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)

Preterm birth is associated with the majority of all death and chronic disability related to pregnancy, birth and the neonatal period. The costs to families and to the health care system are enormous. Current approaches to prevent or arrest preterm labour have been unsuccessful. This failure is largely based on our poor understanding of the regulation of the timing and maintenance of parturition. Oxytocin (OT) is the most potent known uterine stimulant. It is produced in the hypothalamus and secreted into the maternal bloodstream. However, OT also is produced within the uterine decidua in late gestation and the concentrations increase around the time of labour onset. The receptor for OT (OTR) is a G-protein coupled receptor linked through G alpha(q/11) to phospholipase C (PLC). Activation of PLC causes increased inositol trisphosphate (IP3) and diacyl glycerol (DAG). IP3 activates specific receptors in the sarcoplasmic reticulum to release Ca2+ into the cytosol. This may induce further influx of Ca2+ from the extracellular space and the increased Ca2+, after binding to calmodulin, activates myosin light chain kinase to phosphorylate myosin light chains (MLC) and cause contraction of the myocyte. DAG activates protein kinase C (PKC), several isoforms of which have been implicated in uterine contraction, but the substrates for this enzyme in the uterine myocyte are essentially unknown. Oxytocin may also cause "Ca2+-sensitization," a process whereby there is a greater contractile force generated from a given increase in cytosolic Ca2+, although the contribution of this process to myometrial contraction remains an area of debate. This phenomenon occurs mainly due to inhibition of myosin light chain phosphatase (MLCP), the enzyme that reverses the phosphorylation of MLC. There are several important potential mediators of this MLCP-inhibitory pathway in the myometrium, including the small monomeric G-protein RhoA, its downstream kinase Rho-associated kinase (ROK). and the 17-kDa PKC-potentiated inhibitor of protein phosphatase 1c (CPI-17). The roles in the myometrium of other recently identified MLCP interacting molecules also requires further investigation. These Ca2+-sensitization pathways could be important in the mechanisms underlying pre-term or term labour. An increased understanding of the complexities of the multitude of regulatory mechanisms for uterine contractility may lead to new pharmacologic agents for the prevention or reversal of uterine contractions. This, in turn, is necessary to facilitate the development of novel and effective strategies to reduce the incidence of preterm birth.
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PMID:Oxytocin and parturition: a role for increased myometrial calcium and calcium sensitization? 1712 23

Five Pmt isoforms O-mannosylate secretory proteins in Candida albicans. Comparisons of genome-wide transcript patterns of each pmt mutant revealed commonly downregulated genes involved in glycolysis and glycerol production. Increased phosphorylation of the Cek1p- but not the Mkc1p-MAP kinase, as well as increased transcript levels for some stress-related genes were detected in the pmt1 strain but not in the other pmt mutants. The transcriptomal pattern after short-term inhibition of Pmt1p activity confirmed stress responses, but did not indicate an alteration of glycolytic flow. Short- but not long-term adaptation to Pmt1p inhibition required signalling components Cek1p, Mkc1p, Efg1p and Tpk1p. Cna1p (calcineurin) but not its downstream effectors Crz1p and Crz2p was generally essential to allow growth during Pmt1p inhibition; accordingly, cyclosporin A strongly inhibited growth of the pmt1 mutant. The lack of Pmt isoforms influenced transcript levels for the remaining isoforms both positively and negatively, suggesting complex cross-regulation among PMT genes. These results confirm individual functions of Pmt isoforms but suggest a common biphasic adaptation response to Pmt deficiency. While known signalling pathways modulate adaptation for a short-term, long-term adaptation requires calcineurin, adjustments of remaining Pmt activities and of glycolytic flow.
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PMID:Transcriptional and physiological adaptation to defective protein-O-mannosylation in Candida albicans. 1750 32

