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 salt-sensitive phenotype of yeast cells deficient in the phosphoprotein phosphatase, calcineurin, was used to identify genes from the higher plant Arabidopsis thaliana that complement this phenotype. cDNA clones corresponding to two different sequences, designated STO (salt tolerance) and STZ (salt tolerance zinc finger), were found to increased tolerance of calcineurin mutants and of wild-type yeast to both Li+ and Na+ ions. STZ is related to Cys2/His2-type zinc-finger proteins found in higher plants, and STO is similar to the Arabidopsis CONSTANS protein in regions that may also be zinc fingers. Although neither protein has sequence similarity to any protein phosphatase, STO was able to at least partially compensate for all tested additional phenotypic effects of calcineurin deficiency, and STZ compensated for a subset of these effects. Salt tolerance produced by STZ appeared to be partially dependent on ENA1/PMR2, a P-type ATPase required for Li+ and Na+ efflux in yeast, whereas the effect of STO on salt tolerance was independent of ENA1/PMR2. STZ and STO were found to be expressed in Arabidopsis roots and leaves, whereas only STO message was detectable in flowers. An apparent increase in the level of STZ mRNA was observed in response NaCl exposure in Arabidopsis seedlings, but the level of STO mRNA was not altered by this treatment.
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PMID:Two classes of plant cDNA clones differentially complement yeast calcineurin mutants and increase salt tolerance of wild-type yeast. 866 38

Calcineurin is a conserved Ca2+/calmodulin-dependent protein phosphatase that plays a critical role in Ca2+ signaling. We describe new components of a calcineurin-mediated response in yeast, the Ca2+-induced transcriptional activation of FKS2, which encodes a beta-1,3 glucan synthase. A 24-bp region of the FKS2 promoter was defined as sufficient to confer calcineurin-dependent transcriptional induction on a minimal promoter in response to Ca2+ and was named CDRE (for calcineurin-dependent response element). The product of CRZ1 (YNL027w) was identified as an activator of CDRE-driven transcription. Crz1p contains zinc finger motifs and binds specifically to the CDRE. Genetic analysis revealed that crz1Delta mutant cells exhibit several phenotypes similar to those of calcineurin mutants and that overexpression of CRZ1 in calcineurin mutants suppressed these phenotypes. These results suggest that Crz1p functions downstream of calcineurin to effect multiple calcineurin-dependent responses. Moreover, the calcineurin-dependent transcriptional induction of FKS2 in response to Ca2+, alpha-factor, and Na+ was found to require CRZ1. In addition, we found that the calcineurin-dependent transcriptional regulation of PMR2 and PMC1 required CRZ1. However, transcription of PMR2 and PMC1 was activated by only a subset of the treatments that activated FKS2 transcription. Thus, in response to multiple signals, calcineurin acts through the Crz1p transcription factor to differentially regulate the expression of several target genes in yeast.
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PMID:Calcineurin acts through the CRZ1/TCN1-encoded transcription factor to regulate gene expression in yeast. 940 35

Ca2+ signals regulate gene expression in animal and yeast cells through mechanisms involving calcineurin, a protein phosphatase activated by binding Ca2+ and calmodulin. Tcn1p, also named Crz1p, was identified as a transcription factor in yeast required for the calcineurin-dependent induction of PMC1, PMR1, PMR2A, and FKS2 which confer tolerance to high Ca2+, Mn2+, Na+, and cell wall damage, respectively. Tcn1p was not required for other calcineurin-dependent processes, such as inhibition of a vacuolar H+/Ca2+ exchanger and inhibition of a pheromone-stimulated Ca2+ uptake system, suggesting that Tcn1p functions downstream of calcineurin on a branch of the calcium signaling pathway leading to gene expression. Tcn1p contains three zinc finger motifs at its carboxyl terminus resembling the DNA-binding domains of Zif268, Swi5p, and other transcription factors. When fused to the transcription activation domain of Gal4p, the carboxy terminal domain of Tcn1p directed strong calcineurin-independent expression of PMC1-lacZ and other target genes. The amino-terminal domain of Tcn1p was found to function as a calcineurin-dependent transcription activation domain when fused to the DNA-binding domain of Gal4p. This amino-terminal domain also formed Ca2+-dependent and FK506-sensitive interactions with calcineurin in the yeast two-hybrid assay. These findings suggest that Tcn1p functions as a calcineurin-dependent transcription factor. Interestingly, induction of Tcn1p-dependent genes was found to be differentially controlled in response to physiological Ca2+ signals generated by treatment with mating pheromone and high salt. We propose that different promoters are sensitive to variations in the strength of Ca2+ signals generated by these stimuli and to effects of other signaling pathways.
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PMID:Tcn1p/Crz1p, a calcineurin-dependent transcription factor that differentially regulates gene expression in Saccharomyces cerevisiae. 940 36

