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

---

Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examined the role of protein phosphatase type-1 (PP1), type-2A (PP2A), and mitogen-activated protein kinase phosphatase-1 (MKP-1) in altered mesenteric lymph node (MLN) T cell function in a two-hit model of alcohol (EtOH) intoxication and burn injury. Male rats (250 g) were gavaged with EtOH to achieve a blood EtOH level of approximately 100 mg/dL prior to burn or sham injury (25% total body surface area). MLN T cells harvested 24 h after injury show a significant decrease in p38 and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation in T cells from rats receiving a combined insult of EtOH intoxication and burn injury compared with rats receiving EtOH intoxication or burn injury alone. Treatment of cells with inhibitors of PP1/PP2A [calyculin A (CA) and okadaic acid (OA)] prevented the suppression in T cells p38 and ERK-1/2 activation. In addition, the suppression in interleukin-2 and interferon-gamma production was attenuated in T cells cultured in the presence of CA and OA. MKP-1 inhibitor triptolide did not prevent the suppression in T cells p38/ERK-1/2 and cytokine production. Furthermore, there was a significant decrease in PP1alpha phosphorylation (Thr320) and an increase in PP2A (Tyr307) phosphorylation in T cells following a combined insult of EtOH intoxication and burn injury. As phosphorylation of PP1 at Thr320 and PP2A at Tyr307 led to an inhibition of their enzymatic activities, the decrease in the PP1alpha phosphorylation correlates with an increase in its enzyme activity. Thus, these results suggest that activation of PP1 is likely to play a predominant role in T cell suppression following a combined insult of EtOH intoxication and burn injury.
...
PMID:A role of PP1/PP2A in mesenteric lymph node T cell suppression in a two-hit rodent model of alcohol intoxication and injury. 1638 41

Natural products with distinct biological activities are very promising molecular probes to dissect the novel pathways of biology. FR177391, a product of bacteria, was obtained as a natural compound possessing anti-hyperlipidemic effects. FR177391 enhances differentiation of mouse 3T3-L1 fibroblasts to adipocytes and reduces the circulating levels of triglyceride in C57BL/KsJ-db/db mice, a obese non-insulin-dependent diabetes mellitus animal model, although its mechanism of actions remained to be unknown. We report here that the target protein for FR177391 was identified to be protein phosphatase 2A (PP2A) by employing the method of affinity chromatography. FR177391 potently inhibited PP2A activity at nano molar concentration, and shared its binding pocket with a phosphatase inhibitor, okadaic acid. In addition to the phenotypic alterations, the enhancement for phosphorylation of extracellular signal-regulated kinase (ERK) protein was observed in the FR177391-treated 3T3-L1 cells. These results suggest that prolonged activation of ERK protein due to inhibition of its dephosphorylation by PP2A plays an important role in adipocyte maturation and regulation of the blood revels of lipids.
...
PMID:FR177391, a new anti-hyperlipidemic agent from Serratia. IV. Target identification and validation by chemical genetic approaches. 1639 82

The protein phosphatase 2A (PP2A) acts on several kinases in the extracellular signal-regulated kinase (ERK) signaling pathway but whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown. By using both RNA interference and overexpression of PP2A B regulatory subunits, we show that B56, but not B, family members of PP2A increase ERK dephosphorylation, without affecting its activation by MEK. Induction of the early gene product and ERK substrate IEX-1 (ier3) by growth factors leads to opposite effects and reverses B56-PP2A-mediated ERK dephosphorylation. IEX-1 binds to B56 subunits and pERK independently, enhances B56 phosphorylation by ERK at a conserved Ser/Pro site in this complex and triggers dissociation from the catalytic subunit. This is the first demonstration of the involvement of B56-containing PP2A in ERK dephosphorylation and of a B56-specific cellular protein inhibitor regulating its activity in an ERK-dependent fashion. In addition, our results raise a new paradigm in ERK signaling in which ERK associated to a substrate can transphosphorylate nearby proteins.
...
PMID:B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. 1645 41

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits C2-ceramide-induced cell death through blockade of the mitochondrial apoptotic pathway in rat cerebellar granule neurones. However, the gene induction processes and transcription factors involved in the anti-apoptotic effect of PACAP remain unknown. Here, we show that PACAP and C2-ceramide activate activator protein-1 (AP-1) DNA binding in a dose- and time-dependent manner, but generate different AP-1 dimers. Thus, PACAP increased the proportion of c-Fos and Jun D while C2-ceramide increased c-Jun and reduced c-Fos in AP-1 complexes. In addition, PACAP strongly activated c-Fos gene expression while C2-ceramide markedly increased c-Jun phosphorylation. The effect of PACAP on c-Fos expression was blocked by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor, U0126, while phosphorylation of c-Jun induced by C2-ceramide was abrogated by the protein phosphatase 2A (PP2A) inhibitor, okadaic acid. Transfection of immature granule cells with c-Fos siRNA, which strongly reduced basal and PACAP-stimulated levels of the protein, totally prevented the stimulatory effect of PACAP on Bcl-2 expression. The present study demonstrates that AP-1 complexes containing c-Fos mediate the effect of PACAP on Bcl-2 gene expression in cerebellar granule neurones. Our data also indicate that different AP-1 dimers are associated with the pro-apoptotic effect of C2-ceramide and the anti-apoptotic effect of PACAP.
...
PMID:PACAP and C2-ceramide generate different AP-1 complexes through a MAP-kinase-dependent pathway: involvement of c-Fos in PACAP-induced Bcl-2 expression. 1702 29

