typical of immature DC, including loss of surface CD14 expression, de novo low-level expression of B7.1, negligible CD83 expression, marked enhancement of CD40 and ICAM-1, and high major histocompatibility complex class I and II levels. A high level of antigen uptake by macro-pinocytosis was observed. In contrast, CI treatment significantly up-regulates B7.1, B7.2, CD40, CD54, and CD83 and substantially down-regulates CD14 and macro-pinocytosis, a profile consistent with mature DC. Many CI-induced modulations, but none resulting from cytokine treatment alone, were inhibited by the calcineurin phosphatase inhibitor cyclosporin A. Compared with monocytes treated with CI alone, combined treatment of monocytes with GM-CSF, IL-2, IL-12, and CI augmented B7.1 and CD83 expression and enhanced sensitization of autologous CD8+ T cells to melanoma-antigen-derived peptides. These results suggest that several independent pathways of DC activation can cooperatively enhance the function of monocyte-derived DC.
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PMID:Granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-12 synergize with calcium ionophore to enhance dendritic cell function. 1083 60

A tumor suppressor gene at 10q 23.3, designated PTEN, encoding a dual specificity phosphatase with lipid and protein phosphatase activity, has been shown to play an important role in the pathogenesis of a variety of human cancers. Germline mutations in PTEN cause Cowden syndrome (CS), which is characterized by multiple hamartomas and a high risk of breast and thyroid cancers. Frequent loss of heterozygosity at 10q is found in both early and advanced-stage sporadic melanomas; however, mutations or deletions in PTEN are detected mainly in melanoma cell lines. In this study, we examined PTEN expression in 34 unselected sporadic melanomas (4 primary melanomas, 30 metastases) using immunohistochemistry and correlated this with the results of structural studies of this gene. Immunostaining of 34 melanoma samples revealed no PTEN expression in 5 (15%) and low PTEN expression in 17 (50%), whereas the rest of the tumors (35%) had high levels of expression. Hemizygous deletion was found in 32% of the tumors but neither intragenic PTEN mutation nor biallelic deletion was found in any of the samples. Of the 5 melanomas showing no PTEN expression, 4 had no mutation or deletion of PTEN. Of the 13 tumors having weak PTEN immunoreactivity and informative loss of heterozygosity results, 6 had evidence of hemizygous allelic loss of PTEN while the remaining 7 had intact PTEN. These results strongly support PTEN as a major tumor suppressor on 10q involved in melanoma tumorigenesis and suggest an epigenetic mechanism of biallelic functional inactivation not previously observed in other cancers where PTEN might be involved.
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PMID:Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. 1102 16


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