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)

A subset of cyclin-dependent protein kinases--Cdk7, Cdk8, and Cdk9--participates directly, in complex ways, with the fundamental machinery for gene transcription, as elements of general transcription factors whose substrate is the C-terminal domain (CTD) of RNA polymerase II. Here, we review recent data implicating the CTD kinase Cdk9 as a critical determinant of cardiac hypertrophy, in vitro and in vivo. Diverse trophic signals that increase cardiac mass all activated Cdk9 (work load, the small G-protein Gaq, and the calcium-dependent phosphatase calcineurin in mouse myocardium; endothelin-1, a hypertrophic agonist, in cultured cardiomyocytes). Little or no change occurred in levels of the kinase or its activator, cyclin T. Instead, in all four hypertrophic models, Cdk9 activation involves the dissociation of 7SK small nuclear RNA (snRNA), an endogenous inhibitor. In culture, dominant-negative Cdk9 blocked ET-1-induced hypertrophy, whereas an anti-sense "knockdown" of 7SK snRNA provoked spontaneous cell growth. In trans-genie mice, concordant with these results, activation of Cdk9 activity via cardiac-specific overexpression of cyclin Tl suffices to provoke hypertrophy. Together, these findings implicate Cdk9 activity as a pivotal regulator of pathophysiological heart growth. Because hypertrophy, in turn, is a cardinal risk factor for developing cardiac pump failure, these results support the logic of examining Cdk9 as a potential drug target in heart disease.
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PMID:Cyclins that don't cycle--cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size. 1269 56

Inhibitor-2 (I-2) is a regulator of protein phosphatase type-1 (PP1), known to be phosphorylated in vitro by multiple kinases. In particular Thr72 is a Thr-Pro phosphorylation site conserved from yeast to human, but there is no evidence that this phosphorylation responds to any physiological signals. Here, we used electrophoretic mobility shift and immunoblotting with a site-specific phospho-Thr72 antibody to establish Thr72 phosphorylation in HeLa cells and show a 25-fold increase in phosphorylation during mitosis. Mass spectrometry demonstrated I-2 in actively growing HeLa cells was also phosphorylated at three other sites, Ser120, Ser121, and an additional Ser located between residues 70 and 90. In vitro kinase assays using recombinant I-2 as a substrate showed that the Thr72 kinase(s) was activated during mitosis, and sensitivity to kinase inhibitors indicated that the principal I-2 Thr72 kinase was not GSK3 but instead a member of the cyclin-dependent protein kinase family. Immunocytochemistry confirmed Thr72 phosphorylation of I-2 during mitosis, with peak intensity at prophase, and revealed subcellular concentration of the phospho-Thr72 I-2 at centrosomes. Together, the data show dynamic changes in I-2 phosphorylation during mitosis and localization of phosphorylated I-2 at centrosomes, suggesting involvement in mammalian cell division.
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PMID:Phosphorylation of phosphatase inhibitor-2 at centrosomes during mitosis. 1269 55

The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is a human dual-specificity protein phosphatase that dephosphorylates Cdk2 on a conserved threonine residue, T160, in a cyclin dependent manner. Several aberrant KAP transcripts with characteristic deletion regions have been identified in hepatocellular carcinoma tissues. In this report, we demonstrated that multiple aberrant KAP transcripts were also present in a hepatoblastoma cell line (HepG2), albeit harboring a totally different set of deletions. By performing yeast two-hybrid and co-immunoprecipitation experiments, a KAP-Cdk2 interaction domain located in the amino acid 1-34 region was identified. This interaction domain was different from the major protein interface deduced from crystal structure analysis. Using a yeast three-hybrid system, it was shown that the presence of a truncated KAP mutant encoding this interaction domain abolished the wild-type KAP-Cdk2 interaction. In conclusion, a previously unidentified KAP-Cdk2 interaction domain was discovered. Truncated KAP mutants containing this domain interfered with the wild-type KAP-Cdk2 interaction.
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PMID:Abolishment of the interaction between cyclin-dependent kinase 2 and Cdk-associated protein phosphatase by a truncated KAP mutant. 1274 75