Medulloblastoma (MB) is the most common malignant brain tumour in children. Its aetiology is unknown, although several signalling pathways controlling cell proliferation are thought to participate in the progress of the neoplasm. Mutations of the genes encoding proteins participating in the pathways triggered by embryonic growth factors like Sonic hedgehog (Shh) or WNT are often found in MB. Another model of MB development is overexpression or mutation of several types of growth factor receptors, including IGF-IR, EGF-R and PDGFR, that have the ability to activate cellular kinases responsible for promoting cell proliferation. In order to test this hypothesis, in the current paper we tested the activation of two kinases, Akt/PKB (protein kinase B) and Erk (extracellular signal-regulated kinase) and their substrates in 10 sporadic medulloblastoma cases. We show that MBs are a highly heterogeneous group of tumours that show upregulation of various signalling pathways. Nevertheless, both Akt and Erk may contribute to the progression of MB, triggering, at least in some cases, the mTOR (mammalian target of rapamycin) pathway, controlling translation of several cell cycle-related proteins. We hypothesize that Akt and Erk activation may also be associated with downregulation of protein phosphatase 2A (PP2A).
...
PMID:Activation of Akt and Erk pathways in medulloblastoma. 1703 17

Mycobacterium leprae, the causative agent of leprosy, challenges host defense mechanism by impairing the signal transduction of T cells which leads to downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. In this study we sought to identify how soluble forms of M. leprae antigen(s) or particulate (liposome) delivery of the same antigens with two immunomodulators Murabutide and T cell peptide of Trat protein influence the transcription of IL-2 gene in anergic T cells of lepromatous patients. It was demonstrated that MLCwA/ManLAM stimulated cells of BL/LL patients showed defects in both jun-NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activities there by resulting in decreased AP-1 activity. Additionally these cells showed reduced calcium levels, PKC activity and calcineurin (CN) activity. This led to impaired nuclear translocation of NFkappaB and NFAT in these patients. In contrast, when same M. leprae antigen(s) were incorporated with the two immunomodulators in liposomal form, increased transcription of IL-2 gene was observed especially in BL/LL patients which appears to be due to, at least in part, to increased expression of AP-1 Fos and Jun family members, NFkappaB and NFAT1 proteins. The increased expression of these transcription factors correlated with increased ERK/JNK, PKC and CN activities in these patients. Since activation of ERK/JNK/PKC kinases and CN phosphatase are required for stimulation of IL-2 transcription, these data provide a molecular explanation for the block in IL-2 production by M. leprae antigens. Thus the above study revealed suppression of all the three distinct biochemical pathways, viz. Ca-CN-NFAT pathway, PKC-NF-kappaB pathway, and MAPK-AP-1 pathway by M. leprae antigen(s) in anergized T cells of lepromatous patients which were activated by liposomal delivery of M. leprae antigens containing the two immunomodulators leading to optimal induction of IL-2 gene expression, which was required for the activation, and proliferation of T cells in lepromatous patients.
...
PMID:Alterations in T cell signal transduction by M. leprae antigens is associated with downregulation of second messengers PKC, calcium, calcineurin, MAPK and various transcription factors in leprosy patients. 1704 60

Okadaic acid-sensitive serine/threonine phosphatases have been shown to regulate interleukin-2 transcription and T-cell activation. Okadaic acid inhibits protein phosphatase 4 (PP4), a novel PP2A-related serine/threonine phosphatase, at a 50% inhibitory concentration (IC(50)) comparable to that for PP2A. This raises the possibility that some cellular functions of PP2A, determined in T cells by using okadaic acid, may in fact be those of PP4. To investigate the in vivo roles of PP4 in T cells, we generated conventional and T-cell-specific PP4 conditional knockout mice. We found that the ablation of PP4 led to the embryonic lethality of mice. PP4 gene deletion in the T-cell lineage resulted in aberrant thymocyte development, including T-cell arrest at the double-negative 3 stage (CD4(-) CD8(-) CD25(+) CD44(-)), abnormal thymocyte maturation, and lower efficacy of positive selection. PP4-deficient thymocytes showed decreased proliferation and enhanced apoptosis in vivo. Analysis of pre-T-cell receptor (pre-TCR) signaling further revealed impaired calcium flux and phospholipase C-gamma1-extracellular signal-regulated kinase activation in the absence of PP4. Anti-CD3 injection in PP4-deficient mice led to enhanced thymocyte apoptosis, accompanied by increased proapoptotic Bim but decreased antiapoptotic Bcl-xL protein levels. In the periphery, antigen-specific T-cell proliferation and T-cell-mediated immune responses in PP4-deficient mice were dramatically compromised. Thus, our results indicate that PP4 is essential for thymocyte development and pre-TCR signaling.
...
PMID:Conditional knockout mice reveal an essential role of protein phosphatase 4 in thymocyte development and pre-T-cell receptor signaling. 1706 Apr 60

