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 expressions of the three catalytic subunits of protein phosphatase (PP) type 1 and 2A, PP1 alpha, PP1 gamma 1, and PP2AC, were examined in 14 cases of three types of osteogenic tumor using immunohistochemical analysis. The percentage of tumor cells stained positively with antiserum against PP1 catalytic subunit-isoform PP1 gamma 1 was significantly higher in malignant osteogenic tumors than in benign osteogenic tumors. Furthermore, malignant osteogenic tumor showed markedly high S-phase fraction in the cell cycle of tumor cells, as compared to benign osteogenic tumors. These results suggest that PP1 gamma 1 is involved in the accelerated growth of malignant cells in osteogenic tumors.
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PMID:Enhanced expression of catalytic subunit isoform PP1 gamma 1 of protein phosphatase type 1 associated with malignancy of osteogenic tumor. 788 91

Reversible protein phosphorylation is a fundamental mechanism by which many biological functions are regulated. Achievement of such control requires the coordinated action of the interconverting enzymes, the protein kinases and protein phosphatases. By comparison with protein kinases, a limited number of protein phosphatase catalytic subunits are present in the cell, which raises the question of how such a small number of dephosphorylating enzymes can counterbalance the action of the more numerous protein kinases. In mammalian cells, four major classes of Ser/Thr-specific phosphatase catalytic subunits have been identified, comprising two distinct gene families. The high degree of homology among members of the same family, PP1, PP2A and PP2B, and the high degree of evolutionary conservation between organisms as divergent as mammals and yeast, implies that these enzymes are involved in fundamental cell functions. Type 1 enzymes appear to acquire specificity by association with targeting regulatory subunits which direct the enzymes to specific cellular compartments, confer substrate specificity and control enzyme activity. In spite of the progress made in determining the structure of the PP2A subunits, very little is known about the control of this activity and about substrate selection. Recent studies have unravelled a significant number of regulatory subunits. The potential existence of five distinct B or B-related polypeptides, some of which are present in multiple isoforms, two A and two C subunit isoforms, raises the possibility that a combinatorial association could generate a large number of specific PP2A forms with different substrate specificity and/or cellular localization. Moreover, biochemical, biological and genetic studies all concur in suggesting that the regulatory subunits may play an important role in determining the properties of the Ser/Thr protein phosphatases and hence their physiological functions.
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PMID:Serine/threonine protein phosphatases in the control of cell function. 794 75

Interleukin-1 (IL-1) has potent immunoregulatory and inflammatory functions. Its activity is mediated by an 80-kDa receptor on the cell surface and leads to activation of other genes. The underlying molecular events are largely unknown. We investigated the role of phosphatases in activation of the IL-2 gene in EL4 thymoma cells. We found that the protein phosphatase PP1 and PP2A inhibitor okadaic acid (OA) alone was able to significantly stimulate IL-2 production by the IL-1-responsive EL4 subline EL4 5D3 and also by the IL-1-nonresponsive EL4 subline EL4D6/76. In the IL-1-responsive cell line OA strongly synergized with phorbol myristate acetate (PMA) and IL-1. In the IL-1-nonresponsive cell line OA synergized with PMA but not with IL-1. Under suboptimal conditions of PMA/OA synergy an additional synergistic effect of IL-1 was shown. This was true for IL-2 and IL-6 production. Sphingomyelinase or sphingosine had no detectable effect. The kinetics of OA- and PMA-induced expression of IL-2 mRNA and IL-2 protein was different. PMA induced maximal expression between 6 and 12 h and was almost undetectable at 24 h. OA-induced expression was first obvious at 12 h and continued longer than 36 h. In both cases IL-1 caused no shift in kinetics, but potentiated the effects of the different tumor promoters. Utilizing IL-2 promoter-CAT constructs we showed in transfection experiments that the synergistic effect was also evident on the transcriptional level. We conclude from the data that phosphatases play an important role for IL-2 expression and that IL-1 can use additional pathways of activation that are different from events induced by PMA or OA.
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PMID:Activation of the mouse IL-2 gene by okadaic acid: synergy with interleukin-1. 794 25

