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

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

The tumor suppressor protein p53 is phosphorylated at multiple sites in the amino-terminal transactivation domain and at several sites in the carboxy-terminal region. Phosphorylation appears to modulate its DNA binding activity. Here we demonstrate that phosphorylation of p53 also modulates its transcriptional activity. Okadaic acid treatment of cells resulted in enhanced phosphorylation of p53 and concomitantly in enhanced transactivation of an mdm2 promoter-linked luciferase reporter gene. This effect was cell type specific, however, since transactivation was enhanced in rat and mouse fibroblasts but reduced in the human Saos-2 cell line. Moreover, the effect was dependent on the promoter. In rat cells transcription from the mdm2, waf1 (cip1) and bax gene promoters, and the artificial PG13 promoter was enhanced by okadaic acid treatment whereas that from the cyclin G promoter was reduced. When various phosphorylation site mutants of p53 were tested for transactivation of these promoters, they behaved differently. Amino-terminal mutants exhibited reduced transcriptional activities on mdm2, waf1 and cyclin G promoters but enhanced activities with bax and PG13 promoters. On the other hand, a mutant at the cdk phosphorylation site, A313, showed reduced activity with mdm2 and waf1 promoters but enhanced activity with the cyclin G promoter, and finally, mutant A390 exhibited enhanced activity on waf1 and bax promoters, but reduced activity on the cyclin G promoter. These results suggest that phosphorylation of p53 may have different effects on its transcriptional activity, depending on the cellular environment and the particular response element. Moreover, both, amino- and carboxy-terminal phosphorylation sites seem to be involved in modulating the DNA-binding and the transactivation activities.
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PMID:Differential effects of phosphorylation of rat p53 on transactivation of promoters derived from different p53 responsive genes. 900 Jan 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

Okadaic acid (OA), a toxin from the black sponge Halicondria okadai, is a specific inhibitor of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A). OA is a tumor promoter but also induces apoptosis in some tumor cell lines. In this study, we determined whether ras mutation and/or p53 status are characteristics associated with the cell's sensitivity to the induction of apoptosis by OA. Several cell lines that differed in ras and p53 mutations were treated with OA (10-100 nM). At 24 to 48 h after treatment, the percentage of cells undergoing apoptosis was quantitated. The cell lines with mutations in either H-ras (human bladder carcinoma cell line T24 and mouse keratinocyte cell line 308), or K-ras (human colon carcinoma cell lines DLD-1 and HCT116; human prostate cancer cell lines LNCaP and PC-3; human lung cancer cell lines Calu-6 and SKLU-1; and human pancreatic cancer cell line MIAPaCa2) were more sensitive to OA-induced apoptosis (3- to 10-fold) than the cell lines that lacked the ras mutation (mouse epidermal cell lines C50 and JB6; murine fibroblast cell line NIH3T3; human colon cancer cell line HT29; human kidney epithelial cell line Hs715.K; and human pancreatic cancer cell line Bx-PC3). Similarly, using isogenic cell lines we found that overexpression of mutated H-ras in NIH3T3 and in SV40 immortalized human uroepithelial cells (SVHUC) enhanced their sensitivity to undergo apoptosis in response to OA treatment. The T24, DLD-1, SKLU-1, Calu-6, and MIAPaCa2 cell lines express mutated p53. The SVHUC as well as their ras-transfected counterparts have inactive p53 due to complex formation between large "T" antigen and p53. Taken together, these results imply that OA-induced apoptosis may involve a p53-independent pathway. The transfectants (NIH3T3-ras and SVHUC-ras), which express mutated H-ras, have up-regulated PP2A activity. OA treatment inhibited in vivo the levels of PP1 and PP2A activity, and induced apoptosis in SVHUC-ras and other cell lines. We conclude that OA-induced cell death pathway in ras-activated cell lines may involve a cross talk between PP1 and PP2A and ras signaling pathways. In light of the present results, the current theory that OA promotes mouse skin tumor formation by selective expansion of initiated cells that harbor ras mutations needs reevaluation.
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PMID:Ras mutation, irrespective of cell type and p53 status, determines a cell's destiny to undergo apoptosis by okadaic acid, an inhibitor of protein phosphatase 1 and 2A. 1046 39

