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-type cyclin-dependent kinases (CDKs), also known as cdc2, are central to the orderly progression of the cell cycle. We made a functional Green Fluorescent Protein (GFP) fusion with CDK-A (Cdc2-GFP) and followed its subcellular localization during the cell cycle in tobacco cells. During interphase, the Cdc2-GFP fusion protein was found in both the cytoplasm and the nucleus, where it was highly resistant to extraction. In premitotic cells, a bright and narrow equatorial band appeared on the cell surface, resembling the late preprophase band, which disintegrated within 10 min as followed by time-lapse images. Cdc2-GFP was not found on prophase spindles but left the chromatin soon after this stage and associated progressively with the metaphase spindle in a microtubule-dependent manner. Arresting cells in mitosis through the stabilization of microtubules by taxol further enhanced the spindle-localized pool of Cdc2-GFP. Toward the end of mitosis, Cdc2-GFP was found at the midzone of the anaphase spindle and phragmoplast; eventually, it became focused at the midline of these microtubule structures. In detergent-extracted cells, the Cdc2-GFP remained associated with mitotic structures. Retention on spindles was prevented by pretreatment with the CDK-specific inhibitor roscovitine and was enhanced by the protein phosphatase inhibitor okadaic acid. Furthermore, we demonstrate that both the endogenous CDK-A and Cdc2-GFP were cosedimented with taxol-stabilized plant microtubules from cell extracts and that Cdc2 activity was detected together with a fraction of polymerized tubulin. These data provide evidence that the A-type CDKs associate physically with mitotic structures in a microtubule-dependent manner and may be involved in regulating the behavior of specific microtubule arrays throughout mitosis.
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PMID:Dynamic recruitment of Cdc2 to specific microtubule structures during mitosis. 1148 3

Calcium functions as a trigger for the switch between epithelial cell growth and differentiation. We report here that the calcium/calmodulin-dependent phosphatase calcineurin is involved in this process. Treatment of primary mouse keratinocytes with cyclosporin A, an inhibitor of calcineurin activity, suppresses the expression of terminal differentiation markers and of p21(WAF1/Cip1) and p27(KIP1), two cyclin-dependent kinase inhibitors that are usually induced with differentiation. In parallel with down-modulation of the endogenous genes, suppression of calcineurin function blocks induction of the promoters for the p21(WAF1/Cip1) and loricrin differentiation marker genes, whereas activity of these promoters is enhanced by calcineurin overexpression. The calcineurin- responsive region of the p21 promoter maps to a 78-bp Sp1/Sp3-binding sequence next to the TATA box, and calcineurin induces activity of the p21 promoter through Sp1/Sp3-dependent transcription. We find that the endogenous NFAT-1 and -2 transcription factors, major downstream targets of calcineurin, associate with Sp1 in keratinocytes in a calcineurin-dependent manner, and calcineurin up-regulates Sp1/Sp3-dependent transcription and p21 promoter activity in synergism with NFAT1/2. Thus, our study reveals an important role for calcineurin in control of keratinocyte differentiation and p21 expression, and points to a so-far-unsuspected interconnection among this phosphatase, NFATs, and Sp1/Sp3-dependent transcription.
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PMID:Cross talk among calcineurin, Sp1/Sp3, and NFAT in control of p21(WAF1/CIP1) expression in keratinocyte differentiation. 1149 84

