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)

1. Cardiac fibroblasts play an important regulatory role in cardiac remodelling by undergoing proliferation, differentiation and upregulating various gene products, including some cytokines and extracellular matrix (ECM) proteins. A highly potent mediator of cardiac remodelling is angiotensin (Ang) II. 2. In the present study, the suppression subtractive hybridization method was used to identify differentially expressed cDNAs in adult rat cardiac fibroblasts induced by AngII. 3. Following mRNA isolation of non-stimulated and AngII-stimulated cells, cDNAs of both populations were prepared and subtracted by suppression polymerase chain reaction. Sequencing of the partially enriched cDNAs identified 36 genes differentially expressed, including ECM proteins (pro-alpha(1) collagen type III, fibronectin), structural protein (spectrin), enzyme (GTP-specific succinyl-CoA synthetase), transcriptional regulators (glucocorticoid-induced leucine zipper, inhibitor of DNA binding 3) and proteins involved in cell division control (cdc2) or cell signalling (insulin-like growth factor binding protein-3, mutant p53-binding protein, grp75, CGI-121, protein phosphatase type 2A, tspan-2 and Sam68). 4. The diversity of genes identified in the present study further emphasises the central role of AngII in the regulation of cardiac remodelling.
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PMID:Identification of differentially expressed genes induced by angiotensin II in rat cardiac fibroblasts. 1644 97

Sarcopenia is the decline of muscle mass and strength with age. Sarcopenia leads to significant impairment in the ability to carry out normal daily function and thus there is a great need for interventions that will lead to muscle regeneration and repair in the aging population. Age-related sarcopenia in humans, characterized by loss of type I and type II muscle fibers and a decrease in fiber cross-sectional area primarily in type II fibers, can be attenuated by mechanical load on the muscle, which increases cross-sectional area of the remaining fibers, but does not restore fiber numbers characteristic of young muscle. Considerable evidence also implicates age-related declines in muscle insulin-like growth factor action in sarcopenia. IGF-I promotes myoblast proliferation, differentiation, and protein accretion in muscle through multiple signaling mechanisms, including the PI3-kinase, MAP kinase and calcineurin pathways. Exercise and injury induce increases in IGF-I, IGF-I receptors and IGF-I-activated signaling pathways. Although there is evidence that aging muscle retains the ability to synthesize IGF-I, there is also evidence that aging may be associated with attenuation of the ability of exercise to induce an isoform of IGF-I that promotes satellite cell proliferation. Moreover, aging muscle may be resistant to IGF-I, an effect that is reversed by exercise. However, it is clear that over-expression of IGF-I in muscle can protect against age-related sarcopenia.
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PMID:Resistance training, and IGF involvement in the maintenance of muscle mass during the aging process. 1694 53

Eye induction and eye field separation are the earliest events during vertebrate eye development. Both of these processes occur much earlier than the formation of optic vesicles. The insulin-like growth factor (IGF) pathway appears to be essential for eye induction, yet it remains unclear how IGF downstream pathways are involved in eye induction. As a consequence of eye induction, a single eye anlage is specified in the anterior neural plate. Subsequently, this single eye anlage is divided into two symmetric eye fields in response to Sonic Hedgehog (Shh) secreted from the prechordal mesoderm. Here, we report that B56epsilon regulatory subunit of protein phosphatase 2A (PP2A) is involved in Xenopus eye induction and subsequent eye field separation. We provide evidence that B56epsilon is required for the IGF/PI3K/Akt pathway and that interfering with the PI3K/Akt pathway inhibits eye induction. In addition, we show that B56epsilon regulates the Hedgehog (Hh) pathway during eye field separation. Thus, B56epsilon is involved in multiple signaling pathways and plays critical roles during early development.
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PMID:PP2A:B56epsilon is required for eye induction and eye field separation. 1707 14

We have previously shown that disruption of mitochondrial membrane potential by depletion of mitochondrial DNA (mtDNA) or treatment with a mitochondrial ionophore, carbonyl cyanide m-chlorophenylhydrazone, initiates a stress signaling, which causes resistance to apoptosis, and induces invasive behavior in C2C12 myocytes and A549 cells. In the present study we show that calcineurin (Cn), activated as part of this stress signaling, plays an important role in increased glucose uptake and glycolysis. Here we report that, although both insulin and insulin-like growth factor-1 receptor levels (IR and IGF1R, respectively) are increased in response to mitochondrial stress, autophosphorylation of IGF1R was selectively increased suggesting a shift in receptor pathways. Using an approach with FK506, an inhibitor of Cn, and mRNA silencing by small interference RNA we show that mitochondrial stress-activated Cn is critical for increased GLUT 4 and IGF1R expression and activation. The importance of the IGF1R pathway in cell survival under mitochondrial stress is demonstrated by increased apoptosis either by IGF1R mRNA silencing or by treatment with IGF1R inhibitors (AG1024 and picropodophyllin). This study describes a novel mechanism of mitochondrial stress-induced metabolic shift involving Cn with implications in resistance to apoptosis and tumor proliferation.
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PMID:Activation of a novel calcineurin-mediated insulin-like growth factor-1 receptor pathway, altered metabolism, and tumor cell invasion in cells subjected to mitochondrial respiratory stress. 1735 70