Toll-like receptors (TLRs) expressed in mast cells play important roles in orchestrating host defence against bacterial pathogens. Previous studies demonstrated that TLR2 agonist tripalmitoyl-S-glycero-Cys-(Lys)4 (Pam3Cys) stimulates both degranulation and cytokine production in human mast cells but only induces cytokine production in murine mast cells. To determine the molecular basis for this difference, we utilized a human mast cell line LAD 2, murine lung and bone marrow-derived mast cells (MLMC and BMMC). We found that Pam3Cys caused a sustained Ca2+ mobilization and degranulation in LAD 2 mast cells but not in MLMC or BMMC. Despite these differences, Pam3Cys stimulated equivalent chemokine CCL2 generation in all mast cell types tested. Cyclosporin A (CsA), an inhibitor of Ca2+/calcineurin-mediated nuclear factor of activated T cells (NFAT) activation, blocked chemokine production in LAD 2 but not in MLMC or BMMC. In contrast, inhibitors of nuclear factor kappa B (NF-kappaB) completely blocked CCL2 production in MLMC and BMMC but not in LAD 2 mast cells. Pertussis toxin and U0126, which, respectively, inhibit Galphai, extracellular signal-regulated kinase (ERK) phosphorylation substantially inhibited Pam3Cys-induced CCL2 generation in LAD 2 mast cells but had little or no effect on chemokine generation in MLMC and BMMC. These findings suggest that TLR2 activation in human LAD 2 mast cells and MLMC/BMMC promotes the release of different classes of mediators via distinct signalling pathways that depend on Ca2+ mobilization and G protein usage.
...
PMID:Distinct roles of Ca2+ mobilization and G protein usage on regulation of Toll-like receptor function in human and murine mast cells. 1706 16

Tautomycetin is an antifungal antibiotic retaining potent immunosuppressive function. We have identified the roles of tautomycetin on cellular proliferation and transformation of colorectal cancer cells. The proliferation and anchorage-independent growth of HCT-15, HT-29, and DLD-1 colorectal cancer cells were efficiently inhibited without induction of apoptosis by 150 nmol tautomycetin. These growth inhibitory effects were dependent on p21Cip/WAF induction via the extracellular signal-regulated kinase pathway, and the tautomycetin effects were abolished in HCT-116 colon cells and eight other types of cells that did not induce p21Cip/WAF by 150 nmol tautomycetin. The crucial role of p21Cip/WAF1 in the extracellular signal-regulated kinase pathway-dependent antiproliferative responses by tautomycetin was confirmed by using p21Cip/WAF1 gene-deleted HCT-116 cells. The growth inhibitory effect of tautomycetin was acquired by regulation of Raf-1 activity through inhibition of protein phosphatase type 1 and protein phosphatase type 2A with high preference toward protein phosphatase type 1. Tautomycetin could be a potential drug for colorectal cancer.
...
PMID:Tautomycetin inhibits growth of colorectal cancer cells through p21cip/WAF1 induction via the extracellular signal-regulated kinase pathway. 1717 26

The MEK and extracellular signal-regulated kinase/mitogen-activated protein kinase proteins are established regulators of multicellular development and cell movement. By combining traditional genetic and biochemical assays with a statistical analysis of global gene expression profiles, we discerned a genetic interaction between Dictyostelium discoideum mek1, smkA (named for its role in the suppression of the mek1(-) mutation), and pppC (the protein phosphatase 4 catalytic subunit gene). We found that during development and chemotaxis, both mek1 and smkA regulate pppC function. In other organisms, the protein phosphatase 4 catalytic subunit, PP4C, functions in a complex with the regulatory subunits PP4R2 and PP4R3 to control recovery from DNA damage. Here, we show that catalytically active PP4C is also required for development, chemotaxis, and the expression of numerous genes. The product of smkA (SMEK) functions as the Dictyostelium PP4R3 homolog and positively regulates a subset of PP4C's functions: PP4C-mediated developmental progression, chemotaxis, and the expression of genes specifically involved in cell stress responses and cell movement. We also demonstrate that SMEK does not control the absolute level of PP4C activity and suggest that SMEK regulates PP4C by controlling its localization to the nucleus. These data define a novel genetic pathway in which mek1 functions upstream of pppC-smkA to control multicellular development and chemotaxis.
...
PMID:MEK1 and protein phosphatase 4 coordinate Dictyostelium development and chemotaxis. 1735 63


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---