Changes in thyroid status are associated with profound alterations in biochemical and physiological functioning of cardiac muscle, although its impact on cardiac energy metabolism is still debated. Similarities between the changes in cardiac gene expression in pathological hypertrophy leading to heart failure and hypothyroidism prompted scientists to suggest a role for thyroid hormone status in the development of metabolic and functional alterations in this disease. We thus investigated the effects of hypothyroidism on cardiac energy metabolism. Hypothyroid state (HYPO) was induced by thyroidectomy and propyl-thio-uracyl in male rats for 3 weeks. We examined the effects of hypothyroid state on oxidative capacity and mitochondrial substrate utilization by measuring oxygen consumption of saponin permeabilized cardiac fibers, mitochondrial biogenesis by reverse transcription polymerase chain reaction and energy metabolism, and energy transfer enzymes by spectrophotometry. The results show that maximal oxidative capacity of the myocardium was decreased from 24.9 +/- 0.9 in control (CT) to 19.3 +/- 0.7 micromol O(2) min(-1) g dry weight(-1) in HYPO. However, protein content and messenger RNA (mRNA) of PGC-1alpha and mRNA of its transcription cascade that is thought to control mitochondrial content in normal myocardium and heart failure, were unchanged in HYPO. Mitochondrial utilization of glycerol-3P (-70%), malate (-45%), and octanoate (-24%) but not pyruvate was decreased in HYPO. Moreover, the creatine kinase system and energy transfer were hardly affected in HYPO. Besides, hypothyroidism decreased the activation of other signaling pathways like p38 mitogen-activated protein kinases, AMP-activated protein kinase, and calcineurin. These results show that cellular hypothyroidism can hardly account for the specific energetic alterations of heart failure.
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PMID:Mitochondrial and energetic cardiac phenotype in hypothyroid rat. Relevance to heart failure. 1763 11

We have previously reported that central repeated units (CRUs) of Ahnak act as a scaffolding protein networking phospholipase Cgamma and protein kinase C (PKC). Here, we demonstrate that an Ahnak derivative consisting of four central repeated units binds and activates PKC-alpha in a phosphatidylserine/1,2-dioleoyl-sn-glycerol-independent manner. Moreover, NIH3T3 cells expressing the 4 CRUs of Ahnak showed enhanced c-Raf, MEK, and Erk phosphorylation in response to phorbol 12-myristate 13-acetate (PMA) compared with parental cells. To evaluate the effect of loss-of-function of Ahnak in cell signaling, we investigated PKC activation and Raf phosphorylation in embryonic fibroblast cells (MEFs) of the Ahnak knock-out (Ahnak(-/-)) mouse. Membrane translocation of PKC-alpha and phosphorylation of Raf in response to PMA or platelet-derived growth factor were decreased in Ahnak null MEF cells compared with wild type MEFs. Several lines of evidence suggest that PKC-alpha activity is regulated through association with protein phosphatase 2A (PP2A). A co-immunoprecipitation assay indicated that the association of PKC-alpha with PP2A was disrupted in NIH3T3 cells expressing 4 CRUs of Ahnak in response to PMA. Consistently, Ahnak null MEF cells stimulated by PMA showed enhanced PKC-PP2A complex formation, and add-back expression of Ahnak into Ahnak null MEF cells abolished the PKC-PP2A complex formation in response to PMA. These data indicate that Ahnak potentiates PKC activation through inhibiting the interaction of PKC with PP2A.
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PMID:Ahnak protein activates protein kinase C (PKC) through dissociation of the PKC-protein phosphatase 2A complex. 1817 70

