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)

Okadaic acid, a phosphatase inhibitor from a marine organism, mimics tumor necrosis factor/interleukin-1 (TNF/IL-1) in inducing changes in early cellular protein phosphorylation. A total of approximately 116 proteins exhibit significant and concordant changes in phosphorylation or dephosphorylation within 15 min in human fibroblasts activated by either okadaic acid, TNF, or IL-1. The fidelity of this mimicry by okadaic acid extends to the phosphorylation of the 27 hsp complex, stathmin, eIF-4E, myosin light chain, nucleolin, epidermal growth factor receptor, and other cdc2-kinase substrates (c-abl, RB, and p53). The okadaic acid-induced pattern of protein phosphorylation is distinct from that observed in cells treated with phorbol 12-myristate 13-acetate or with ligands like epidermal growth factor, cyclic AMP agonists, bradykinin, or interferons. Like TNF, okadaic acid also induces the transcription of immediate early response genes like c-jun and Egr-1 as well as the interleukin-6 genes. The overall early effects of okadaic acid uniquely parallel those of TNF/IL-1 and not those of other cytokines or ligands. Regulation of protein phosphatase inhibition is discussed as a mechanism for TNF/IL-1 signal transduction.
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PMID:Okadaic acid mimics multiple changes in early protein phosphorylation and gene expression induced by tumor necrosis factor or interleukin-1. 137 Apr 82

Simian virus 40 (SV40) large-T antigen and the cellular protein p53 were phosphorylated in vivo by growing cells in the presence of 32Pi. The large-T/p53 complex was isolated by immunoprecipitation and used as a substrate for protein phosphatase 2A (PP2A) consisting of the catalytic subunit (C) and the two regulatory subunits, A and B. Three different purified forms of PP2A, including free C, the AC form, and the ABC form, could readily dephosphorylate both proteins. With both large-T and p53, the C subunit was most active, followed by the AC form, which was more active than the ABC form. The activity of all three forms of PP2A toward these proteins was strongly stimulated by manganese ions and to a lesser extent by magnesium ions. The presence of complexed p53 did not affect the dephosphorylation of large-T antigen by PP2A. The dephosphorylation of individual phosphorylation sites of large-T and p53 were determined by two-dimensional peptide mapping. Individual sites within large-T and p53 were dephosphorylated at different rates by all three forms of PP2A. The phosphates at Ser-120 and Ser-123 of large-T, which affect binding to the origin of SV40 DNA, were removed most rapidly. Three of the six major phosphopeptides of p53 were readily dephosphorylated, while the remaining three were relatively resistant to PP2A. Dephosphorylation of most of the sites in large-T and p53 by the AC form was inhibited by SV40 small-t antigen. The inhibition was most apparent for those sites which were preferentially dephosphorylated. Inhibition was specific for the AC form; no effect was observed on the dephosphorylation of either protein by the free C subunit or the ABC form. The inhibitory effect of small-t on dephosphorylation by PP2A could explain its role in transformation.
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PMID:Dephosphorylation of simian virus 40 large-T antigen and p53 protein by protein phosphatase 2A: inhibition by small-t antigen. 184 68

The detection of p53 in human keratinocytes is dependent on the specific anti-p53 monoclonal antibody that is used. Differences in antibody recognition are postulated to be due to the masking or exposure of particular epitopes in different conformations of p53. This study addresses the role of phosphorylation on p53-epitope accessibility in human keratinocytes. Keratinocytes were treated with the phosphatase inhibitor, okadaic acid, to determine the effect of inhibiting cellular phosphatases on p53 phosphorylation and epitope recognition. These studies suggest there is a correlation between the level of p53 phosphorylation and the antigenic reactivity of certain p53 epitopes in human keratinocytes. We also examined the ability of the catalytic subunits of protein phosphatase 1 and 2A to dephosphorylate p53 derived from human keratinocytes in vitro. These data suggest that PP2A may be the phosphatase that acts on p53 in cultured human keratinocytes.
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PMID:The effect of phosphorylation on the antigenic reactivity of p53 in cultured human keratinocytes. 754 6

