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)

A total of 116,118 basepairs (bp) derived from three cosmids spanning the ERCC1 locus of human chromosome 19q13.3 have been sequenced with automated fluorescence-based sequencers and analysed by polymerase chain reaction amplification and computer methods. The assembled sequence forms two contigs totalling 105,831 bp, which contain a human fosB proto-oncogene, a gene encoding a protein phosphatase, two genes of unknown function and the previously-characterized ERCC1 DNA repair gene. This light band region has a high average density of 1.4 Alu repeats per kilobase. Human chromosome light bands could therefore contain up to 75,000 genes and 1.5 million Alu repeats.
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PMID:Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3. 130 97

Molecular cloning of glycogen synthase kinase-3 (GSK-3) has demonstrated the existence of a novel form, termed GSK-3 beta, which is highly related to the well characterised GSK-3 alpha protein but derived from a distinct gene. The cDNA cloning also revealed a striking degree of amino acid identity between the two GSK-3 proteins, particularly the beta-form, and the zeste-white3/shaggy (zw3sgg) homeotic gene of Drosophila melanogaster. Abrogation of zw3sgg causes pleiotropic effects on fruitfly development affecting segmental organisation and cell fate determination. In view of the potential importance of GSK-3 beta in mammalian development and the lack of previous characterisation, we have expressed this protein in insect cells using recombinant baculovirus. A rapid purification scheme has been developed yielding essentially pure GSK-3 beta protein in three chromatographic steps. The protein has autonomous protein kinase activity and similar, but not identical, substrate preferences to GSK-3 alpha. Both GSK-3 proteins activate the MgATP-dependent form of protein phosphatase-1 and thus display 'factor A' activity. Since GSK-3 beta exhibits an identical site specificity to GSK-3 alpha with respect to phosphorylation of the proto-oncogene/transcription factors c-jun and c-myc, it is likely that the Drosophila zw3sgg protein kinase has a similar specificity for such transcription factors which may underlie the pleiotropic phenotypes observed when the Drosophila homologue is mutationally inactivated.
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PMID:Baculovirus-mediated expression and characterisation of rat glycogen synthase kinase-3 beta, the mammalian homologue of the Drosophila melanogaster zeste-white 3sgg homeotic gene product. 134 4

The product of the c-abl proto-oncogene (c-Abl) is phosphorylated on three sites during interphase and seven additional sites during mitosis. Two interphase and all mitotic c-Abl sites are phosphorylated by cdc2 kinase isolated from either interphase or mitotic cells, with the mitotic cdc2 having an 11-fold higher activity. Inhibition of phosphatases with okadaic acid in interphase cells leads to the phosphorylation of c-Abl mitotic sites, indicating that those sites are preferentially dephosphorylated during interphase. The differential phosphorylation of c-Abl in the cell cycle is therefore determined by an equilibrium between cdc2 kinase and protein phosphatase activities. Treatment of interphase cells with okadaic acid leads to a rounded morphology similar to that observed during mitosis.
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PMID:Differential phosphorylation of c-Abl in cell cycle determined by cdc2 kinase and phosphatase activity. 218 53

In isolated rat hepatocytes angiotensin II and phorbol 12-myristate 13-acetate (PMA) induce the expression of c-fos. We studied the possible transduction pathway(s) involved in this effect using inhibitors of serine-threonine and tyrosine protein kinases. Calphostin and staurosporine, inhibitors of protein kinase C and other serine-threonine protein kinases, block in a dose-dependent manner the effect of angiotensin II and PMA. Interestingly, genistein also blocks the induction of this proto-oncogene, suggesting a role for tyrosine protein kinases. Inhibitors of serine-threonine protein phosphatases, such as okadaic acid, microcystin LR and calyculin also induce c-fos expression. These data suggest that protein phosphatases exert a tonic inhibitory control of c-fos expression. The effect of these phosphatase inhibitors were not blocked by staurosporine, calphostin or genistein. Our results suggest that the expression of c-fos in rat hepatocytes is regulated by complex phosphorylation-dephosphorylation cascade(s) probably involving serine/threonine and tyrosine protein kinase and protein phosphatase activities.
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PMID:Protein kinases and phosphatases modulate c-fos expression in rat hepatocytes. Effects of angiotensin II and phorbol myristate acetate. 753 72