We have purified a form of protein phosphatase 1 (PP1) from HeLa cell nuclei, in which the phosphatase is complexed to a regulatory subunit termed p99. We report here the cloning and characterisation of the p99 component. p99 mRNA is widely expressed in human tissues and immunofluorescence analysis with anti-p99 antibodies showed a punctate nucleoplasmic staining with additional accumulations within the nucleolus. The C-terminus of p99 contains seven RGG RNA-binding motifs, followed by eleven decapeptide repeats containing six or more of the following conserved residues (GHRPHEGPGG), and finally a putative zinc finger domain. Recombinant p99 suppresses the phosphorylase phosphatase activity of PP1 by > 90% and the canonical PP1-binding motif on p99 (residues 396-401) is unusual in that the phenylalanine residue is replaced by tryptophan.
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PMID:Purification and characterisation of p99, a nuclear modulator of protein phosphatase 1 activity. 945 May 50

Serum amyloid A (SAA), a plasma protein inducible in response to many inflammatory conditions, is associated with the pathogenesis of several diseases including reactive amyloidosis, rheumatoid arthritis, and atherosclerosis. We have previously reported an element of the SAA promoter, designated SAA-activating sequence (SAS), that is involved in the inflammation-induced SAA expression, and a nuclear factor, SAS-binding factor (SAF), that interacts with the SAS element has been identified previously (A. Ray and B. K. Ray, Mol. Cell. Biol. 16:1584-1594, 1996). To evaluate how SAF is involved in SAA promoter activation, we have investigated structural features and functional characteristics of this transcription factor. Our studies indicate that SAF belongs to a family of transcription factors characterized by the presence of multiple zinc finger motifs of the Cys2-His2 type at the carboxyl end. Of the three cloned SAF cDNAs (SAF-1, SAF-5, and SAF-8), SAF-1 isoform showed a high degree of homology to MAZ/ZF87/Pur-1 protein while SAF-5 and SAF-8 isoforms are unique and are related to SAF-1/MAZ/ZF87/Pur-1 at the zinc finger domains but different elsewhere. Although structurally distinct, all members are capable of activating SAS element-mediated expression and display virtually identical sequence specificities. However, varying levels of expression of members of this gene family were observed in different tissues. Functional activity of SAF is regulated by a posttranslational event as SAF DNA-binding and transactivation abilities are increased by a protein phosphatase inhibitor, okadaic acid, and inhibited by a protein kinase inhibitor, H7. Consistent with this observation, increased DNA binding of the cloned SAF and its hyperphosphorylation, in response to okadaic acid treatment of the transfected cells, were observed. Taken together, our results suggest that, in addition to tissue-specific expression, SAFs, a family of zinc finger transcription factors, undergo a modification by a posttranslational event that confers their SAA promoter-binding activity and transactivation potential.
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PMID:Isolation and functional characterization of cDNA of serum amyloid A-activating factor that binds to the serum amyloid A promoter. 981 19

