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)

We report that the small tumor (small-t) antigen of simian virus 40 (SV40) forms complexes with nuclear protein phosphatase 2A (PP2A) and regulates the phosphorylation and transcriptional transactivation function of the cyclic AMP (cAMP)-regulatory element binding protein (CREB). PP2A coimmunoprecipitated with small t from nuclear extracts from HepG2 cells expressing small t or from rat liver nuclear extracts to which recombinant small t was added. Protein phosphatase 1 was not detected in small-t immunoprecipitates. In HepG2 cells expressing small t, dibutyryl-cAMP (Bt2cAMP) stimulated the phosphorylation of CREB 65-fold, whereas CREB phosphorylation was stimulated only 5- to 8-fold by Bt2cAMP in cells not expressing small t. Small t also inhibited the dephosphorylation of cAMP-dependent protein kinase (PKA)-phosphorylated CREB in rat liver nuclear extracts. In cells expressing small t, Bt2cAMP-stimulated transcription from the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter was enhanced over the level of transcription from the PEPCK promoter in cells not expressing small t. Small t also enhanced Bt2cAMP-stimulated transcription from a Gal4-responsive promoter in cells expressing a chimeric protein containing the Gal4 DNA-binding domain linked to the CREB transactivation domain. However, small t did not stimulate transcription either from a 5' deletion mutant of the PEPCK promoter that is not able to bind CREB or from the Gal4-responsive promoter in the absence of the Gal4-CREB protein. These data suggest that small t enhances Bt2cAMP-stimulated gene transcription by inhibiting the dephosphorylation of PKA-phosphorylated CREB by nuclear PP2A. These findings support previous observations that nuclear PP2A is the primary phosphatase that dephosphorylates PKA-phosphorylated CREB.
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PMID:Simian virus 40 small tumor antigen inhibits dephosphorylation of protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. 806 21

The clinically important immunosuppressant drugs cyclosporin A and FK506 (tacrolimus) inhibit in T-cells calcineurin phosphatase activity and nuclear translocation of the cytosolic component of the transcription factor nuclear factor of activated T-cells (NF-ATc) that is involved in the induction of early genes during T-cell activation. This effect has been proposed to explain at least part of the immunosuppressive effect of these drugs. Previous studies in pancreatic islet cell lines have shown that cyclosporin A and FK506 through inhibition of calcineurin interfere also with the function of the transcription factor cAMP response element binding protein (CREB) that is activated by cAMP and calcium signals and binds to cAMP/calcium response elements (CRE). By transient expression of CRE-reporter genes or GAL4-CREB fusion proteins, the present study shows that inhibition of CREB/CRE-directed transcription by cyclosporin A and FK506 occurs in a great variety of cell types including in cell lines derived from tissues in which adverse effects of the immunosuppressants develop. CREB activity and CRE-mediated transcription was blocked by these drugs also in Jurkat T-cells. When taken together with recent evidence for an essential role of CREB in T-cell activation and proliferation, the present results suggest that inhibition of CREB/CRE-directed transcription may be a molecular mechanism of the immunosuppressive effect of cyclosporin A and FK506.
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PMID:Inhibition of CREB- and cAMP response element-mediated gene transcription by the immunosuppressive drugs cyclosporin A and FK506 in T cells. 934 28

We have examined herein whether membrane Ig (mIg) stimulates junB transcription through a protein kinase A (PKA)-dependent or PKA-independent pathway. PKA phosphotransferase activity was not increased following mIg cross-linking of Bal17 B cells. However, junB transcriptional activation was dependent upon PKA activity, as evidenced by inhibition of goat anti-mouse IgM-stimulated junB promoter-chloramphenicol acetyltransferase reporter gene activity in transfected Bal17 B cells treated with the PKA inhibitor H-89. mIg-stimulated junB promoter-chloramphenicol acetyltransferase activity was also blocked in B cells expressing a specific PKA inhibitor peptide, whereas in vivo expression of an inactive PKA inhibitor peptide variant was not inhibitory. Expression of a mutant cAMP response element binding protein (CREB) containing an inactivated kinase A phosphoacceptor site at Ser133 reduced mIg-stimulated junB transcription. Okadaic acid increased CREB1 phosphorylation at Ser133 and junB transcriptional activation, suggesting the action of protein phosphatase-1 (PP-1) or -2A (PP-2A). Extracts from unstimulated B cells exhibited phosphatase activity against an in vitro PKA-phosphorylated peptide containing the Ser133 phosphoacceptor site. The involvement of a phosphatase activity in regulating mIg-stimulated junB transcription is supported by our finding that extracts from goat anti-mouse IgM-stimulated B cells exhibited a significantly reduced level of Ser133 phosphatase activity. Hence, the level of CREB1 phosphorylation is governed by the balance between PKA and phosphatase activities. junB transcriptional activation results in part from mIg signals that negatively regulate a CREB1-targeted PP-1 or PP-2A activity.
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PMID:Transcriptional regulation of the junB gene in B lymphocytes: role of protein kinase A and a membrane Ig-regulated protein phosphatase. 936 90