The p53 tumor suppressor protein is thought to play a major role in the defense of the cell against agents that damage DNA. In this report, we describe the identification and characterization of a protein kinase that phosphorylates mouse p53 at a single site, serine 34, a major site of phosphorylation in the cell. The protein kinase is activated strikingly following treatment of cells with ultraviolet radiation, has a native molecular weight of approximately 45,000, and can be resolved from mitogen-activated protein (MAP) kinase by chromatography on Superose 6 and DEAE-cellulose. The p53 kinase activity co-purifies with UV-activated c-Jun kinase activity on heparin-Sepharose and on a c-Jun (but not a v-Jun-) affinity column. Treatment of the partially purified kinase with CL100, a protein phosphatase that specifically dephosphorylates MAP kinase homologues, inhibits its activity. Taken together, the data suggest that this p53 kinase is likely to be activated by phosphorylation and may be a member of the stress-activated protein kinase subfamily of MAP kinases. UV irradiation of SV3T3 cells leads to increased phosphorylation of p53 at serine 34, indicating that phosphorylation of p53 by this kinase is likely to be physiological. Phosphorylation of p53 by this protein kinase may be a key event in a signal transduction mechanism that coordinately controls key nuclear proteins in response to oxidative stress or DNA damaging agents.
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PMID:p53 is phosphorylated in vitro and in vivo by an ultraviolet radiation-induced protein kinase characteristic of the c-Jun kinase, JNK1. 789 Jun 69

The p53 binding protein, termed p53BP2, was identified as a protein interacting with protein phosphatase 1 (PP1) in the yeast two hybrid system. The interaction was confirmed by co-immunoprecipitation of p53BP2 with epitope-tagged PP1 in vitro. The p53BP2-PP1 complex was stable to NaCl at concentrations which dissociate the p53-p53BP2 complex, and the binding of PP1 and p53 to p53BP2 was mutually exclusive. The region required for interaction with PP1 was shown to be contained within amino acids 297-431 of p53BP2, which includes two ankyrin repeats. The phosphorylase phosphatase activity of PP1 was inhibited by p53BP2 at nanomolar concentrations. These results suggest that PP1 may be involved in dephosphorylation and regulation of p53 through interaction with p53BP2.
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PMID:Protein phosphatase 1 interacts with p53BP2, a protein which binds to the tumour suppressor p53. 854 41

Ultraviolet radiation may be divided into the non-solar UVC region, the solar UVB (290-320 nm) region which is strongly absorbed by nucleic acids, and the solar UVA (320-380 nm) region which is less strongly absorbed by nucleic acids and proteins but causes a variety of oxidative events. As a consequence of these different properties, UVC/UVB radiations induce an array of stress proteins quite distinct from those induced by UVA radiations. Although many studies with UVC and UVB radiations involve lethal doses, it is clear that these radiations have the property of mimicking growth factor responses and stimulate various signal transduction pathways that lead to gene activation including transcriptional activation of the jun and fos proto-oncogenes. Furthermore, UVB irradiation of skin, at physiologically relevant doses can increase the levels of various stress proteins including ornithine decarboxylase, various cytokines, the p53 tumor suppressor protein and to a limited extent, nuclear oncogene products. Non-cytoxic exposures of UVA radiation can lead to the up-regulation of several genes including collagenase, heme oxygenase 1, a specific protein phosphatase (CL 100) and phospholipases. At least for heme oxygenase 1, there is evidence that the alteration may be involved in a pathway of defense against oxidative stress. However, much information is lacking in the quest to build up a complete picture of the physiological and pathological significance of the many UV inducible stress responses reported.
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PMID:UV activation of mammalian stress proteins. 885 79

We and others previously showed that cyclin G is a transcriptional target of the p53 tumor suppressor protein. However, cellular proteins which might form a complex with cyclin G have not yet been identified. To gain insight into the biological role of cyclin G, we used the yeast two-hybrid screen and isolated two mouse cDNAs encoding cyclin G-interacting proteins. Interestingly, both positive cDNAs encoded B' regulatory subunits of protein phosphatase 2A (PP2A). One clone encodes B'alpha, while the other clone codes for a new member of the B' family, B'beta. B'beta is 70% identical to other members of the B' family. B'alpha associated both in vitro and in vivo with cyclin G but not with the other mammalian cyclins. Furthermore, cyclin G formed a complex with B'alpha only after induction of p53 in p53 temperature-sensitive cell lines. These results indicate that cyclin G forms a specific complex with the B' subunit of PP2A and that complex formation is regulated by p53. Potential roles for the cyclin G-B' complex in p53-mediated pathways are discussed.
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PMID:p53-dependent association between cyclin G and the B' subunit of protein phosphatase 2A. 888 88

