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)

In eukaryotic cells, accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) leads to a stress response. Cells respond to ER stress by upregulating the synthesis of ER resident protein chaperones, thus increasing the folding capacity in this organelle. In addition, this response also activates pathways to induce programmed cell death. The stress-induced chaperone synthesis is regulated at the level of transcription. In Saccharomyces cerevisiae, the transmembrane protein, Ire1p, with both serine/threonine kinase and site-specific endoribonuclease activities is implicated as the sensor of unfolded proteins in the ER that transmits the signal from the ER to activate transcription in the nucleus. Activation of the unfolded protein response (UPR) pathway also requires the bZIP transcription factor, Haclp. Although HACl is transcribed constitutively, the mRNA is poorly translated. Upon accumulation of unfolded proteins, Ire1p generates a new processed form of HACl mRNA that is efficiently translated by removal of a 252 base sequence. Using the yeast-interaction trap system we identified additional components of the UPR. A yeast transcriptional coactivator complex, Gcn5p/Ada, which is composed of Gcn5p, Ada2p, Ada3p, and Ada5p, was identified that interacts with Ire1p and Hac1p. Deletion of GCN5, ADA2, and/or ADA3 reduces, and deletion of ADA5 completely abrogates, the transcriptional induction in response to misfolded protein in the ER. A protein phosphatase, Ptc2p, was also identified as a negative regulator of the UPR that directly interacts with and dephosphorylates activated Ire1p. Recently, two mammalian homologues of Ire1p, IRE1 and IRE2, were identified. hIre1p, is preferentially localized to the nuclear envelope and requires a functional nuclease activity to transmit the UPR. These results indicate that some features of the UPR are conserved from yeast to humans and may be composed of a multicomponent complex that is regulated by phosphorylation status and is associated with the nuclear envelope to regulate processes including transcriptional induction and mRNA processing. We propose that activation of Ire1p induces splicing of HACl mRNA as well as engages and targets the Gcn5/Ada/Hac1 protein complex to genes that are transcriptionally activated in response to unfolded protein in the ER. The transcriptional activation is facilitated by targeting the histone acetylase, Gcn5p in yeast, to promote histone acetylation at chromatin encoding ER stress-responsive genes. In addition, activation of Ire1p leads to increased lipid biosynthesis, thereby allowing ER expansion to accommodate increasing lumenal constituents. Under conditions of more severe stress, cells activate an Ire1p-dependent death pathway that is mediated through induction of GADD153/CHOP.
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PMID:The cellular response to protein misfolding in the endoplasmic reticulum. 1044 Feb 30

Hypoxia activates a number of gene products through degradation of the transcriptional coactivator cAMP response element binding protein (CREB). Other transcriptional regulators (e.g., beta-catenin and NF-kappa B) are controlled through phosphorylation-targeted proteasomal degradation, and thus, we hypothesized a similar degradative pathway for CREB. Differential display analysis of mRNA derived from hypoxic epithelia revealed a specific and time-dependent repression of protein phosphatase 1 (PP1), a serine phosphatase important in CREB dephosphorylation. Subsequent studies identified a previously unappreciated proteasomal-targeting motif within the primary structure of CREB (DSVTDS), which functions as a substrate for PP1. Ambient hypoxia resulted in temporally sequential CREB serine phosphorylation, ubiquitination, and degradation (in vitro and in vivo). HIV-tat peptide-facilitated loading of intact epithelia with phosphopeptides corresponding to this proteasome targeting motif resulted in inhibition of CREB ubiquitination. Further studies revealed that PP1 inhibitors mimicked hypoxia-induced gene expression, whereas proteasome inhibitors reversed the hypoxic phenotype. Thus, hypoxia establishes conditions that target CREB to proteasomal degradation. These studies may provide unique insight into a general mechanism of transcriptional regulation by hypoxia.
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PMID:Phosphorylation-dependent targeting of cAMP response element binding protein to the ubiquitin/proteasome pathway in hypoxia. 1103 95