Transcription of the human caveolin gene, directed by a TATA-less promoter, is downregulated in actively dividing cells during S-phase, together with free cholesterol (FC) efflux. It is upregulated by medium low density lipoprotein FC levels in quiescent cells. In this study, a common mechanism has been identified to coordinate the growth- and FC-dependent expression of caveolin. In human skin fibroblasts, transcription factors E2F/DP-1 and Sp1 bound to adjacent consensus sites at -151 to -138 bp of the caveolin promoter DNA sequence in a complex stabilized by tumor suppressor protein p53. Wild-type p53 also bound directly to DNA to a caveolin promoter sequence containing two consensus half-sites (-292 to -283 bp and -273 to -264 bp) for this transcription factor. SREBP-1, previously identified as a transcriptional regulator of caveolin expression in response to FC, mediated its effect via the same E2F/Sp1 site. Overexpression of E2F or p53 increased E2F binding to the -148 to -141 bp site, increased FC efflux, and inhibited cell division. The mutant protein p53(143V-->A) was inactive. Okadaic acid, previously shown to inhibit growth, FC efflux, and caveolin expression, inhibited E2F/Sp1 binding, while higher concentrations of extracellular FC increased it. The present findings provide a molecular link between the cell cycle and FC homeostatic effects of caveolin. These results also describe a novel mechanism of action for p53 in a TATA-less gene promoter and provide further evidence for a significant regulatory role for FC in cell cycle progression.
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PMID:p53 regulates caveolin gene transcription, cell cholesterol, and growth by a novel mechanism. 1068 46

p53 is a multifunctional protein and its activity can be modulated by phosphorylation and dephosphorylation. In this study, we sought to examine the notion that serine/threonine phosphatases (PP-1 and PP-2A) are active modulators of the p53-dependent apoptotic pathway. Exposure of neonatal rat cardiomyocytes to the established apoptotic agents, bafilomycin A1 (BAF) or staurosporine (STAU) induced apoptosis and caused a decrease in PP-1 activity of 35%. This response was restricted to apoptotic stimuli as treatment with phenylephrine neither decreased PP-1 and PP-2A activity nor induced DNA fragmentation in cardiomyocytes. The level of phosphorylated p53 was increased as a result of BAF or STAU-treatment. We further examined the effect of PP-1 inhibition on cardiomyocytes by the use of the phosphatase inhibitor, okadaic acid, and an antisense strategy. Okadaic acid (100 nM) resulted in a decrease in PP-1 activity of 45%, enhanced phosphorylation of p53, and stimulated apoptosis. Furthermore, overexpression of the antisense PP-1 catalytic subunit transcript caused a 44% decrease in expression of PP-1, with no change in the levels of the PP-2A catalytic subunit, and also evoked DNA fragmentation. Our data support the view that decreased activity of PP-1 is an important signaling event in the apoptotic process.
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PMID:Inhibition of protein phosphatase-1 is linked to phosphorylation of p53 and apoptosis. 1177 3

Okadaic acid (OA) is a protein phosphatase (PP) inhibitor and induces hyperphosphorylation of p53. We investigated whether the inhibition of PP1 by OA promotes the phosphorylation of the serine 15 of p53. In vitro dephosphorylation assay showed that PP1 dephosphorylated ultraviolet C (UVC)-induced phospho-ser15 of p53, and that OA treatment inhibited it. One of the PP1 regulators, growth arrest and DNA damage 34 (GADD34), disturbed PP1 binding with p53, interfered with the dephosphorylation of p53 and increased the amount of phospho-p53 after UVC-treatment. This report provides the first evidence that PP1, but not PP2A, dephosphorylates phospho-serine 15 of p53.
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PMID:Protein phosphatase 1, but not protein phosphatase 2A, dephosphorylates DNA-damaging stress-induced phospho-serine 15 of p53. 1517 17