The enzyme PP1gamma2 is a testis- and sperm-specific isoform of type 1 protein phosphatase (PP1), and it is the only isoform of PP1 in spermatozoa. The enzyme PP1gamma2 is essential for spermatogenesis and is also a key enzyme in the development and regulation of sperm motility. The carboxy terminus of the enzyme contains a consensus amino acid sequence for phosphorylation by cyclin-dependent kinases. Using antibodies specific to this phosphorylated amino acid sequence domain, we found that phosphorylated PP1gamma2 is present in bovine epididymal spermatozoa. The level of phosphorylated PP1gamma2 is significantly higher in motile caudal compared to immotile caput epididymal spermatozoa. A number of treatments, such as 2-chloro adenosine, cAMP analogues, cAMP phosphodiesterase inhibitors, and calcium, which stimulate sperm motility, did not alter the level of phosphorylated PP1gamma2. However, calyculin A, which is an inhibitor of protein phosphatase subtypes PP1 and PP2A, significantly increases the level of phosphorylated PP1gamma2 in both caput and caudal epididymal spermatozoa. Partial purification by column chromatography showed that phosphorylated PP1gamma2 is catalytically active. Phosphorylated PP1gamma2 is the only spontaneously catalytically active form of the enzyme in caudal sperm extracts. Western blot analysis shows that the enzyme cyclin-dependent kinase 2, one of the enzymes that phosphorylates the consensus domain at the carboxy terminus in PP1 isoforms, is present in spermatozoa. Western blot analysis of proteins extracted from purified head and tail fragments of spermatozoa showed that phosphorylated PP1gamma2 is present predominantly in the sperm head. Fluorescence immunocytochemistry also showed that phosphorylated PP1gamma2 is present predominantly in the posterior region of the sperm head. The distinct subcellular localization and changes in its level during sperm maturation suggest a possible role for sperm phosphorylated PP1gamma2 in signaling events during fertilization.
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PMID:Increased phosphorylation of a distinct subcellular pool of protein phosphatase, PP1gamma2, during epididymal sperm maturation. 1456 12

Impairment of cell cycle control has serious effects on inflammation, tissue repair, and carcinogenesis. We report here the G1 cell cycle arrest by monochloramine (NH2Cl), a physiological oxidant derived from activated neutrophils, and its mechanism. When Jurkat cells were treated with NH2Cl (70 microM, 10 min) and incubated for 24 h, the S phase population decreased significantly with a slight increase in the hypodiploid cell population. The G0/ G1 phase and G2/M phase populations did not show marked changes. Three hours after NH2Cl treatment, the retinoblastoma protein (pRB) was dephosphorylated especially at Ser780 and Ser795, both of which are important phosphorylation sites for the G1 checkpoint function. The phosphorylation at Ser807/811 showed no apparent change. The expression of cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors showed no apparent change. Moreover, the kinase activity that phosphorylates pRB remained constant even after NH2Cl treatment. The protein phosphatase activity that dephosphorylates pRB showed a marginal increase. Notably, when the recombinant pRB was oxidized by NH2Cl in vitro, the oxidized pRB became difficult to be phosphorylated by kinases, especially at Ser780 and Ser795, but not at Ser807/811. Amino acid analysis of oxidized pRB showed methionine oxidation to methionine sulfoxide. The NH2Cl-treated Jurkat cell proteins also showed a decrease in methionine. These observations suggested that direct pRB oxidation was the major cause of NH2Cl-induced cell cycle arrest. In the presence of 2 mM NH4+, NaOCl (200 microM) or activated neutrophils also induced a G1 cell cycle arrest. As protein methionine oxidation has been reported in inflammation and aging, cell cycle modulation by pRB oxidation may occur in various pathological conditions.
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PMID:Cell cycle arrest by monochloramine through the oxidation of retinoblastoma protein. 1473 95

