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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The wild-type p53 protein suppresses transformation, but certain missense mutants of p53 can transform cells. Although the wild-type p53 protein contains a transcriptional activation domain, no p53-responsive element has been identified. Here, we identified the p53-responsive element within the Tax-responsive element [21-base-pair (bp) enhancer] of human T-cell leukemia virus type I. Mutation analysis of the 21-bp enhancer indicated that the 16-bp sequence containing the cAMP-responsive element and its surrounding sequence was responsible for p53-induced transactivation. This 16-bp sequence was demonstrated to bind specifically to wild-type human p53 protein in vitro. Using a series of deletion mutants of p53, we showed that almost the entire region of p53 is needed for the transactivating capacity. Furthermore, the transforming mutants of p53 were unable to act as transcriptional activators. The p53-responsive element identified here should be useful to analyze the mechanism by which p53 regulates expression of a set of genes with a negative effect on cellular growth.
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PMID:Overlap of the p53-responsive element and cAMP-responsive element in the enhancer of human T-cell leukemia virus type I. 153 57

Multi-autocrine loops of the epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), platelet-derived growth factor (PDGF) and TGF beta system are expressed in human gastrointestinal carcinomas. In esophageal and gastric carcinomas, they evidently play an important role in tumor progression. Gastrin, one of the major gut hormones, may also act as an autocrine growth factor for gastric and colonic carcinomas. The HST1 and INT-2 genes, belonging to the fibroblast growth factor gene family, are coamplified in approximately 50% of primary tumors and in all the metastatic tumors of esophageal carcinoma. TGF alpha and EGF are the ligands of the tumor cells that overexpress EGF receptor in esophageal carcinomas. The synchronous expression of EGF and its receptor, as well as TGF alpha and ras p21, is evidently correlated with the depth of tumor invasion, metastasis and prognosis of gastric carcinomas. Amplification of c-erbB-2 and EGF receptor genes has been observed in many metastatic sites of gastric carcinomas regardless of histological type. In addition to TGF alpha and EGF, TGF beta and PDGF A chain produced by tumor cells may stimulate collagen synthesis not only by fibroblasts but also by tumor cells themselves, resulting in extensive progression and diffuse fibrosis of scirrhous gastric carcinomas. Moreover, TGF alpha or EGF and estrogen may also play a cooperative role in the development of scirrhous gastric carcinoma. In colorectal carcinoma, it has been shown that the accumulation of several alterations in ras genes and p53 genes is most important for the conversion of adenoma to carcinoma. Critical genetic changes, including activation of oncogenes, mutation and deletion of tumor suppressor genes and disturbances in transcriptional regulatory sequences, may bring about aberrant expression of growth factors and their receptors in gastrointestinal carcinomas. The understanding of the significance of EGF-related growth factors in tumor progression provides a framework for a biological approach to the therapy of human gastrointestinal carcinomas. 8-Cl-cAMP, which inhibits expression of oncogenes and TGF alpha, may be useful not only for cancer therapy but also for the study of cell differentiation.
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PMID:Growth factors and oncogenes in human gastrointestinal carcinomas. 215 13