Gene expression of protein phosphatases 1 alpha, 1 gamma 1, 2A alpha, and 2C alpha in 14 rat ascites hepatoma cell lines was studied by Northern blot hybridization. The expression of PP1 alpha and PP2C alpha was increased and decreased, respectively, in all of the ascites hepatoma (AH) cells compared to rat liver, whereas the expression of PP1 gamma 1 and PP2A alpha was increased in about 50% of them. Relative gene expression was affected by several factors, such as harvest time, transplantation rate, percentage of free cells, and sex; the first factor was more important than the others. Relative gene expression of PP1 alpha had a negative correlation with harvest time, whereas gene expression of PP1 gamma 1 and PP2A alpha had a nonlinear (hyperbolic) correlation with harvest time. We suggest that there is a relationship between growth rate and expression of protein phosphatase genes. Our data also suggest that PP1 gamma 1 mRNA is positively controlled by PP2A alpha mRNA.
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PMID:Gene expression of protein phosphatases in rat ascites hepatoma cell lines. 802 93

Two novel protein serine/threonine phosphatases were cloned from a rat fat cell library with probes generated by a polymerase chain reaction-based cloning approach. One of these cDNAs encoded a protein presumably representing the rat homologue of PPV from Drosophila (75% identity of amino acids). The other novel cDNA encoded a protein phosphatase of 499 amino acids and was designated PPT. Its catalytic domain contains motifs typical for protein phosphatases but is only distantly related with PP1, PP2A, and PP2B (38-42% identical amino acids). When expressed in Escherichia coli, the catalytic domain of PPT exhibited protein phosphatase activity (dephosphorylation of phosphorylase a) that was inhibitable by okadaic acid. As a unique feature among other members of this gene family, PPT has an amino-terminal extension of 200 amino acids harboring three tandemly arranged tetratricopeptide repeat (TPR) motifs. This domain has previously been found in other proteins involved in the regulation of RNA synthesis or mitosis. mRNA of PPT was predominantly found in brain and, in lower levels, in testis, but was nearly undetectable in spleen, lung, skeletal muscle, kidney, and liver. It is suggested that the TPR domain of PPT may be involved in the regulation of the function of this novel protein phosphatase.
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PMID:Molecular cloning of a protein serine/threonine phosphatase containing a putative regulatory tetratricopeptide repeat domain. 807 8

We have studied the effect of the protein phosphatase (PP) inhibitor, okadaic acid (OKA) on histamine release elicited by immunologic and non-immunologic stimuli in peritoneal and pleural rat mast cells. When cells were stimulated with antigen (egg albumin), OKA strongly inhibited histamine release. This finding suggests that PP1 and PP2A substrates mediate immunoglobulin E-(IgE) dependent secretion in mast cells. In contrast, after non-immunologic activation of mast cells with different drugs, such as the neuropeptide growth hormone releasing factor (GRF) and the cytostatic agents Adriamycin, navelbine and mitoxantrone, there is no effect of OKA on histamine secretion. These results indicate that IgE-dependent secretion is mediated by substrates of PP1 and PP2A, whereas following non-immunological stimuli, they activate pathways that lead to protein phosphorylation; these proteins are not substrates of PP1 and PP2A.
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PMID:Effect of okadaic acid on immunologic and non-immunologic histamine release in rat mast cells. 811 30

The yeast two hybrid system has been employed to identify cDNAs encoding proteins which interact with the gamma 1 isoform of human protein phosphatase 1. Here we report the isolation of cDNA encoding human protein phosphatase inhibitor. The deduced human sequence of 205 amino acids shows 92% identity to inhibitor 2 from rabbit. Human inhibitor 2 was expressed in E. coli and purified to homogeneity. The expressed human protein inhibited both native and bacterially expressed PP1, with the same Ki (1 nM) as inhibitor 2 purified from skeletal muscle. A gene or pseudogene for inhibitor 2 may be present near the major histocompatibility complex on chromosome 6.
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PMID:Cloning of the complete coding region for human protein phosphatase inhibitor 2 using the two hybrid system and expression of inhibitor 2 in E. coli. 811 16