The transcriptional coactivator CREB-binding protein (CBP) is known to play an important role in coupling signal transduction pathways to changes in gene expression. In many cases, this is achieved by the stimulus-specific recruitment of CBP to promoter-bound transcription factors. However, a number of recent studies have suggested that signal transduction pathways can also directly influence CBP-mediated transcriptional activity. Here we show that in Jurkat cells the activity of the CBP C-terminal transactivation domain is strongly upregulated in response to either T cell receptor stimulation or the combination of ionomycin and phorbol ester. We further show that maximal stimulation of CBP-mediated transcription requires the synergistic activation of both the calcineurin and Ras-MAPK signaling pathways. These results indicate that CBP can function as a T cell activation-inducible transcriptional coactivator and is therefore likely to play an important role in T cell activation-induced gene expression.
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PMID:T cell activation signals upregulate CBP-dependent transcriptional activity. 1123 36

Endurance exercise training induces mitochondrial biogenesis in skeletal muscle. The peroxisome proliferator activated receptor co-activator 1alpha (PGC-1alpha) has recently been identified as a nuclear factor critical for coordinating the activation of genes required for mitochondrial biogenesis in cell culture and rodent skeletal muscle. To determine whether PGC-1alpha transcription is regulated by acute exercise and exercise training in human skeletal muscle, seven male subjects performed 4 weeks of one-legged knee extensor exercise training. At the end of training, subjects completed 3 h of two-legged knee extensor exercise. Biopsies were obtained from the vastus lateralis muscle of both the untrained and trained legs before exercise and after 0, 2, 6 and 24 h of recovery. Time to exhaustion (2 min maximum resistance), as well as hexokinase II (HKII), citrate synthase and 3-hydroxyacyl-CoA dehydrogenase mRNA, were higher in the trained than the untrained leg prior to exercise. Exercise induced a marked transient increase (P < 0.05) in PGC-1alpha transcription (10- to > 40-fold) and mRNA content (7- to 10-fold), peaking within 2 h after exercise. Activation of PGC-1alpha was greater in the trained leg despite the lower relative workload. Interestingly, exercise did not affect nuclear respiratory factor 1 (NRF-1) mRNA, a gene induced by PGC-1alpha in cell culture. HKII, mitochondrial transcription factor A, peroxisome proliferator activated receptor alpha, and calcineurin Aalpha and Abeta mRNA were elevated (approximately 2- to 6-fold; P < 0.05) at 6 h of recovery in the untrained leg but did not change in the trained leg. The present data demonstrate that exercise induces a dramatic transient increase in PGC-1alpha transcription and mRNA content in human skeletal muscle. Consistent with its role as a transcriptional coactivator, these findings suggest that PGC-1alpha may coordinate the activation of metabolic genes in human muscle in response to exercise.
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PMID:Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. 1256 9

Cardiac hypertrophy is induced by a number of stimuli and can lead to cardiomyopathy and heart failure. Cardiomyocyte hypertrophy is characterized by increased cell size and altered gene expression. By differential-display polymerase chain reaction and Western blotting we found that the transcriptional coactivator MBF1 was upregulated during hypertrophy in cardiomyocyte cultures. Furthermore, MBF1 protein level increased in two animal models of hypertrophy, angiotensin II treatment and aortic banding. MBF1 antisense oligodeoxynuclotides blocked phenylephrine-induced hypertrophy, suggesting MBF1 plays a key role in hypertrophic growth. In contrast, overexpression of MBF1 potentiated the hormone-induced response of the atrial natriuretic peptide promoter. MBF1 overexpressed by transient transfection cooperated with the transcription factor c-Jun in activation of transcription but not with GATA4. MBF1 and c-Jun induced the activity of a transiently transfected atrial natriuretic peptide promoter, whereas neither MBF1 nor c-Jun could induce the promoter alone. Moreover, MBF1 bound to c-Jun in vitro. These data suggest that MBF1 is a transcriptional coactivator of c-Jun regulating hypertrophic gene expression. Inhibitor studies suggested that MBF1 activates the atrial natriuretic peptide promoter independently of the calcineurin and CaMK signaling pathways. Our results indicate that MBF1 participates in hormone-induced cardiomyocyte hypertrophy and activates hypertrophic gene expression as a coactivator of c-Jun.
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PMID:Multiprotein bridging factor 1 cooperates with c-Jun and is necessary for cardiac hypertrophy in vitro. 1272 99