The highly efficient formation of phosphatidic acid from exogenous 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) in rat brain synaptic nerve endings (synaptosomes) from cerebral cortex and hippocampus is reported. Phosphatidic acid synthesized from SAG or 1,2-dipalmitoyl-sn-glycerol (DPG) was 17.5 or 2.5 times higher, respectively, than from endogenous synaptosomal diacylglycerides. Insulin increased diacylglycerol kinase (DAGK) action on endogenous substrate in synaptic terminals from hippocampus and cerebral cortex by 199 and 97%, respectively. Insulin preferentially increased SAG phosphorylation from hippocampal membranes. In CC synaptosomes insulin increased phosphatidic acid (PA) synthesis from SAG by 100% with respect to controls. Genistein (a tyrosine kinase inhibitor) inhibited this stimulatory insulin effect. Okadaic acid or cyclosporine, used as Ser/Threo protein phosphatase inhibitors, failed to increase insulin effect on PA formation. GTP gamma S and particularly NaF were potent stimulators of PA formation from polyunsaturated diacylglycerol but failed to increase this phosphorylation when added after 5 min of insulin exposure. GTP gamma S and NaF increased phosphatidylinositol 4,5 bisphosphate (PIP2) labeling with respect to controls when SAG was present. On the contrary, they decreased polyphosphoinositide labeling with respect to controls in the presence of DPG. Our results indicate that a DAGK type 3 (DAGKepsilon) which preferentially, but not selectively, utilizes 1-acyl-2-arachidonoyl-sn-glycerol and which could be associated with polyphosphoinositide resynthesis, participates in synaptic insulin signaling. GTP gamma S and NaF appear to be G protein activators related to insulin and the insulin receptor, both affecting the signaling mechanism that augments phosphatidic acid formation.
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PMID:Insulin action on polyunsaturated phosphatidic acid formation in rat brain: an "in vitro" model with synaptic endings from cerebral cortex and hippocampus. 1913 Feb 21

Maintenance of the integrity of the cell wall in fungi is essential. One mechanism that cells use to maintain cell wall integrity in response to cell wall damage is to up-regulate chitin synthesis. In Candida albicans, the PKC cell wall integrity, Ca(2+)/calcineurin and high osmolarity glycerol (HOG) signalling pathways co-ordinately regulate chitin synthesis in response to cell wall stress. The transcription factors downstream of these pathways and their DNA binding sites within the promoters of target genes are well characterised in Saccharomyces cerevisiae, but not in C. albicans. The promoters of the C. albicans class I CHS genes (CaCHS2 and CaCHS8) were functionally dissected with the aim of identifying and characterising the transcription factors and promoter elements that mediate the transcriptional up-regulation of CaCHS2 and CaCHS8 in response to cell wall stress. This analysis provided evidence that the PKC cell wall integrity pathway may operate through RLM1-elements in the CaCHS2 and CaCHS8 promoters, but that promoter sequences that respond to the Ca(2+)/calcineurin and HOG signalling pathways in S. cerevisiae did not directly regulate chitin synthase 2 and 8 gene transcription in C. albicans.
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PMID:Dissection of the Candida albicans class I chitin synthase promoters. 1915 67

Fungi occupy diverse environments and are subjected to many extreme conditions. Among the stressful conditions faced by fungi are pH changes, osmotic changes, thermal changes, oxide radicals, nutrient deprivation, and exposure to chemicals. These adversities can be found either in the environment or in animal and human hosts. The cell wall integrity (CWI) pathway provides a means to fortify and repair damages to the cell wall in order to withstand stressful environments. The CWI pathway in comprised of cell wall stress sensors that lead to activation of a mitogen-activated protein kinase (MAPK) cascade. Signaling through the MAPK cascade leads to expression of transcription factors that facilitate biosynthesis of cell wall components and actin organization. Given the relatively limited number of components of the CWI pathway and the very diverse stimuli, there must be a means of expanding the pathway. To manage the diverse stress conditions, the CWI pathway cross talks with other pathways or proteins, and these cross talk events enhance the signaling capabilities of the CWI pathway. Lateral influences that facilitate maintaining the cell wall under stress conditions are TOR signaling, calcineurin signaling, the high-osmolarity glycerol pathway, the cyclic AMP-protein kinase A pathway, and additional proteins. In this article, we highlight several of the cross talk events that have been described for Saccharomyces cerevisiae and several other fungi.
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PMID:Our paths might cross: the role of the fungal cell wall integrity pathway in stress response and cross talk with other stress response pathways. 1971 45