Middle-T antigen is the oncogenic protein of Polyomavirus and associates with several cellular enzymes involved in signal transduction, e.g., Src tyrosine kinases, phosphatidylinositol 3-kinase (PI 3-kinase), protein phosphatase 2A (PP2A), and Shc, an SH2 domain-containing adapter protein. We have shown earlier that middle-T is a target of a cell cycle-regulated serine/threonine-specific kinase, presumably p34cdc2. Phosphorylation of middle-T by p34cdc2 results in increased apparent M, weight of the protein on SDS-polyacrylamide gels. Two threonine residues in positions 160 and 291, respectively, were identified in the middle-T sequence as putative targets of a cyclin-dependent kinase. Replacement of threonine 160 by alanine resulted in a transformation-defective mutant protein that was still capable of forming all the complexes with cellular proteins, suggesting that additional characteristics of middle-T are required for cell transformation. In the present study we report that the defect of the T160A middle-T mutant is compensated by mutations introduced into a domain encompassing amino acids 253 to 302. In particular, mutating serine 283, a canonical phosphorylation site for a cyclin-dependent kinase, to an alanine residue rendered the T160A middle-T mutant wild type. Based on these results we suggest that cell cycle-specific phosphorylation of specific serine and threonine residues by cyclin-dependent kinases regulates middle-T function.
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PMID:Domains in middle-T antigen that cooperate in polyomavirus-mediated oncogenic transformation. 1183 8

Many dramatic alterations in various cellular processes during the cell cycle are known to involve ion channels. In ascidian embryos and Caenorhabditis elegans oocytes, for example, the activity of inwardly rectifying Cl(-) channels is enhanced during the M phase of the cell cycle, but the mechanism underlying this change remains to be established. We show here that the volume-sensitive Cl(-) channel, ClC-2 is regulated by the M-phase-specific cyclin-dependent kinase, p34(cdc2)/cyclin B. ClC-2 channels were phosphorylated by p34(cdc2)/cyclin B in both in vitro and cell-free phosphorylation assays. ClC-2 phosphorylation was inhibited by olomoucine and abolished by a (632)Ser-to-Ala (S632A) mutation in the C-terminus, indicating that (632)Ser is a target of phosphorylation by p34(cdc2)/cyclin B. Injection of activated p34(cdc2)/cyclin B attenuated the ClC-2 currents but not the S632A mutant channel currents expressed in Xenopus oocytes. ClC-2 currents attenuated by p34(cdc2)/cyclin B were increased by application of the cyclin-dependent kinase inhibitor, olomoucine (100 microM), an effect that was inhibited by calyculin A (5 nM) but not by okadaic acid (5 nM). A yeast two-hybrid system revealed a direct interaction between the ClC-2 C-terminus and protein phosphatase 1. These data suggest that the ClC-2 channel is also counter-regulated by protein phosphatase 1. In addition, p34(cdc2)/cyclin B decreased the magnitude of ClC-2 channel activation caused by cell swelling. As the activities of both p34(cdc2)/cyclin B and protein phosphatase 1 vary during the cell cycle, as does cell volume, the ClC-2 channel could be regulated physiologically by these factors.
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PMID:Phosphorylation and functional regulation of ClC-2 chloride channels expressed in Xenopus oocytes by M cyclin-dependent protein kinase. 1198 77

In Alzheimer's disease, neurofibrillary degeneration results from the aggregation of abnormally phosphorylated Tau proteins into filaments and it may be related to the reactivation of mitotic mechanisms. In order to investigate the link between Tau phosphorylation and mitosis, Xenopus laevis oocytes in which most of the M-phase regulators have been discovered were used as a cell model. The human Tau isoform htau412 (2+3-10+) was microinjected into prophase I oocytes that were then stimulated by progesterone that activate cyclin-dependent kinase pathways. Hyperphosphorylation of the Tau isoform, which is characterized by a decrease of its electrophoretic mobility and its labelling by a number of phosphorylation-dependent antibodies, was observed at the time of germinal vesicle breakdown. Surprisingly, Tau immunoreactivity, considered as typical of Alzheimer's pathology (AT100 and phospho-Ser422), was observed in meiosis II. Because meiosis II is considered as a mitosis-like phase, we investigated if our observation was also relevant to a neurone-like model. Abnormal Tau phosphorylation was detected in mitotic human neuroblastoma SY5Y cells overexpressing Tau. Regarding AT100-immunoreactivity and phospho-Ser422, we suggest that phosphatase 2A inhibition and a phosphorylation combination of mitotic kinases may lead to this Alzheimer-type phosphorylation. Our results not only demonstrate the involvement of mitotic kinases in Alzheimer-type Tau phosphorylation but also indicate that Xenopus oocyte could be a useful model to identify the kinases involved in this process.
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PMID:Abnormal Tau phosphorylation of the Alzheimer-type also occurs during mitosis. 1242 51