Calcium is a key element in intracellular signaling in skeletal muscle. Changes in intracellular calcium levels are thought to mediate the fast-to-slow transformation of muscle fiber type. One factor implicated in gene regulation in adult muscle is the nuclear factor of activated T-cells (NFAT) isoform c1, whose dephosphorylation by the calcium/calmodulin-dependent phosphatase calcineurin facilitates its nuclear translocation. Here, we report that differentiated C2C12 myotubes predominantly expressing fast-type MyHCII protein undergo fast-to-slow transformation following calcium-ionophore treatment, with several transcription factors and a transcriptional coactivator acting in concert to upregulate the slow myosin heavy chain (MyHC) beta promoter. Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. To elucidate the mechanism involved in regulating MyHCbeta gene expression, we analyzed the -2.4-kb MyHCbeta promoter construct for cis-regulatory elements. Using electrophoretic mobility shift assays (EMSAs), chromatin immunoprecipitation assays (ChIP), and nuclear complex coimmunoprecipitation (NCcoIP) assays, we demonstrated calcium-ionophore-induced binding of NFATc1 to a NFAT consensus site adjacent to a MyoD-binding E-box. At their respective binding sites, both NFATc1 and MyoD recruited the transcriptional coactivator p300, and in turn, MEF-2D bound to the MyoD complex. The calcium-ionophore-induced effects on the MyHCbeta promoter were shown to be calcineurin-dependent. Together, our findings demonstrate calcium-ionophore-induced activation of the beta MyHC promoter by NFATc1, MyoD, MEF-2D, and p300 in a calcineurin-dependent manner.
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PMID:Activation of the beta myosin heavy chain promoter by MEF-2D, MyoD, p300, and the calcineurin/NFATc1 pathway. 1711 65

CREB is a prototypic bZIP transcription factor and a master regulator of glucose metabolism, synaptic plasticity, cell growth, apoptosis, and tumorigenesis. Transducers of regulated CREB activity (TORCs) are essential transcriptional coactivators of CREB and an important point of regulation on which various signals converge. In this study, we report on the activation of TORC1 through MEKK1-mediated phosphorylation. MEKK1 potently activated TORC1, and this activation was independent of downstream effectors MEK1/MEK2, ERK2, JNK, p38, protein kinase A, and calcineurin. MEKK1 induced phosphorylation of TORC1 both in vivo and in vitro. Expression of the catalytic domain of MEKK1 alone in cultured mammalian cells sufficiently caused phosphorylation and subsequent activation of TORC1. MEKK1 physically interacted with TORC1 and stimulated its nuclear translocation. An activation domain responsive to MEKK1 stimulation was mapped to amino acids 431-650 of TORC1. As a physiological activator of CREB, interleukin 1alpha triggered MEKK1-dependent phosphorylation of TORC1 and its consequent recruitment to the cAMP response elements in the interleukin 8 promoter. Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling.
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PMID:Activation of TORC1 transcriptional coactivator through MEKK1-induced phosphorylation. 1878 53