Insulin resistance and metabolic syndrome are rapidly expanding public health problems. Acting through the PI3K/Akt pathway, insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO transcription factors, a class of highly conserved proteins important in numerous physiological functions. However, even as FoxO is a downstream target of insulin, FoxO factors also control upstream signaling elements governing insulin sensitivity and glucose metabolism. Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity. FoxO-activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition. We reported previously that FoxO factors attenuate cardiomyocyte calcineurin (PP2B) activity. We now show that calcineurin forms a complex with Akt and inhibition of calcineurin enhances Akt phosphorylation. In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions. Repression of Akt-PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO-dependent increases in Akt phosphorylation and kinase activity. Resveratrol, an activator of Sirt1, increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart. Importantly, FoxO-mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin-triggered glucose uptake. Also, inactivation of the gene coding for FoxO3 enhances insulin-dependent Akt phosphorylation. Taken together, this study demonstrates that changes in FoxO activity have a dose-responsive repressive effect on insulin signaling in cardiomyocytes through inhibition of protein phosphatases, which leads to altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism.
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PMID:FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases. 1807 53

The NFkappaBs regulate an array of physiological and pathological processes, including propagation of mitochondrial respiratory stress signaling in mammalian cells. We showed previously that mitochondrial stress activates NFkappaB using a novel calcineurin-requiring pathway that is different from canonical or non-canonical pathways. This study shows that IkappaBbeta is essential for the propagation of mitochondrial stress signaling. Knock down of IkappaBbeta, but not IkappaBalpha, mRNA reduced the mitochondrial stress-mediated activation and nuclear translocation of cRel:p50, inhibiting expression of nuclear target genes RyR1 and cathepsin L. IkappaBbeta mRNA knock down also reduced resistance to staurosporine-induced apoptosis and decreased in vitro invasiveness. Induced receptor switching to insulin-like growth factor-1 receptor and increased glucose uptake are hallmarks of mitochondrial stress. IkappaBbeta mRNA knock down selectively abrogated the receptor switch and altered tubulin cytoskeletal organization. These results show that mitochondrial stress signaling uses an IkappaBbeta-initiated NFkappaB pathway that is distinct from the other known NFkappaB pathways. Furthermore, our results demonstrate the distinctive physiological roles of the two inhibitory proteins IkappaBbeta and IkappaBalpha.
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PMID:A distinctive physiological role for IkappaBbeta in the propagation of mitochondrial respiratory stress signaling. 1827 19

Although the ultimate outcome of prolonged exposure of cells to stress is often death, the early response appears to be the activation of survival pathways that are likely to give the cell an opportunity to repair low-level damage. How these stress-initiated survival pathways influence B cell lymphoma/leukemia 2 (Bcl-2) proteins, the core cell death machinery, has remained unclear; however, two papers now provide insight into stress-mediated survival mechanisms. The liver is unusually resistant to p53-mediated apoptosis. It appears that p53-mediated induction of the gene that encodes insulin-like growth factor-binding protein-1 (IGFBP1) attenuates the cell death response in hepatocytes by preventing the formation of a complex between p53 and the proapoptotic protein BAK. This is especially interesting as IGFBP1 is not a member of the Bcl-2 family, yet it inhibited BAK. In three unrelated cell lines, another regulatory interaction that influences cell survival occurs at the mitochondria. In this case, protein phosphatase 1gamma (PP1gamma) regulated the phosphorylation status of the Bcl-2/Bcl-X(L)-associated death promoter (BAD). The prefoldin family member URI is normally phosphorylated by S6 kinase 1, which liberates PP1gamma from a URI-PP1gamma complex. However, the withdrawal of growth factors or nutrients stabilizes this complex, which renders PP1gamma inactive. The net response of this stress stimulus is an increased abundance of phosphorylated BAD, which raises the threshold required to trigger cell death. These two studies have identified new players and mechanisms that integrate stress responses and cell death.
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PMID:Cell stress gives a red light to the mitochondrial cell death pathway. 1828 8