Oxidative stress induces cell death and growth arrest. In this study, the regulation and the functional role of the retinoblastoma family proteins pRb, p107, and p130 in the cellular response to oxidative stress were investigated. Treatment of endothelial cells with H2O2 induced rapid hypophosphorylation of the retinoblastoma family proteins. This event did not require p53 or p21Waf1/Cip1/Sdi1 and was not associated with cyclin/cyclin-dependent kinase down-modulation. Four lines of evidence indicate that H2O2-induced hypophosphorylation of pRb, p107, and p130 was because of the activity of protein phosphatase 2A (PP2A). First, cell treatment with two phosphatase inhibitors, okadaic acid and calyculin A, prevented the hypophosphorylation of the retinoblastoma family proteins, at concentrations that specifically inhibit PP2A. Second, SV40 small t, which binds and inhibits PP2A, when overexpressed prevented H2O2-induced dephosphorylation of the retinoblastoma family proteins, whereas a SV40 small t mutant unable to bind PP2A was totally inert. Third, PP2A core enzyme physically interacted with pRb and p107, both in H2O2-treated and untreated cells. Fourth, a PP2A phosphatase activity was co-immunoprecipitated with pRb, and the activity of pRb-associated PP2A was positively modulated by cell treatment with H2O2. Because DNA damaging agents inhibit DNA synthesis in a pRb-dependent manner, it was determined whether the PP2A-mediated dephosphorylation of the retinoblastoma family proteins played a role in this S-phase response. Indeed, it was found that inhibition of PP2A by SV40 small t over-expression prevented DNA synthesis inhibition induced by H2O2.
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PMID:Oxidative stress induces protein phosphatase 2A-dependent dephosphorylation of the pocket proteins pRb, p107, and p130. 1262 Oct 62

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

It has been known for over a decade that inhibition of protein phosphatase 1 (PP1) activity prevents entry into M phase, but the relevant substrate has not been identified. We report here that PP1 is required for dephosphorylation of the Cdc2-directed phosphatase Cdc25 at Ser287 (of Xenopus Cdc25; Ser216 of human Cdc25C), a site that suppresses Cdc25 during interphase. Moreover, PP1 recognizes Cdc25 directly by interacting with a PP1-binding motif in the Cdc25 N-terminus. We have also found that 14-3-3 binding to phospho-Ser287 protects Cdc25 from premature dephosphorylation. Upon entry into M phase, 14-3-3 removal from Cdc25 precedes Ser287 dephosphorylation, suggesting the existence of a phosphatase- independent pathway for 14-3-3 removal from Cdc25. We show here that this dissociation of 14-3-3 from Cdc25 requires the activity of the cyclin-dependent kinase Cdk2, providing a molecular explanation for the previously reported requirement for Cdk2 in promoting mitotic entry. Collectively, our data clarify several steps important for Cdc25 activation and provide new insight into the role of PP1 in Cdc2 activation and mitotic entry.
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PMID:PP1 control of M phase entry exerted through 14-3-3-regulated Cdc25 dephosphorylation. 1459 72

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

Budding yeast protein phosphatase Cdc14 is sequestered in the nucleolus in an inactive state during interphase by the anchor protein Net1. Upon entry into anaphase, the Cdc14 early anaphase release (FEAR) network initiates dispersal of active Cdc14 throughout the cell. We report that the FEARnetwork promotes phosphorylation of Net1 by cyclin-dependent kinase (Cdk) complexed with cyclin B1 or cyclin B2. These phosphorylations appear to be required for FEAR and sustain the proper timing of late mitotic events. Thus, a regulatory circuit exists to ensure that the arbiter of the mitotic state, Cdk, sets in motion events that culminate in exit from mitosis.
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PMID:Phosphorylation by cyclin B-Cdk underlies release of mitotic exit activator Cdc14 from the nucleolus. 1527 93


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