Triton-insoluble cytoskeleton of nonpigment cells has bound protein kinase that phosphorylates, with or without added cAMP, tubulins and the intermediate filament proteins p60, p56, p53, and p45a to give multiple charge variants. In the absence of 8-Br-cAMP, Triton-insoluble cytoskeletons from xanthophores also phosphorylate p60, p56, and p45a, but not p53; tubulin phosphorylation may also be reduced. In the presence of 8-Br-cAMP, p53, as well as several other peptides, are phosphorylated. One of these latter peptides was identified as the carotenoid droplet (pigment organelle) protein p57, whose phosphorylation and dephosphorylation precede pigment dispersion and aggregation respectively (Lynch et al.: J. Biol. Chem. 261:4204-4211, 1986). The amount of pp57 produced depends on the state of pigment distribution in the xanthophores used to prepare the cytoskeletons for labeling. With cytoskeletons from xanthophores with aggregated pigment, pp57 is a major labeled phosphoprotein seen in two-dimensional gels. With cytoskeletons prepared from xanthophores with dispersed pigment, the yield of labeled pp57 is greatly reduced (by at least 90%). Together with earlier results, we propose that, in the aggregated state, p57 serves to bind carotenoid droplets to the cytoskeletons, most likely the microtubules. The significance of other cAMP-dependent phosphorylation reactions is unknown but may be related to cAMP-induced cytoskeleton rearrangement in intact xanthophores.
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PMID:cAMP-independent and cAMP-dependent protein phosphorylations by isolated goldfish xanthophore cytoskeletons: evidence for the association of cytoskeleton with a carotenoid droplet protein. 254 7

Stimulation of beta-adrenoreceptors in rat parotid acinar cells in vitro by the beta-adrenergic agonist isoproterenol induces steady-state levels of c-fos mRNA and c-fos protein in these cells. A dramatic increase in the steady-state levels of c-fos mRNA was observed at 60 min, followed by a decrease at 2 h with a second peak at 4 h. c-fos induction in rat parotid acinar cells in vitro seems to be mediated by cAMP. Increased levels of p53 and c-myc mRNA were detected only at 60 min. c-abl and c-sis were also induced by isoproterenol but in a pattern different from that seen with c-fos. c-abl was the only oncogene in rat parotid gland which showed increased expression after chronic isoproterenol treatment of rats. In rat parotid acinar cells we observed no correlation between DNA synthesis and c-fos induction.
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PMID:Regulation of proto-oncogenes in rat parotid acinar cells in vitro after stimulation of beta-adrenergic receptors. 284 68

Stimulation of beta-adrenoreceptors in the RSMT-A5 epithelial cell line is accompanied by an early and transient increase in the expression of the proto-oncogene c-fos. Maximal induction was at 30 min, returning to basal levels after 2 h. Similar results were obtained when cells were incubated with 8-bromo-cAMP. The induction of c-fos is specific since the expression of p53, a transformation-related gene, is not modulated by isoproterenol or 8-bromo-cAMP. The increase in c-fos gene expression is not associated with proliferative activity in these epithelial cells.
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PMID:Beta-adrenergic regulation of c-fos gene expression in an epithelial cell line. 284 42

Activation of Ca2+ -calmodulin- and cyclic AMP-dependent protein kinases has been suggested to be involved in stimulus-secretion coupling in the pancreatic beta-cell. To study the properties of suc kinases and their endogenous protein substrates homogenates of rat islets of Langerhans were incubated with [gamma-32P]ATP. Phosphorylated proteins were separated by sodium dodecyl sulphate polyacrylamide gel electrophoresis and detected by autoradiography. The phosphorylation of certain proteins could be enhanced by Ca2+ plus calmodulin or by cyclic AMP. The major effect of Ca2+ and calmodulin was to stimulate the phosphorylation of a protein (P53) of molecular weight 53,100 +/- 500 (n = 15). Maximum phosphorylation of protein P53 occurred within 2 min with 2 micrometers free Ca2+ and 0.7 micrometers calmodulin. Incorporation of label into protein P53 was inhibited by trifluoperazine or W7 but not by cyclic AMP-dependent protein kinase inhibitor. Phosphorylation of a proteins of similar molecular weight could be enhanced to a lesser extent in the absence of Ca2+ but in the presence of cyclic AMP and 3-isobutylmethylxanthine: this phosphorylation was blocked by cyclic AMP-dependent protein kinase inhibitor. Cyclic AMP also stimulated incorporation of label into polypeptides of molecular weights 55,000 and 70-80,000. The results are consistent with the hypothesis that protein phosphorylation mechanisms may play a role in the regulation of insulin secretion.
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PMID:Effects of Ca2+, calmodulin and cyclic AMP on the phosphorylation of endogenous proteins by homogenates of rt islets of langerhans. 627 12

