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)

Interleukin (IL)-3-induced Bcl2 phosphorylation at Ser(70) may be required for its full and potent antiapoptotic activity. However, in the absence of IL-3, increased expression of Bcl2 can also prolong cell survival. To determine how Bcl2 may be functionally phosphorylated following IL-3 withdrawal, a stress-activated Bcl2 kinase (SAK) was sought. Results indicate that anisomycin, a potent activator of the stress kinase JNK/SAPK, can induce Bcl2 phosphorylation at Ser(70) and that JNK1 can be latently activated following IL-3 withdrawal to mediate Bcl2 phosphorylation. JNK1 directly phosphorylates Bcl2 in vitro, co-localizes with Bcl2, and collaborates with Bcl-2 to mediate prolonged cell survival in the absence of IL-3 or following various stress applications. Dominant-negative (DN)-JNK1 can block both anisomycin and latent IL-3 withdrawal-induced Bcl2 phosphorylation (>90%) and potently enhances cell death. Furthermore, low dose okadaic acid (OA), a potent protein phosphatase 1 and 2A inhibitor, can activate the mitogen-activated protein kinases JNK1 and ERK1/2, but not p38 kinase, to induce Bcl2 phosphorylation and prolong cell survival in factor-deprived cells. Since PD98059, a specific MEK inhibitor, can only partially inhibit OA-induced Bcl2 phosphorylation but completely blocks OA-induced Bcl2 phosphorylation in cells expressing DN-JNK1, this supports the conclusion that OA may stimulate Bcl2 phosphorylation via a mechanism involving both JNK1 and ERK1/2. Collectively, these findings indicate a novel role for JNK1 as a SAK and may explain, at least in part, how functional phosphorylation of Bc12 can occur in the absence of growth factor.
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PMID:Novel role for JNK as a stress-activated Bcl2 kinase. 1132 15

Because multiple molecular signal transduction pathways regulate cerebellar long-term depression (LTD), which is thought to be a possible molecular and cellular basis of cerebellar learning, the systematic relationship between cerebellar LTD and the currently known signal transduction pathways remains obscure. To address this issue, we built a new diagram of signal transduction pathways and developed a computational model of kinetic simulation for the phosphorylation of AMPA receptors, known as a key step for expressing cerebellar LTD. The phosphorylation of AMPA receptors in this model consists of an initial phase and an intermediate phase. We show that the initial phase is mediated by the activation of linear cascades of protein kinase C (PKC), whereas the intermediate phase is mediated by a mitogen-activated protein (MAP) kinase-dependent positive feedback loop pathway that is responsible for the transition from the transient phosphorylation of the AMPA receptors to the stable phosphorylation of the AMPA receptors. These phases are dually regulated by the PKC and protein phosphatase pathways. Both phases also require nitric oxide (NO), although NO per se does not show any ability to induce LTD; this is consistent with a permissive role as reported experimentally (Lev-Ram et al., 1997). Therefore, the kinetic simulation is a powerful tool for understanding and exploring the behaviors of complex signal transduction pathways involved in cerebellar LTD.
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PMID:Exploration of signal transduction pathways in cerebellar long-term depression by kinetic simulation. 1146 41

Astrocytes, the most abundant glial cell type in the brain, are considered to have physiological and pathological roles in neuronal activities. We found that reperfusion of cultured astrocytes after Ca2+ depletion causes Ca2+ overload followed by delayed cell death and the Na(+)-Ca2+ exchanger in the reverse mode is responsible for this Ca(2+)-mediated cell injury (Ca2+ paradox injury). The Ca2+ paradox injury of cultured astrocytes is considered to be an in vitro model of ischemia/reperfusion injury, since a similar paradoxical change in extracellular Ca2+ concentration is reported in ischemic brain tissue. This review summarizes the mechanisms underlying the Ca(2+)-mediated injury of astrocytes and the protective effects of drugs against Ca2+ reperfusion injury. This study shows that Ca2+ reperfusion injury of astrocytes is accompanied by apoptosis as evidenced by DNA fragmentation and nuclear condensation. Calpain, reactive oxygen species, calcineurin, caspase-3, and NF-kappa B are involved in Ca2+ reperfusion-induced delayed apoptosis of astrocytes. Several drugs including CV-2619, T-588 and ibudilast protect astrocytes against the delayed apoptosis. CV-2619 prevents astrocytes from the delayed apoptosis by production of nerve growth factor, resulting in an activation of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 (PI3) kinase signal pathways. The protective effect of T-588 is mainly mediated by an activation of MAP/ERK signal cascade. Moreover, ibudilast prevents the Ca2+ reperfusion-induced delayed apoptosis of astrocytes via cyclic GMP signaling pathway. Further studies in this system will contribute to the development of new drugs that attenuate ischemia/reperfusion injury via modulation of astrocytes.
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PMID:[Delayed apoptosis and its regulation in astrocytes]. 1155 50