The purpose of this review is to enlighten the mechanisms of skeletal muscle dysfunction in heart failure. The muscle hypothesis suggests that chronic heart failure (CHF) symptoms, dyspnoea and fatigue are due to skeletal muscle alterations. Hyperventilation due to altered ergoreflex seems to be the cause of shortness of breath. Qualitative and quantitative changes occurring in the skeletal muscle, such as muscle wastage and shift from slow to fast fibers type, are likely to be responsible for fatigue. Mechanisms leading to muscle wastage in chronic heart failure, include cytokine-triggered skeletal muscle apoptosis, but also ubiquitin/proteasome and non-ubiquitin-dependent pathways. The regulation of fibre type involves the growth hormone/insulin-like growth factor 1/calcineurin/ transcriptional coactivator PGC1 cascade. The imbalance between protein synthesis and degradation plays an important role. Protein degradation can occur through ubiquitin-dependent and non-ubiquit-independent pathways. Systems controlling ubiquitin/ proteasome activation have been described. These are triggered by tumour necrosis factor and growth hormone/ insulin-like growth factor 1. However, an important role is played by apoptosis. In humans, and experimental models of heart failure, programmed cell death has been found in skeletal muscle and interstitial cells. Apoptosis is triggered by tumour necrosis factor and in vitro experiments have shown that it can be induced by its second messenger sphingosine. Apoptosis correlates with the severity of the heart failure syndrome. It involves activation of caspases 3 and 9 and mitochondrial cytochrome c release. Sarcomeric protein oxidation and its consequent contractile impairment can form another cause of skeletal muscle dysfunction in CHF.
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PMID:Physiological basis for contractile dysfunction in heart failure. 1899 74

The second messenger calcium plays an essential role in mediating the T-cell receptor (TCR) signaling pathway leading to cytokine production and T-cell clonal expansion. The immunosuppressive drugs cyclosporine A and FK506 have served both as therapeutic agents and as molecular probes for unraveling the protein phosphatase calcineurin as a rate-limiting enzyme involved in the transmission of calcium signal from the cytosol into the nucleus to reprogram gene expression. The use of mouse knockout models has helped to verify and further elucidate the functions of different isoforms of calcineurin in both helper T-cell activation and thymocyte development. In addition to calcineurin, three other classes of calmodulin-binding proteins have also been shown to play important roles in calcium signaling in T cells. Thus, Cabin1 and class II histone deacetylases have been found to constitute a novel calcium-signaling module in conjunction with the transcription factor myocyte enhance factor family and the transcriptional coactivator p300 to suppress and activate cytokine gene transcription in a calcium-dependent manner. The calmodulin-dependent protein kinases II and IV were also shown to play negative and positive regulatory functions, respectively, in TCR-mediated cytokine production. The crosstalks among these and other signal transducers in T cells form an extensive nonlinear signaling network that dictates the final outcome of the TCR signaling pathway.
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PMID:Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved in T-cell activation. 1929 Sep 28

Pathophysiological conditions causing mitochondrial dysfunction and altered transmembrane potential (psim) initiate a mitochondrial respiratory stress response, also known as mitochondrial retrograde response, in a variety of mammalian cells. An increase in the cytosolic Ca2+ [Ca2+]c as part of this signaling cascade activates Ca2+ responsive phosphatase, calcineurin (Cn). Activation of IGF1R accompanied by increased glycolysis, invasiveness, and resistance to apoptosis is a phenotypic hallmark of C2C12 skeletal muscle cells subjected to this stress. The signaling is associated with activation and increased nuclear translocation of a number of transcription factors including a novel NFkappaB (cRel:p50) pathway, NFAT, CREB and C/EBPdelta. This culminates in the upregulation of a number of nuclear genes including Cathepsin L, RyR1, Glut4 and Akt1. We observed that stress regulated transcription activation of nuclear genes involves a cooperative interplay between NFkappaB (cRel:p50), C/EBPdelta, CREB, and NFAT. Our results show that the functional synergy of these factors requires the stress-activated heterogeneous nuclear ribonucleoprotein, hnRNPA2 as a transcriptional coactivator. We report here that mitochondrial stress leads to induced expression and activation of serine threonine kinase Akt1. Interestingly, we observe that Akt1 phosphorylates hnRNPA2 under mitochondrial stress conditions, which is a crucial step for the recruitment of this coactivator to the stress target promoters and culmination in mitochondrial stress-mediated transcription activation of target genes. We propose that mitochondrial stress plays an important role in tumor progression and emergence of invasive phenotypes.
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PMID:Role of calcineurin, hnRNPA2 and Akt in mitochondrial respiratory stress-mediated transcription activation of nuclear gene targets. 2015 90


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