The double disruptant of the S. cerevisiae protein phosphatase (PPase) genes, PTP2 (phosphotyrosine-specific PPase) and MSG5 (phosphotyrosine and phosphothreonine/serine-PPase) causes calcium-sensitive growth (Cas). Previous study using Fluorescent-activated cell sorting (FACS) analysis showed that this growth defect with calcium occurs at G1-S transition in the cell cycle. We discovered that six non-essential protein kinase (PKase) disruptions (Deltabck1, Deltamkk1, Deltaslt2/Deltampk1, Deltamck1, Deltassk2 and Deltayak1) suppressed the Cas-phenotype of the Deltaptp2 Deltamsg5 double disruptant. Bck1p, Mkk1p and Slt2p are components of the mitogen-activated protein kinase (MAPK) cascade of cell wall integrity pathway (Slt2 pathway), and Mck1p is its down regulator. Ssk2p is the MAPK kinase kinase of the high-osmolarity glycerol (HOG) pathway, while Yak1p is a negative regulator for the cAMP-dependent PKA pathway. FACS analysis revealed that only the disruption of Deltassk2 and Deltayak1 but not Deltabck1, Deltamkk1, Deltaslt2 and Deltamck1 was able to suppress the delayed G1-S transition, suggesting that suppression of the growth defect is not always accompanied by suppression of the G1-S transition delay. The discovery of these PKases as suppressors revealed that in addition to the previously anticipated Slt2 pathway, HOG, Yak1p and Mck1p regulatory pathways may also be involved in the calcium sensitivity of the Deltaptp2 Deltamsg5 double disruptant.
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PMID:Identification of protein kinase disruptions as suppressors of the calcium sensitivity of S. cerevisiae Deltaptp2 Deltamsg5 protein phosphatase double disruptant. 2005 84

Attenuated activity of echinocandin antifungals at high concentrations, known as the "paradoxical effect," is a well-established phenomenon in Candida albicans and Aspergillus fumigatus. In the yeast C. albicans, upregulation of chitin biosynthesis via the protein kinase C (PKC), high-osmolarity glycerol response (HOG), and Ca(2+)/calcineurin signaling pathways is an important cell wall stress response that permits growth in the presence of high concentrations of echinocandins. However, nothing is known of the molecular mechanisms regulating the mold A. fumigatus and its paradoxical response to echinocandins. Here, we show that the laboratory strain of A. fumigatus and five of seven clinical A. fumigatus isolates tested display various magnitudes of paradoxical growth in response to caspofungin. Interestingly, none of the eight strains showed paradoxical growth in the presence of micafungin or anidulafungin. Treatment of the DeltacnaA and DeltacrzA strains, harboring gene deletions of the calcineurin A subunit and the calcineurin-dependent transcription factor, respectively, with high concentrations of caspofungin revealed that the A. fumigatus paradoxical effect is calcineurin pathway dependent. Exploring a molecular role for CnaA in the compensatory chitin biosynthetic response, we found that caspofungin treatment resulted in increased chitin synthase gene expression, leading to a calcineurin-dependent increase in chitin synthase activity. Taken together, our data suggest a mechanistic role for A. fumigatus calcineurin signaling in the chitin biosynthetic response observed during paradoxical growth in the presence of high-dose caspofungin treatment.
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PMID:Transcriptional regulation of chitin synthases by calcineurin controls paradoxical growth of Aspergillus fumigatus in response to caspofungin. 2012

Expression profiles of protein phosphatase (PPase) disruptants were analyzed by use of Pearson's correlation coefficient to find profiles that correlated with those of 316 Reference Gene (RG) disruptants harboring deletions in genes with known functions. Twenty-six Deltappase disruptants exhibited either a positive or negative correlation with 94 RG disruptants when the p value for Pearson's correlation coefficient was >0.2. Some of the predictions that arose from this analysis were tested experimentally and several new Delta ppase phenotypes were found. Notably, Delta sit4 and Delta siw14 disruptants exhibited hygromycin B sensitivity, Delta sit4 and Delta ptc1 disruptants grew slowly on glycerol medium, the Delta ptc1 disruptant was found to be sensitive to calcofluor white and congo red, while the Delta ppg1 disruptant was found to be sensitive to congo red. Because on-going analysis of expression profiles of Saccharomyces cerevisiae disruptants is rapidly generating new data, we suggest that the approach used in the present study to explore PPase function is also applicable to other genes.
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PMID:Deciphering cellular functions of protein phosphatases by comparison of gene expression profiles in Saccharomyces cerevisiae. 2034 64


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