Cardiac myocytes can undergo programmed cell death in response to a variety of insults and apoptotic elimination of myocytes from the adult myocardium can lead directly to cardiomyopathy and death. Although it remains to be shown that therapy specifically targeting apoptosis will improve the prognosis of ischemic heart disease or heart failure, a number of studies in the past year have shed light on potential ways to intervene in the process. Progress in the past year includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as beta-adrenoceptor agonists, nitric oxide and calcineurin. Further evidence supports the pathophysiologic relevance of apoptosis in human heart disease. The tracking of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein (MAP) kinases p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminus kinase (JNK) in cardiac cell fate.
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PMID:Molecular mechanisms of apoptosis in the cardiac myocyte. 1171 88

Protein phosphatase 2A (PP2A) is a multimeric serine/threonine phosphatase that carries out multiple functions. Although numerous observations suggest that PP2A plays a major role in downregulation of the mitogen-activated protein (MAP) kinase pathway, the precise mechanisms are unknown. To clarify the role of PP2A in growth factor (insulin, epidermal growth factor [EGF], and insulin-like growth factor 1 [IGF-1]) stimulation of the Ras/MAP kinase pathway, simian virus 40 small t antigen was expressed in Rat-1 fibroblasts which overexpress insulin receptors. Small t antigen is known to specifically inhibit PP2A by binding to the A PP2A regulatory subunit, interfering with the ability of PP2A to bind to its cellular substrates. Overexpressed small t protein was coimmunoprecipitated with PP2A and inhibited cellular PP2A activity but did not inhibit protein phosphatase 1 (PP1) activity. Insulin, IGF-1, and EGF stimulation also inhibited PP2A activity. Growth factor-stimulated Ras, Raf-1, MAP kinase, and mitogen-activated extracellular-signal-regulated kinase kinase (MEK) activities were elevated in small-t-antigen-expressing cells. Furthermore, Shc tyrosine phosphorylation and its association with Grb2 were also elevated in small-t-antigen-expressing cells. Expression levels of Shc, Ras, MEK, or MAP kinase and phosphorylation of insulin, EGF, and IGF-1 receptors were not altered. Interestingly, we found that PP2A associated with Shc in the basal state and dissociated in response to insulin and EGF and that this dissociation was inhibited by 65% in small-t-antigen-expressing cells. In addition, we found that PP2A associates with the phosphotyrosine-binding domain (PTB domain) of Shc and that phosphorylation of tyrosine 317 of Shc was required for PP2A-Shc dissociation. We conclude (i) that PP2A negatively regulates the Ras/MAP kinase pathway by binding to Shc, inhibiting tyrosine phosphorylation; (ii) that the Shc-PP2A association is mediated by the Shc PTB domain but the interaction is independent of phosphotyrosine binding, indicating a new molecular function for the PTB domain; (iii) that growth factor stimulation, or small-t-antigen expression, causes dissociation of the PP2A-Shc complex, facilitating Shc phosphorylation and downstream activations of the Ras/MAP kinase pathway; and (iv) that this defines a new mechanism of small-t-antigen action to promote mitogenesis.
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PMID:Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling. 1188 20

Individual subunits of protein phosphatase 2A (PP2A), protein phosphatase 4, and protein phosphatase 5 were knocked out in Drosophila Schneider 2 cells by using RNA interference. Ablation of either the scaffold (A) or catalytic (C) subunits of PP2A caused the disappearance of all PP2A subunits. Treating cells with double-stranded RNA targeting all four of the Drosophila PP2A regulatory subunits caused the disappearance of both the A and C subunits. The loss of PP2A subunits was associated with decreased protein stability indicating that only the heterotrimeric forms of PP2A are stable in intact cells. Ablation of total PP2A by using double-stranded RNA against either the A or C subunit, or specific ablation of the R2/B regulatory subunit, enhanced insulin-induced ERK activation. These results indicated that the R2/B subunit targets PP2A to the mitogen-activated protein (MAP) kinase cascade in Schneider 2 cells, where it acts as a negative regulator. A severe loss of viability occurred in cells in which total PP2A or both isoforms of the Drosophila R5/B56 subunit had been ablated. The reduced viability of these cells correlated with the induction of markers of apoptosis including membrane blebbing and stimulation of caspase-3-like activity. These observations indicated that PP2A has a powerful antiapoptotic activity that is specifically mediated by the R5/B56 regulatory subunits. In contrast to PP2A, ablation of protein phosphatase 4 caused only a slight reduction in cell growth but had no effect on MAP kinase signaling or apoptosis. Depletion of protein phosphatase 5 had no effects on MAP kinase, cell growth, or apoptosis.
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PMID:Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. 1190 83