Okadaic acid (OA) is a serine/threonine protein phosphatase inhibitor and has been shown to induce apoptosis in a number of different tumor cell lines, including human breast carcinoma (HBC) cells. The molecular basis of OA-induced apoptosis remains to be investigated. Here, we demonstrate that the OA concentration that inhibits only protein phosphatase 1 and 2A was sufficient to induce apoptosis in HBC cells. In MCF-7 cells, the OA-induced apoptosis was coupled with the overexpression of endogenous p53, p21Waf1/Cip1, and Bax proteins, whereas the Rb protein levels were decreased. OA also induced apoptosis and concomitantly enhanced the p21Waf1/Cip1 and Bex levels in human papilloma virus protein E6-transfected variants of MCF-7 cells, in which p53 function had been disrupted. OA, by contrast, had no effect on the levels or the subcellular localization of Gadd45 and Bcl2 proteins in either wild-type of E6-transfected MCF-7 cells. Bcl-xL, Bcl-xS, and Bak levels were also unchanged after OA treatment in both cell types. OA-induced apoptosis and its effect on the expression of the above molecular markers occurred in the absence of any detectable changes in the cell cycle phase distribution. On the basis of our findings, we conclude the following: (a) OA-induced apoptosis in HBC cells occurs independently of cell cycle arrest; (b) the wild-type p53 function is not an absolute prerequisite for OA-induced cell death; and (c) OA-induced apoptosis is associated with up-regulation of endogenous p21Waf1/Cip1 and Bax protein levels.
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PMID:Cell cycle-independent regulation of p21Waf1/Cip1 and retinoblastoma protein during okadaic acid-induced apoptosis is coupled with induction of Bax protein in human breast carcinoma cells. 895 27

Inhibitors of type 1 and type 2A protein phosphatases were used to examine the involvement of protein phosphorylation in regulating the functions of endogenous p53. Exposure of Balb/c 3T3 cells to okadaic acid, an inhibitor of protein phosphatases 1 and 2A, increased the phosphorylation of p53 without changing p53 levels. Okadaic acid treatment enhanced the binding of p53 to a consensus DNA target sequence and caused a 5-8-fold increase in p53 transcriptional activity. Transient expression of SV40 small tumor antigen, a specific inhibitor of protein phosphatase 2A, caused a 4-fold increase in p53 transcriptional activity. Incubation of Balb/c 3T3 cells with okadaic acid also induced programmed cell death in a dose- and time-dependent manner. Decreases in viability, morphological changes, and the appearance of DNA fragmentation were dependent on p53 since cells lacking functional p53 were resistant to okadaic acid-induced apoptosis. The p53-dependent apoptosis induced by okadaic acid was rapid and did not require p53 transcriptional activity. The fact that SV40 small tumor antigen did not induce apoptosis provides additional evidence that p53 transcriptional activity is not sufficient for p53-mediated apoptosis. These results indicate that signaling pathways involving protein phosphorylation play critical roles in controlling the apoptotic activity of p53. Furthermore, a basal level of protein phosphatase 1 or 2A activity is necessary to prevent p53-dependent apoptosis.
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PMID:Inhibition of protein phosphatase activity induces p53-dependent apoptosis in the absence of p53 transactivation. 918 45

The tumor suppressor protein p53 is a transcription factor frequently inactivated in human cancers. We have studied the DNA binding potential and the transcriptional activity of p53 variants and p53 protein complexes in in vitro transcription assays. p53 specific transcription was measured via introduction of radioactive UTP into G-free cassette transcripts regulated by promoter sequences containing p53 response elements. Latent and activated p53 fractions were prepared from insect cells infected with p53 encoding baculoviruses by chromatography on heparin columns. p53 fractions distinguishable by their specific DNA binding activities and their recognition by monoclonal antibody PAb421 were obtained. Specific DNA binding and binding to PAb421 are mutually exclusive. The C-terminus of p53 can be phosphorylated by casein kinase II, protein kinase C and cyclin dependent kinases. The antibody PAb421 binds within the PKC phosphorylation site of p53 and is able to activate DNA binding of latent p53 in vitro. Activation of p53 by PAb421 also results in enhanced transactivation in vitro. Dephosphorylation of latent p53 with phosphatase 2A does not change these properties. This suggests that a conformational change in the carboxyl terminal domain of p53 controls the transactivation potential of p53.
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PMID:Protein interactions at the carboxyl terminus of p53 result in the induction of its in vitro transactivation potential. 924 59


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