A distinct feature of the striatum is that much of the expression of neurochemicals in this forebrain structure follows a compartmental (striosome/matrix) ordering. How this pattern of neurochemical compartmentation is developed and regulated is still unknown. In the present paper we propose that a key feature of this early striatal plasticity is differential control of the activation kinetics of the cAMP response element binding protein (CREB), which in turn influences striatal expression of genes containing cAMP response elements in their promoter sequences. Specifically, we propose that activity-dependent regulation of the kinetics of CREB phosphorylation, brought about early expressed protein phosphatases and protein phosphatase inhibitors in the developing striatal compartments, helps to set up and to maintain patterning of the neurochemical prototypes characteristic of striatal compartments.
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PMID:Activity-regulated phosphorylation of cAMP response element binding protein in the developing striatum: implications for patterning the neurochemical phenotypes of striatal compartments. 969 Nov 96

In human normal thyrocytes, the cAMP-responsive signaling pathway plays a central role in gene regulation, cell proliferation, and differentiation. Constitutive activation of the cAMP signal transduction system has been documented in thyroid autonomously hyperfunctioning adenomas in which activating mutations in either the TSH receptor gene or the Gsalpha protein gene (gsp oncogene) have been described. The molecular mechanism whereby cAMP induces thyrocyte proliferation is unknown, but recent evidence suggests that the transcription factor cAMP response element binding protein (CREB) may serve as an important biochemical intermediate in this proliferative response. Herein we have investigated the expression of CREB in normal and tumoral thyroid tissues from a series of ten unrelated patients with autonomously hyperfunctioning adenomas, previously screened for mutations in the TSH receptor and Gsalpha genes. In all tumors examined, the expression of the activated, phosphorylated form of CREB was markedly reduced compared with that of the corresponding paired normal thyroid tissue, and this reduction was independent of the presence of mutations in the TSH receptor gene and Gsalpha gene. Moreover, no correlation was observed in these tissues between CREB phosphorylation and either protein kinase A activity or protein phosphatase expression. Thus, these data suggest that in human hyperfunctioning thyroid adenomas, the PKA/CREB system does not play a role in cell proliferation.
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PMID:The 3',5'-cyclic adenosine monophosphate response element binding protein (CREB) is functionally reduced in human toxic thyroid adenomas. 1065 Sep 54

In the rat pineal gland cAMP mediates nocturnal induction of the enzyme arylalkylamine N-acetyltransferase (AA-NAT) as well as of transcription factors such as inducible cAMP early repressor (ICER), Fos-related antigen-2 (Fra-2) and JunB. Cyclic AMP stimulates the phosphorylation of the DNA binding protein cAMP response element binding protein (CREB). While cAMP-induced CREB phosphorylation appears to be a prerequisite for AA-NAT and ICER gene expression, it is not known whether CREB phosphorylation accounts for the full cAMP response of the two genes. Furthermore, the significance of CREB phosphorylation in cAMP-activated Fra-2 and JunB transcription is unknown. In the present in vitro study we used the serine/threonine protein phosphatase inhibitor okadaic acid (OA) to phosphorylate CREB without altering intrapineal cAMP concentration. It was observed that OA (10(-7) M) was less effective than dibutyryl cAMP (dbcAMP; 10(-3) M) in inducing AA-NAT mRNA and ICER mRNA, respectively. On the basis of this finding, it is concluded that CREB phosphorylation alone is apparently not sufficient for the full cAMP response of the two genes. By contrast, OA and dbcAMP equally stimulated the accumulation of the mRNAs of Fra-2 and JunB. Therefore cAMP may induce Fra-2 and JunB transcripts via CREB phosphorylation. Our observations suggest that CREB phosphorylation plays a critical role in diversification of cAMP-dependent gene induction in the rat pineal.
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PMID:A differential role of CREB phosphorylation in cAMP-inducible gene expression in the rat pineal. 1080 34