In eucaryotes, M-phase promoting factor (MPF) triggers meiosis in germ cells and mitosis in somatic cells. MPF is composed of two proteins of which one is homologous with the protein kinase encoded by gene cdc2 of Schizosaccharomyces pombe (p34cdc2) and the other is a cyclin whose concentration oscillates during the cell cycle. Inactivation of p34cdc2 (MPF) requires cyclin degradation, which occurs during the metaphase-anaphase transition of the M-phase. Cyclin degradation is not only associated with cell cycle progression, but is also required for this event. At the G2/M transition, p34cdc2 protein kinase is activated and catalyzes phosphorylation of numerous key proteins, thus enabling cell changes to occur. p34cdc2 undergoes multiple-site phosphorylation in a cell cycle-dependent manner. At onset of mitosis, the protein phosphatase cdc25 catalyzes dephosphorylation of the p34cdc2 kinase at the threonine 14 and tyrosine 15 sites. This event may be the rate-limiting step controlling onset of mitosis in cells of vertebrates. A second protein kinase, encoded by the proto-oncogene c-mos, acts as a cytostatic factor preventing cyclin degradation and keeping unfertilized eggs from progressing beyond the second meiotic metaphase.
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PMID:[Control of cell division in eucaryotes]. 839 83

Stimulation of the T cell antigen receptor (TCR) induces a number of intracellular signaling pathways which lead to the transcription of a variety of new genes. Of the newly synthesized proteins, the earliest to be detected on the cell surface is the type II integral membrane protein CD69. Cross-linking of this activation antigen induces signaling events related to T cell activation. The proto-oncogene product Ras has been reported to up-regulate CD69. However, which of the potential effectors of Ras induces the expression of CD69 has remained unclear. Using transient transfection, we have shown a constitutively active form of the serine/threonine kinase Raf-1 to be sufficient to induce CD69 expression in human Jurkat T cells. Raf-1 was further shown to be necessary for PMA-induced CD69 expression, since transfection of a dominant inhibitory form of Raf-1 blocked the up-regulation of CD69 by PMA. In addition, studies with the calcium ionophore ionomycin identified a previously uncharacterized pathway regulating the expression of CD69 in T cells. Elevation of intracellular calcium induced the expression of CD69 in both Jurkat cells and peripheral blood T cells. This effect was sensitive to the immunosuppressive drug cyclosporin A, indicating that calcium-induced CD69 expression is mediated by the protein phosphatase calcineurin. Taken together, these results define Raf-1 as the major signaling mediator of CD69 expression in T cells and suggest that multiple mechanisms exist to regulate the level of CD69 expression following TCR stimulation.
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PMID:Raf-1 provides a dominant but not exclusive signal for the induction of CD69 expression on T cells. 856 3

Recent evidence indicates that the c-Myc proto-oncogene activates transcription of cdc25A. The Cdc25A protein phosphatase is required both for progression through mitosis and for Myc-induced apoptosis, making cdc25A the most attractive Myc target gene identified so far.
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PMID:Cell cycle: on target with Myc. 899 10