Intracellular calcium is one of the important signals that initiates the myogenic program. The calcium-activated phosphatase calcineurin is necessary for the nuclear import of the nuclear factor of activated T cell (NFAT) family members, which interact with zinc finger GATA transcription factors. Whereas GATA-6 plays a role in the maintenance of the differentiated phenotype in vascular smooth muscle cells (VSMCs), it is unknown whether the calcineurin pathway is associated with GATA-6 and plays a role in the differentiation of VSMCs. The smooth muscle-myosin heavy chain (Sm-MHC) gene is a downstream target of GATA-6, and provides a highly specific marker for differentiated VSMCs. Using immunoprecipitation Western blotting, we showed that NFATc1 interacted with GATA-6. Consistent with this, NFATc1 further potentiated GATA-6-activated Sm-MHC transcription. Induction of VSMCs to the quiescent phenotype caused nuclear translocation of NFATc1. In differentiated VSMCs, blockage of calcineurin down-regulated the amount of GATA-6-DNA binding as well as the expression of Sm-MHC and its transcriptional activity. These findings demonstrate that the calcineurin pathway is associated with GATA-6 and is required for the maintenance of the differentiated phenotype in VSMCs.
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PMID:Calcineurin-GATA-6 pathway is involved in smooth muscle-specific transcription. 1188 39

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by several major morphological hallmarks such as senile plaques, neurofibrillary tangles and a loss of cholinergic basal forebrain neurons. Apart from cholinergic markers like choline acetyltransferase and acetylcholinesterase, there have been reports on changes in muscarinic acetylcholine receptors (mAChR) as well as on influences of zinc metabolism in the disease. As recent studies gave hints about a possible link between mAChRs and zinc uptake, the human neuroblastoma cell line SK-SH-SY5Y was used to evaluate the role of M1-mAChR on zinc uptake. Zinc levels were semi-quantitatively detected by using the zinc-specific fluorophor Zn-AF2-DA. In the presence of 1 microM extracellular zinc, M1-mAChR stimulation with talsaclidine increased intracellular zinc levels as did stimulation of PKC by phorbol esters. Furthermore, the effect of extracellular zinc on the expression of the zinc finger protein PNUTS (protein phosphatase 1 nuclear targeting subunit 10) was investigated and revealed an upregulation of PNUTS expression in the presence of 1 microM extracellular zinc by 294% when compared to incubation in zinc free medium. In summary, this report demonstrates that intracellular zinc uptake in SK-SH-SY5Y cells is controlled by M1-mAChR mediated signalling pathways and that zinc may act as a cofactor for transcriptional regulation of zinc finger genes such as PNUTS.
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PMID:Zinc uptake is mediated by M1 muscarinic acetylcholine receptors in differentiated SK-SH-SY5Y cells. 1640 70

Calcineurin is a major player in calcium-dependent signal transduction pathways of eukaryotes. Calcineurin acts on transcription factors (e.g. CRZ1 in Saccharomyces cerevisiae) and governs the expression of genes in a species-dependent fashion. In Candida albicans, the calcineurin pathway is involved in tolerance to antifungal agents, cation homeostasis and virulence. However, the components of the calcineurin pathway are still poorly investigated in this yeast species. Taking S. cerevisiae as a model to reconstitute this pathway, two CRZ1-like genes, CRZ1 and CRZ2 (for calcineurin-responsive zinc finger 1 and 2 genes), were found with C(2)H(2) zinc finger domains. Only CRZ1 was able to restore the calcium hypersusceptibility of a S. cerevisiae crz1Delta mutant and to mediate calcium-dependent gene expression in this yeast species. Several experiments showed that CRZ1 was dependent on calcineurin in C. albicans: (i) phenotypic analysis of a crz1Delta/Delta mutant showed impaired growth as compared with the wild type in the presence of cations (Ca(2+), Mn(2+)) as does a mutant lacking calcineurin subunit A (cnaDelta/Delta) and (ii) a green fluorescent protein (GFP)-Crz1p fusion protein showed a calcium- and calcineurin-dependent nuclear localization. To further analyse the relationship between calcineurin and CRZ1, a comprehensive analysis of calcineurin/Crz1p-dependent gene expression following addition of Ca(2+) (200 mM) was performed. Among the expression of 264 genes altered by at least twofold, the upregulation of 60 genes was dependent on both calcineurin and CRZ1. Interestingly, a motif [5'-G(C/T)GGT-3'] with similarity to the target sequence of Crz1p (GNGGCG/TCA) from S. cerevisiae was identified as a putative regulatory sequence in the upstream regions of these calcineurin/Crz1p-dependent genes. However, additional experiments showed that calcineurin may have other targets in addition to CRZ1. First, CRZ1 was not involved in tolerance to antifungal agents (fluconazole, terbinafine) on the opposite to calcineurin. Second, CRZ1 was only moderately influencing virulence in a mice model of infection which is in sharp contrast to the strong avirulence of cnaDelta/Delta mutant in the same animal model. Even though this work establishes CRZ1 as a calcineurin target, further studies are needed to identify other calcineurin-dependent elements in C. albicans.
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PMID:CRZ1, a target of the calcineurin pathway in Candida albicans. 1646 87