The Cdc25 protein phosphatase is a key enzyme involved in the regulation of the G(2)/M transition in metazoans and yeast. However, no Cdc25 ortholog has so far been identified in plants, although functional studies have shown that an activating dephosphorylation of the CDK-cyclin complex regulates the G(2)/M transition. In this paper, the first green lineage Cdc25 ortholog is described in the unicellular alga Ostreococcus tauri. It encodes a protein which is able to rescue the yeast S. pombe cdc25-22 conditional mutant. Furthermore, microinjection of GST-tagged O. tauri Cdc25 specifically activates prophase-arrested starfish oocytes. In vitro histone H1 kinase assays and anti-phosphotyrosine Western Blotting confirmed the in vivo activating dephosphorylation of starfish CDK1-cyclinB by recombinant O. tauri Cdc25. We propose that there has been coevolution of the regulatory proteins involved in the control of M-phase entry in the metazoan, yeast and green lineages.
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PMID:The first green lineage cdc25 dual-specificity phosphatase. 1500 33

Mitotic entry and exit require activation and inactivation of the Cdk1-cyclin B kinase complex, respectively. The Cdc25 protein phosphatase family activates Cdk1-cyclin B at the G2/M transition by removing inhibitory phosphate groups. Cdc25 family members, held inactive during interphase, are activated during mitotic progression in an amplification loop involving Cdk1-cyclin B. While Cdc25 activation at the G2/M transition is required for the timely initiation of mitosis, recent evidence suggests that the inactivation of Cdc25 in late mitosis may play a role in supporting Cdk1-cyclin B inactivation. Here, we discuss the mechanisms of Cdc25 regulation and how they pertain to both mitotic entry and exit.
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PMID:Inactivating Cdc25, mitotic style. 1510 15

The functions of the retinoblastoma protein (pRb) are in part regulated by reversible and cell cycle-dependent phosphorylation. While the regulation of pRb by cyclin-dependent kinases (Cdks) has been studied extensively, the role(s) of protein phosphatase 1 (PP1) in controlling pRb are only partially understood. In this chapter, we will describe experimental approaches to investigate the interactions between pRb and PP1. Methods will be presented to study the cell cycle-dependent dephosphorylation of pRb by various PP1 isozymes, the specificity of PP1 isozymes for distinct pRb phosphorylation sites, the dephosphorylation of pRb associated with apoptosis, and the cell cycle- and pRb-dependent phosphorylation of PP1.
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PMID:Interaction between the retinoblastoma protein and protein phosphatase 1 during the cell cycle. 1522 May 19

The Simian Virus 40 (SV40) small-t antigen (ST) plays an important role in driving cell proliferation, enhancing transformation by the large-T (LT) antigen. Potential targets of ST are the cyclin kinase inhibitor p27 and the cyclin A gene itself. Transactivation of the cyclin A promoter by ST depends on the interaction of ST with protein phosphatase 2A (PP2A) and occurs through a cell cycle-regulated E2F site near the transcription start site of the promoter. A third SV40 early protein, 17KT, also transactivates the cyclin A promoter but, in this case, transactivation depends on the dnaJ domain of the protein.
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PMID:PP2A-dependent transactivation of the cyclin A promoter by SV40 ST is mediated by a cell cycle-regulated E2F site. 1568 Apr 24

The tumoricidal mechanism of methyl-3,5-diiodo-4-(4'-methoxypropoxy)benzoate (DIME), or DIPE, has been analyzed beyond its first recognized cellular site, which is the inhibition of tubulin polymerization. DIME (or DIPE) pretreatment of Eras cells for 3 days abolished ceramide basic fibroblast growth factor (bFGF)-induced glycolysis, coinciding with a block produced by the phosphoprotein dephosphorylation of cdc 25 by protein phosphatase 2A (PP2A). Protein dephosphorylation is directly activated by DIME (or DIPE), and enzyme activities that are dependent on P-proteins are significantly down-regulated (e.g. Topo I and II, MAP-kinase, and cdc-cyclin kinase). Purified PP2A is one target of activation by DIME (or DIPE), and an alkaline phosphatase isoenzyme is also induced by the drug. It is proposed that the pleiotropic effects of DIME (or DIPE) on cancer cells involve the activation of protein dephosphorylations, as well as inhibition of tubulin polymerization.
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PMID:Mechanisms of antitumor action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy)benzoate: drug-induced protein dephosphorylations and inhibition of the permissive action of ceramide on growth factor induced cell proliferation. 1570 18


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