Collapsin response mediator protein 2 (CRMP2) binds to microtubules and regulates axon outgrowth in neurons. This action is regulated by sequential phosphorylation by the kinases cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3 (GSK3) at sites that are hyperphosphorylated in Alzheimer disease. The increased phosphorylation in Alzheimer disease could be due to increases in Cdk5 and/or GSK3 activity or, alternatively, through decreased activity of a CRMP phosphatase. Here we establish that dephosphorylation of CRMP2 at the residues targeted by GSK3 (Ser-518/Thr-514/Thr-509) is carried out by a protein phosphatase 1 family member in vitro, in neuroblastoma cells, and primary cortical neurons. Inhibition of GSK3 activity using insulin-like growth factor-1 or the highly selective inhibitor CT99021 causes rapid dephosphorylation of CRMP2 at these sites. In contrast, pharmacological inhibition of Cdk5 using purvalanol results in only a gradual and incomplete dephosphorylation of CRMP2 at the site targeted by Cdk5 (Ser-522), suggesting a distinct phosphatase targets this residue. A direct comparison of dephosphorylation at the Cdk5 versus GSK3 sites in vitro shows that the Cdk5 site is comparatively resistant to phosphatase treatment. The presence of the peptidyl-prolyl isomerase enzyme, Pin1, does not affect dephosphorylation of Ser-522 in vitro, in cells, or in Pin1 transgenic mice. Instead, the relatively high resistance of this site to phosphatase treatment is at least in part due to the presence of basic residues located nearby. Similar sequences in Tau are also highly resistant to phosphatase treatment. We propose that relative resistance to phosphatases might be a common feature of Cdk5 substrates and could contribute to the hyperphosphorylation of CRMP2 and Tau observed in Alzheimer disease.
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PMID:Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation. 1846 Apr 67

Inappropriate regulation of the PI3-kinase/PTEN/Akt kinase-signalling cassette, a key downstream target of insulin/insulin-like growth factor signalling (IIS), is associated with several major human diseases such as diabetes, obesity and cancer. In Drosophila, studies have recently revealed that different subcellular pools of activated, phosphorylated Akt can modulate different IIS-dependent processes. For example, a specific pool of activated Akt within the cytoplasm alters aspects of lipid metabolism, a process that is misregulated in both obesity and diabetes. However, it remains unclear how this pool is regulated. Here we show that the protein phosphatase PP2A-B' regulatory subunit Widerborst (Wdb), which coimmunoprecipitates with Akt in vivo, selectively modulates levels of activated Akt in the cytoplasm. It alters lipid droplet size and expression of the lipid storage perilipin-like protein LSD2 in the Drosophila ovary, but not in epithelial cells of the eye imaginal discs. We conclude that isoforms of PP2A-B' can act as subcellular-compartment-specific regulators of PI3-kinase/PTEN/Akt kinase signalling and IIS, potentially providing new targets for modulating individual subcellular pools of activated Akt in insulin-linked disease.
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PMID:The protein phosphatase PP2A-B' subunit Widerborst is a negative regulator of cytoplasmic activated Akt and lipid metabolism in Drosophila. 1882 8

Our previous study demonstrated that zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via Akt and glycogen synthetase kinase 3beta (GSK-3beta). We aimed to address the mechanism by which zinc activates Akt. Treatment of H9c2 cells with ZnCl(2) (10 microM) in the presence of the zinc ionophore pyrithione (4 microM) for 20 min enhanced Akt phosphorylation (Ser(473)), indicating that zinc can rapidly activate Akt. Zinc did not alter either phosphatase and tensin homolog deleted on chromosome 10 (PTEN) phosphorylation and total PTEN protein levels or PTEN oxidation, implying that PTEN may not play a role in the action of zinc. However, zinc-induced Akt phosphorylation was blocked by both the nonselective receptor tyrosine kinase (RTK) inhibitor genistein and the selective insulin-like growth factor-1 RTK (IGF-1RTK) inhibitor AG1024, indicating that zinc activates Akt via IGF-1RTK. Zinc-induced phosphorylation of protein tyrosine and Ser/Thr was also abolished by AG1024. In addition, zinc markedly enhanced phosphorylation of IGF-1 receptor (IGF-1R), which was again reversed by genistein and AG1024. A confocal imaging study revealed that AG1024 abolished the preventive effect of zinc on oxidant-induced mPTP opening, confirming that IGF-1RTK plays a role in zinc-induced cardioprotection. Furthermore, zinc decreased the activity of protein phosphatase 2A (PP2A), a major protein Ser/Thr phosphatase, implying that protein Ser/Thr phosphatases may also play a role in the action of zinc on Akt activity. Taken together, these findings demonstrate that exogenous zinc activates Akt via IGF-1RTK and prevents the mPTP opening in cardiac cells. Inactivation of Ser/Thr protein phosphatases may also contribute to zinc-induced Akt activation.
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PMID:Molecular mechanism underlying Akt activation in zinc-induced cardioprotection. 1952 80


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