The low molecular weight phosphotyrosine-protein phosphatase (LMW-PTP) is a cytosolic phosphotyrosine-protein phosphatase specifically interacting with the activated platelet-derived growth factor (PDGF) receptor through its active site. Overexpression of the LMW-PTP results in modulation of PDGF-dependent mitogenesis. In this study we investigated the effects of this tyrosine phosphatase on the signaling pathways relevant for PDGF-dependent DNA synthesis. NIH 3T3 cells were stably transfected with active or dominant negative LMW-PTP. The effects of LMW-PTP were essentially restricted to the G1 phase of the cell cycle. Upon stimulation with PDGF, cells transfected with the dominant negative LMW-PTP showed an increased activation of Src, whereas the active LMW-PTP induced a reduced activation of this proto-oncogene. We observe that c-Src binding to PDGF receptor upon stimulation is prevented by overexpression of LMW-PTP. These effects were associated with parallel changes in myc expression. Moreover, wild-type and dominant negative LMW-PTP differentially regulated STAT1 and STAT3 activation and tyrosine phosphorylation, whereas they did not modify extracellular signal-regulated kinase activity. However, these modifications were associated with changes in fos expression despite the lack of any effect on extracellular signal-regulated kinase activation. Other independent pathways involved in PDGF-induced mitogenesis, such as phosphatidylinositol 3-kinase and phospholipase C-gamma1, were not affected by LMW-PTP. These data indicate that this phosphatase selectively interferes with the Src and the STATs pathways in PDGF downstream signaling. The resulting changes in myc and fos proto-oncogene expression are likely to mediate the modifications observed in the G1 phase of the cell cycle.
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PMID:The Src and signal transducers and activators of transcription pathways as specific targets for low molecular weight phosphotyrosine-protein phosphatase in platelet-derived growth factor signaling. 950 79

Colony-stimulating factor 1 (CSF-1) is required for the development of monocytes/macrophages from progenitor cells and for the survival and activation of mature macrophages. The receptor for CSF-1 is the product of the c-fms proto-oncogene, which, on binding ligand, can stimulate a mitogenic response in the appropriate cells. To investigate which genes are regulated in response to CSF-1-stimulation in murine bone-marrow-derived macrophages (BMM), we employed mRNA differential display reverse transcriptase-mediated PCR to identify cDNA species induced by CSF-1. Both Northern and Western blot analyses confirmed the increased expression of one of the cDNA species identified as coding for the catalytic subunit of protein phosphatase 2A (PP2A), an observation not previously reported during the response to a growth factor. To determine the significance of the increased expression of PP2A in response to CSF-1, the PP2A inhibitor okadaic acid (OA) was added to CSF-1-treated BMM and found to inhibit DNA synthesis in a dose-dependent manner. Further analysis with flow cytometry in the presence of OA led to the novel conclusion that PP2A activity is critical for CSF-1-driven BMM cell cycle progression in both early G1 and S phases. Surprisingly, in the light of previous studies with other cells, the PP2A-dependent proliferation could be dissociated from activation by extracellular signal-regulated protein kinase (ERK) in macrophages because OA did not affect either the basal or CSF-1-induced ERK activity in BMM. Two-dimensional SDS/PAGE analysis of lysates of 32P-labelled BMM, which had been treated with CSF-1 in the presence or absence of OA, identified candidate substrates for PP2A.
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PMID:Protein phosphatase 2A is expressed in response to colony-stimulating factor 1 in macrophages and is required for cell cycle progression independently of extracellular signal-regulated protein kinase activity. 1021 88

The role of serine/threonine protein phosphatase type 2A (PP2A) in cellular growth control has not yet been thoroughly established. Earlier experiments with okadaic acid, a phosphatase inhibitor, suggested that PP2A may act as an anti-oncogene, although a direct role for this enzyme in the transformation process has not been demonstrated. We therefore investigated whether altered levels of PP2A expression would affect the transformation of mouse fibroblasts by the Ha-ras oncogene. Here we report that cells with elevated levels of PP2A expression were more resistant to focus formation induced by Ha-ras. At the molecular level, this was paralleled by the reduced Ha-ras-stimulated expression of the c-fos promoter, a proto-oncogene target for Ha-ras signaling. Thus, our results support a negative role for PP2A in the process of cellular transformation and may ascribe tumor-suppressing functions to this enzyme.
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PMID:Reduction of Ha-ras-induced cellular transformation by elevated expression of protein phosphatase type 2A. 1032 61


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