The sequence of a Drosophila melanogaster cDNA encoding a novel 35 kDa protein serine/threonine phosphatase, termed PPV, is presented. PPV is 40-41% identical to Drosophila PP1, 53% identical to Drosophila PP2A and 63% identical to Saccharomyces cerevisiae SIT4. Complementation studies demonstrated that PPV can functionally rescue a temperature sensitive mutant of SIT4, a protein phosphatase required for the G1 to S transition of the cell cycle. When placed under the SIT4 promoter, PPV cDNA is able to replace the SIT4 gene in S. cerevisiae. The amino-terminal domain of PPV fused to another phosphatase catalytic region (PP1) also rescues the temperature sensitive SIT4 mutant and the SIT4 deletion mutant, implicating this region in binding to regulatory subunits and/or altering specificity. In Drosophila, a substantial transient increase in both PPV mRNA and protein occurs in late syncytial and early cellular blastoderm embryos. At the latter stage PPV is localized to the cytoplasm of cells at the cortex. This increase in PPV correlates with introduction of the G2 phase of the cell cycle, elevated zygotic transcription and cellularization, indicating that PPV may play a role in one or more of these processes.
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PMID:Drosophila protein phosphatase V functionally complements a SIT4 mutant in Saccharomyces cerevisiae and its amino-terminal region can confer this complementation to a heterologous phosphatase catalytic domain. 822 92

The suppressor of position effect variegation (PEV) locus Su-var(3)6 maps to 87B5-10. The breakpoints of deficiencies that define this interval have been placed on a 250-kb molecular map of the region. The locus is allelic to the ck19 complementation group previously shown to encode a type 1 serine-threonine protein phosphatase (PP1) catalytic subunit. When introduced into flies by P element-mediated transformation, a 5.8-kb genomic fragment carrying this gene overcomes the suppressor phenotype of Su-var(3)6(01) and recessive lethality of all mutations of the locus. Four of the mutant alleles at the locus show a broad correlation between high levels of suppression of PEV, a high frequency of aberrant mitosis and low PP1 activity in larval extracts. However, some alleles with low PP1 activity show weak suppression of PEV with a high frequency of abnormal mitosis, whereas others show strong suppression of PEV with normal mitosis. The basis for these discussed.
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PMID:Mutations in the protein phosphatase 1 gene at 87B can differentially affect suppression of position-effect variegation and mitosis in Drosophila melanogaster. 822 13

Complementary DNA encoding a catalytic subunit of protein phosphatase 1, termed PP1 beta, was isolated from a human teratocarcinoma library. Hybridisation with different cDNA fragments showed that all human tissues examined contained 3.1 kb, 4.0 kb and 5.4 kb PP1 beta mRNAs arising from alternative splicing of the 3' noncoding region. The level of the 5.4 kb mRNA relative to the 3.1 kb mRNA was higher in skeletal muscle than in other tissues and the PP1 beta/PP1 alpha mRNA ratio in rabbit tissues was highest in skeletal muscle. The 3' noncoding region of PP1 beta showed extreme conservation (> or = 90% identity) between man and rodents over 1.7 kb, suggesting that this region is of functional importance. The gene for human PP1 beta (PPP1CB) was localised to chromosome 2 by analysis of somatic cell hybrid DNA and mapped to band q23 by fluorescence in situ hybridization. These data show that the genes for three protein phosphatase catalytic subunits PP1 alpha, PP1 beta, PP1 gamma are all located on different chromosomes.
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PMID:Three genes for protein phosphatase 1 map to different human chromosomes: sequence, expression and gene localisation of protein serine/threonine phosphatase 1 beta (PPP1CB). 831 65


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