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

This investigation examined the effects of chronic ethanol treatment (15 days) and its withdrawal (24 h) on the expression and phosphorylation of cyclic AMP-response element-binding (CREB) protein in the rat cortex. The effects of chronic ethanol treatment and withdrawal on protein kinase A (PKA) activity and on the expression of the regulatory RII-beta- and the alpha-subtype catalytic subunits of PKA, and on the protein expression of Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) and calcineurin in the rat cortex were also investigated. It was found that ethanol withdrawal but not ethanol treatment produced a significant decrease in the phosphorylated CREB (p-CREB) and CaM kinase IV protein levels in the frontal, parietal, and piriform cortex. Ethanol treatment and its withdrawal had no effect on the protein levels of total CREB in the frontal, parietal, and piriform cortex. On the other hand, ethanol treatment produced a significant reduction in the protein levels of CREB, p-CREB, and CaM kinase IV in the cingulate gyrus, and these changes reverted to normal levels during ethanol withdrawal. Total CREB protein levels were significantly higher in the cingulate gyrus during ethanol withdrawal. It was also observed that mRNA levels of CREB were significantly higher in the rat cortex during ethanol withdrawal but not during ethanol treatment. The protein levels of RII-beta- and alpha-subtype catalytic subunits of PKA and PKA activity were not modified in the rat cortex by chronic ethanol treatment and its withdrawal. Furthermore, the expression of calcineurin in the rat cortex was not altered during ethanol treatment and withdrawal. Taken together, these results suggest the possibility that decreased CREB-dependent events in the neurocircuitry of the frontal, parietal, and piriform cortex may play an important role in the phenomenon of alcohol dependence and also that decreased CREB-dependent events in the neurocircuitry of the cingulate gyrus may play a role in alcohol tolerance.
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PMID:Effects of chronic ethanol intake and its withdrawal on the expression and phosphorylation of the creb gene transcription factor in rat cortex. 1118 17

We have evaluated the importance of the Ser/Thr protein phosphorylation and dephosphorylation for chondrogenesis in high-density chicken limb bud mesenchymal cell cultures (HDCs) by using H89, a cell-permeable protein kinase inhibitor, and okadaic acid (OA), a phosphoprotein phosphatase (PP)-specific inhibitor molecule. When 20 nM OA was applied to the HDCs on Days 2 and 3 of culturing, it significantly inhibited protein phosphatase 2A (PP2A), enhanced cartilage formation, and elevated the activity of cAMP-dependent protein kinase (PKA). Application of 20 microM H89 significantly decreased the activity of PKA and blocked the chondrogenesis in HDCs. Furthermore, OA enhanced cartilage formation and elevated the suppressed activity of PKA even in the H89-pretreated HDCs. cGMP-dependent protein kinase was not detected in HDCs, while protein kinase Cmu (PKCmu), which is also inhibited by nanomolar concentrations of H89, was present throughout the culturing period. Neither OA nor H89 influenced the expression of the catalytic subunit of PKA or the cAMP response element binding protein, CREB. However, a significantly elevated amount of Ser-133-phosphorylated-CREB (P-CREB) was detected following addition of OA, while H89 treatment resulted in a decrease of the amount of P-CREB. Our results demonstrate that PP2A plays a role in the regulation of the PKA signaling pathway and that the phosphorylation level of CREB is influenced by the activity of both enzymes during in vitro chondrogenesis.
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PMID:Protein phosphatase 2A is involved in the regulation of protein kinase A signaling pathway during in vitro chondrogenesis. 1192

The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding protein (CREB) and that both pathways are modulated by their respective endogenous receptor ligands. By addition of specific pathway modulators against the G protein subunit Galphai, phospholipase C, protein kinase C, calcineurin, p38 MAP kinase, and MEK1, we find that the constitutive and ligand-dependent inductions are mediated by multiple yet similar pathways in both receptors. The NFAT and CREB transcription factors and their upstream activators are known inducers of host and virally encoded genes. We propose that the activity of these virally encoded chemokine receptors coordinates host and potentially viral gene expression similarly. As ORF74 is a known inducer of neoplasia, these findings may have important implications for cytomegalovirus-associated pathogenicity.
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PMID:Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74. 1524 64


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