IL-9 is a Th2 cytokine that exerts pleiotropic activities on T cells, B cells, mast cells, hematopoietic progenitors, and lung epithelial cells, but no effect of this cytokine has been reported so far on mononuclear phagocytes. Human blood monocytes preincubated with IL-9 for 24 h before LPS or PMA stimulation exhibited a decreased oxidative burst, even in the presence of IFN-gamma. The inhibitory effect of IL-9 was specifically abolished by anti-hIL-9R mAb, and the presence of IL-9 receptors was demonstrated on human blood monocytes by FACS. IL-9 also down-regulated TNF-alpha and IL-10 release by LPS-stimulated monocytes. In addition, IL-9 strongly up-regulated the production of TGF-beta1 by LPS-stimulated monocytes. The suppressive effect of IL-9 on the respiratory burst and TNF-alpha production in LPS-stimulated monocytes was significantly inhibited by anti-TGF-beta1, but not by anti-IL-10Rbeta mAb. Furthermore, IL-9 inhibited LPS-induced activation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases in monocytes through a TGF-beta-mediated induction of protein phosphatase activity. In contrast, IL-4, which exerts a similar inhibitory effect on the oxidative burst and TNF-alpha release by monocytes, acts primarily through a down-regulation of LPS receptors. Thus, IL-9 deactivates LPS-stimulated blood mononuclear phagocytes, and the mechanism of inhibition involves the potentiation of TGF-beta1 production and extracellular signal-regulated kinase inhibition. These findings highlight a new target cell for IL-9 and may account for the beneficial activity of IL-9 in animal models of exaggerated inflammatory response.
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PMID:IL-9 inhibits oxidative burst and TNF-alpha release in lipopolysaccharide-stimulated human monocytes through TGF-beta. 1193 70

Angiotensin II activates three major mitogen-activated protein kinases (MAPK) in vascular smooth muscle cells. Although other angiotensin II-induced MAPKs activation require transactivation of a growth factor receptor, the detailed mechanism by which angiotensin II activates c-Jun NH(2)-terminal kinase (JNK) remains unclear. Here, an immunosuppressant, cyclosporin A but not FK506, selectively inhibited angiotensin II-induced JNK activation in vascular smooth muscle cells. However, cyclosporin A had no inhibitory effect on angiotensin II-induced protein synthesis. Thus, angiotensin II-induced JNK activation but not protein synthesis is mediated by a mechanism sensitive to cyclosporin A, which is independent from calcineurin in vascular smooth muscle cells.
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PMID:Cyclosporin A inhibits angiotensin II-induced c-Jun NH(2)-terminal kinase activation but not protein synthesis in vascular smooth muscle cells. 1204 91

Mammalian oocytes are arrested at metaphase of the second meiotic division (MII) before fertilization. When oocytes are stimulated by spermatozoa, they exit MII stage and complete meiosis. It has been suggested that an immediate increase in intracellular free calcium concentration and inactivation of maturation promoting factor (MPF) are required for oocyte activation. However, the underlying mechanism is still unclear. In the present study, we investigated the role of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase, and their interplay in rat oocyte activation. We found that MAP kinase became dephosphorylated in correlation with pronucleus formation after fertilization. Protein kinase C activators, phorbol 12-myriatate 13-acetate (PMA) and 1,2-dioctanoyl-rac-glycerol (diC8), triggered dephosphorylation of MAP kinase and pronucleus formation in a dose-dependent and time-dependent manner. Dephosphorylation of MAP kinase was also correlated with pronucleus formation when oocytes were treated with PKC activators. Effects of PKC activators were abolished by the PKC inhibitors, calphostin C and staurosporine, as well as a protein phosphatase blocker, okadaic acid (OA). These results suggest that PKC activation may cause rat oocyte pronucleus formation via MAP kinase dephosphorylation, which is probably mediated by OA-sensitive protein phosphatases. We also provide evidence supporting the involvement of such a process in fertilization.
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PMID:Activation of protein kinase C induces mitogen-activated protein kinase dephosphorylation and pronucleus formation in rat oocytes. 1208

Although the understanding of how toxicants alter cardiac ion-channel function has matured rapidly over the past 20-30 yr, little is known about how xenobiotics may alter the signaling pathways of cardiac myocyte growth and death. Signaling molecules and pathways responsible for the growth of cardiac myocytes include the mitogen-activated protein kinases (MAPKs), janus kinase-signal transducer and activator of transcription (JAK-STATs), nuclear receptor signaling, calcineurin, and the mobilization of free calcium. Signaling molecules and pathways responsible for programmed cardiac myocyte death include the death receptors, mitochondrial proteins, p53 tumor suppressor protein, ceramide signaling, and caspases. Overlap or "crosstalk" between the various growth and death pathways in the myocardium is evident, and these pathways likely exist in a delicate balance where, for example, slight reductions in growth signaling may favor pathways leading to cardiac myocyte apoptosis. Several classical cardiotoxicants are now known to alter signaling pathways in cardiac myocytes; however, the significance of these effects is not entirely clear. Furthermore, xenobiotics that alter the interstitium or extracellular matrix, or both, may significantly alter signaling pathways in cardiac myocytes. The goal of this review is to summarize current findings regarding the interaction of xenobiotics with myocardial signal transduction pathways in the hope of stimulating new insights and highlighting important areas for future research.
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PMID:Interaction of xenobiotics with myocardial signal transduction pathways. 1218 77


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