Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 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

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

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

Understanding how alterations in growth control pathways are translated into changes in the cell cycle regulatory machinery is a major challenge for understanding the development of human cancers. The ability of both tumor suppressor proteins, p53 and BRCA1, to induce the expression of p21(WAF1/Cip1) in combination with the inhibitory activity of p21(WAF1/Cip1) against cyclin-dependent kinases suggests that the regulation of p21(WAF1/Cip1) expression is an important aspect of mammalian cell cycle growth control. To elucidate the role of serine/threonine protein phosphatase type 5 (PP5) in processes regulating cell cycle progression, we developed antisense oligodeoxynucleotides targeted against PP5 (e.g. ISIS 15534) that specifically inhibit PP5 gene expression. Employing ISIS 15534, we demonstrate that the specific inhibition of PP5 gene expression has a marked antiproliferative effect on cells, characterized by induction of p21(WAF1/Cip1) and the subsequent arrest of cell growth. Investigations into the mechanisms leading to growth arrest reveal that, in the absence of PP5, the expression of p21(WAF1/Cip1) is induced in p53-competent A549 cells but not in p53 protein-deficient T-24 cells. Employing a stable cell line derived from p53-deficient human fibroblast that contains tetracycline-regulated transactivator and operator plasmids to control the expression of wild-type p53 (TR9-7 cells), we then show that the induction of p21(WAF1/Cip1), which occurs in response to the inhibition of PP5 expression, requires the p53 protein. Additional studies indicate that PP5 acts upstream of p53, influencing both the phosphorylation state and the ability of p53 to bind DNA, without causing an increase in p53 gene transcription. Together these studies suggest that PP5 is a regulatory component of a signaling pathway that affords replicating cells G1 checkpoint growth control and that it is the regulation of PP5 that, in turn, controls p53-mediated expression of p21(WAF1/Cip1) and growth arrest in this pathway. In addition, since the inhibition of PP5 gene expression has marked antiproliferative activity and the overexpression of p21(WAF1/Cip1) blocks the growth of tumor cells, these studies suggest that compounds that inhibit of PP5 gene expression may be useful in the treatment of human cancers.
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PMID:Serine/threonine protein phosphatase type 5 acts upstream of p53 to regulate the induction of p21(WAF1/Cip1) and mediate growth arrest. 957 75

It is well established that phosphorylation and dephosphorylation are key cellular events which regulate important metabolic activities such as gene expression, cell cycle progression, and apoptosis. The polyether fatty acid, okadaic acid has been shown previously to activate apoptosis in a variety of cell lines. Although this marine sponge toxin is known to inhibit protein phosphatase (PP)-2A and PP-1, it is not certain in most cases whether inhibition of PP-1 or PP-2A is necessary to activate apoptosis. Furthermore, it is not clear how inhibition of these phosphatases leads to apoptosis. Here we present evidence that inhibition of PP-2A by okadaic acid does not activate apoptosis in the lens system. However, when PP-1 is inhibited by okadaic acid, rabbit lens epithelial cells undergo rapid apoptosis. Associated with this process is the several-fold up-regulation of the tumor suppressor gene p53 and the pro-apoptotic gene bax at both mRNA and protein levels. Analyses of the temporal pattern of expression of the two genes reveal that the up-regulation is maximized in a few hours after treatment with okadaic acid, when the majority of the treated cells become committed to apoptosis. A brief treatment of the cells with a protein synthesis inhibitor can abolish okadaic acid-induced up-regulation of both P53 and Bax proteins. Concomitant with this inhibition, okadaic acid-induced apoptosis is also temporarily blocked. These results suggest that okadaic acid-induced expression of p53, bax, and other genes are necessary for the activation of the apoptotic programs in lens systems.
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PMID:Okadaic acid-induced lens epithelial cell apoptosis requires inhibition of phosphatase-1 and is associated with induction of gene expression including p53 and bax. 982 80

The p53 tumour suppressor protein is regulated by several mechanisms including multisite phosphorylation. One of the protein kinases which has an established role in regulating p53 function is the protein kinase CK2. The regulation by CK2 occurs both through interaction of p53 with CK2 itself (the regulatory beta subunit) and phosphorylation at the penultimate residue of p53, serine 386 (murine p53). Strikingly, this phosphorylation event controls several independent functions of p53 including site-specific DNA binding, strand renaturation, transcriptional repression and the anti-proliferative function of p53. However, CK2 is a constitutively-active enzyme and therefore the mechanism by which the phosphorylation of p53 at serine 386 is itself regulated, or indeed the question as to whether phosphorylation of this site is regulated at all, remains unresolved. In this paper we provide evidence that serine 386 is highly resistant to dephosphorylation in cultured cells, even though this site can be dephosphorylated in vitro by recombinant protein phosphatase 1. These data suggest that, once phosphorylated at the CK2 site, a p53 molecule remains in this modified form throughout its lifespan. To address the issue of whether the level of serine 386 phosphorylation may be regulated through controlling the subcellular compartmentalisation of p53 and CK2, we examined the subcellular localisation of p53 and CK2alpha in C57MG cells and Rat-1 fibroblasts by immunofluorescence staining. Both proteins were present in the cytoplasm and enriched in the nucleus, with minor variations in the intensity of subcellular location over the course of the cell cycle. Similarly, activation of p53 by UV irradiation or DNA damage-inducing drugs had no effect on either the localisation or levels of CK2alpha, even although significant nuclear p53 accumulation was observed. A striking observation arising from these studies was the intense staining of CK2alpha with the centrosomes, suggesting a potentially important role for this kinase in microtubule formation and/or chromosomal segregation.
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PMID:Protein kinase CK2-dependent regulation of p53 function: evidence that the phosphorylation status of the serine 386 (CK2) site of p53 is constitutive and stable. 1009 8


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