Plant plasma membrane (PM) proteins play important roles in signal transduction during defense response to an attacking pathogen. By using an improved method of PM protein preparation and PM-bound green fluorescent protein fusion protein as a visible marker, we conducted PM proteomic analysis of the rice suspension cells expressing the disease resistance gene Xa21, to identify PM components involved in the early defense response to bacterial blight (Xanthomonas oryzae pv. oryzae). A total of 20 regulated protein spots were observed on 2-D gels of PM fractions at 12 and 24 h after pathogen inoculation, of which some were differentially regulated between the incompatible and compatible interactions mediated by Xa21, with good correlation between biological repeats. Eleven protein spots with predicted functions in plant defense were identified by MS/MS, including nine putative PM-associated proteins H+-ATPase, protein phosphatase, hypersensitive-induced response protein (OsHIR1), prohibitin (OsPHB2), zinc finger and C2 domain protein, universal stress protein (USP), and heat shock protein. OsHIR1 was modified by the microbial challenge, leading to two differentially accumulated protein spots. Transcript analysis showed that most of the genes were also regulated at transcriptional levels. Our study would provide a starting point for functionality of PM proteins in the rice defense.
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PMID:Proteomic analysis of rice plasma membrane reveals proteins involved in early defense response to bacterial blight. 1740 82

Recent years have shown a huge growth in the market of industrial baker's yeasts (Saccharomyces cerevisiae), with the need for strains affording better performance in prefrozen dough. Evidence suggests that during the freezing process, cells can suffer biochemical damage caused by osmotic stress. Nevertheless, the involvement of ion-responsive transcriptional factors and pathways in conferring freeze resistance has not yet been examined. Here, we have investigated the role of the salt-responsive calcineurin-Crz1p pathway in mediating tolerance to freezing by industrial baker's yeast. Overexpression of CRZ1 in the industrial HS13 strain increased both salt and freeze tolerance and improved the leavening ability of baker's yeast in high-sugar dough. Moreover, engineered cells were able to produce more gas during fermentation of prefrozen dough than the parental strain. Similar effects were observed for overexpression of TdCRZ1, the homologue to CRZ1 in Torulaspora delbrueckii, suggesting that expression of calcineurin-Crz1p target genes can alleviate the harmful effects of ionic stress during freezing. However, overexpression of STZ and FTZ, two unrelated Arabidopsis thaliana genes encoding Cys(2)/His(2)-type zinc finger proteins, also conferred freeze resistance in yeast. Furthermore, experiments with Deltacnb1 and Deltacrz1 mutants failed to show a freeze-sensitive phenotype, even in cells pretreated with NaCl. Overall, our results demonstrate that overexpression of CRZ1 has the potential to be a useful tool for increasing freeze tolerance and fermentative capacity in industrial strains. However, these effects do not appear to be mediated through activation of known salt-responding pathways.
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PMID:Overexpression of the calcineurin target CRZ1 provides freeze tolerance and enhances the fermentative capacity of baker's yeast. 1755 46


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