There is substantial interest in identifying agents that differentially activate keratinocyte differentiation versus apoptosis. Okadaic acid (OA) is a tumor promoter in mouse skin that also stimulates apoptosis of murine keratinocytes. OA also enhances human keratinocyte differentiation; however, the impact of OA treatment on apoptosis in these cells has not been examined. We show that OA promotes normal human keratinocyte apoptosis as evidenced by increased accumulation of cells having sub-G1/S DNA content, decreased mitochondrial integrity, increased annexin V binding, increased cytoplasmic cytochrome c level, and increased procaspase 3 and PARP cleavage. Cyclin A, cyclin D1, cdk2, cdk4, p53 and p21 levels are reduced. These changes are associated with release of the PKCdelta catalytic domain and increased phosphorylation of PKCdelta-T(505)-responses consistent with PKCdelta activation. In contrast, phosphorylation of PKCdelta-Y(311) is not increased. The apoptotic response is enhanced in OA treated cells in the presence of p38delta, a PKCdelta target. OA treatment selectively activated p38delta, and OA-dependent apoptosis is not inhibited by treatment with the p38alpha/beta inhibitor, SB203580. These findings are consistent with the idea that the response is mediated by p38delta. Our data indicate that OA is an agent that regulates both keratinocyte differentiation and apoptosis, and that this regulation is mediated via activation of a PKCdelta/p38delta signaling cascade.
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PMID:Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis. 1725 48

Okadaic acid (OA) is a tumor promoter in two-stage carcinogenesis experiments. Nevertheless, the effects of OA on cell transformation, cell proliferation and apoptosis vary widely, and the molecular events underlying these effects of OA are not well understood. In the present study, we examined the promoting activity and the associated effects on cell growth and apoptosis mediated by OA in BALB/c 3T3 cells, and evaluated alterations of gene transcriptional expression by microarray analysis. The promoting activity of OA was estimated by a two-stage transformation assay, in which cells were treated first with a low dose of the initiator N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and then with OA for 14 days. It showed that OA, at concentrations of 7.8-31.3 ng/ml, enhanced the transformation of MNNG-treated cells. In the promotion phase, cells exposed to OA (7.8 ng/ml) grew slowly for the first 2 days and subsequently died. As determined by Hoechst 33342 fluorescent dye and Annexin-V/PI dual-colored flow cytometry, OA induced morphologically apoptotic cells and increased the percentage of early apoptotic cells. The gene expression profile induced by OA at five time points in the promotion phase was determined by use of a specific mouse toxicological microarray containing 1796 clones, and a total of 177 differentially expressed genes were identified. By gene ontology analysis, 31 of these were determined to be functionally involved with cell growth and/or maintenance. In this group, numerous genes associated with the cell proliferation and cell cycle progression were down-regulated at early and/or middle time points. Among these was a subset of genes associated with apoptosis, in which Bnip3, Cycs, Casp3 and Bag1 genes are involved in the mitochondrial pathway of apoptosis. Ier3, Mdm2 and Bnip3 genes may be p53 targets. Furthermore, real-time PCR confirmed the expression changes of five genes selected at random from the differentially expressed genes. We conclude that OA induces cell growth inhibition and apoptosis in the two-stage, MNNG-initiated transformation of BALB/c 3T3 cells. The results of gene expression profile analysis imply that multiple molecular pathways are involved in OA-induced proliferation inhibition and apoptosis. Mitochondrial and p53-associated apoptotic pathways also may contribute to OA-induced apoptosis.
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PMID:Differential expression of genes associated with cell proliferation and apoptosis induced by okadaic acid during the transformation process of BALB/c 3T3 cells. 1793 41


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