A nuclear p53/55 protein kinase has been isolated from nuclear ribonucleoprotein particles from human tumor cells. The enzyme was purified approximately 2200-fold cell nuclei by sequential ribonuclease digestion of the RNP particles, DEAE cellulose and phosphocellulose chromatography. The kinase which was cAMP independent, catalyzed the phosphorylation of rabbit muscle glycogen synthase in the amino terminal domain, and conversion of the I to D form. The D synthase had a phosphorylation stoichiometry of 8 moles 32P per mole of synthase subunit with maximal specificity for ATP as phosphate donor; its Km was 30 microM. An antinucleolar antibody inhibited enzyme activity by 80%. Substrates for most other kinases were inactive. The kinase was essentially unaffected by the Walsh inhibitor, EGTA, regulatory subunits of protein kinase, calmodulin, trifluoperazine or heparin. Its activity was lost at 1 mM polyamine, but was enhanced 3-fold by MnCl2 and 4- to 9-fold by deoxymononucleotides. The nuclei of HeLa cells contained 64% of the total kinase of which 64% of the total kinase of which 11% were in nucleoli; the specific activity of the nucleolar kinase was twice that of the nuclear supernatant and four times that of the cytoplasmic kinase. These results indicate that nucleolar ribonucleoprotein particles of human tumor cells contain a cAMP-independent protein kinase which is similar to glycogen synthase kinase.
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PMID:Purification of p53/55 kinase from nuclear ribonucleoproteins of Namalwa cells. 643 81

Protein phosphorylation has evolved as the most versatile posttranslational modification widely used by cells. Signal transduction pathways mediated by activation of MAP kinases and protein kinase C trigger the exit of cells from the quiscence (Go-->G1 transition). Indeed, binding of growth factors at the cell surface triggers their receptors, usually possessing a tyrosine kinase on the cytoplasmic side, to phosphorylate other molecules passing on the information sequentially to GRB2 protein, to p21ras, to c-Raf-1, to MAP kinase kinase, to MAP kinase, to p90rsk, to transcription factors. Activated PKC, MAP kinase, and pp90src can translocate to the nucleus where they phosphorylate a number of protein transcription regulators in a cell cycle-dependent manner or in response to cell stimulation for exit from quiescence. The cell cycle is mainly regulated by p34cdc2 or otherwise called cdc2 in association with cyclins B at G2/M and by Cdk2 in association with cyclins A, D1, and E at G1/S checkpoints; phosphorylation of histone H1 and lamins by cdc2 triggers chromosome assembly and nuclear envelope breakdown, respectively, as a prelude to mitosis. Cdc2 activities functioning as a G2/M regulator are controlled by its phosphorylation and dephosphorylation at Ser/Thr residues. MAP kinases might be the missing link in the chain connecting the Go to G1 transition with the cell cycle regulation, whereas phosphorylation of replication protein factors, retinoblastoma, and p53 might link the G1 to S transition with the control of DNA synthesis. A number of transcription factors are known to stimulate DNA replication, including p53, c-Myc, AP-1, Oct-1, T-antigen; the DNA binding activities of all these proteins and their interaction with other transcription factors are controlled by phosphorylation. The nuclear import of several proteins including NF kappa B, Dorsal, glucocorticoid receptor, ISGF3, rNFIL-6, T antigen, and the kinases PKC, MAP, and p90rsk, are dependent on their phosphorylation at specific sites. Histone phosphorylation stimulated at discrete stages of the cell cycle or in response to cAMP or other stimuli might induce profound changes in chromatin organization.
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PMID:Phosphorylation of transcription factors and control of the cell cycle. 754 80

Endogenously generated or exogenously applied nitric oxide (NO) redox species induce apoptotic cell death in murine RAW 264.7 macrophages. Activation of the inducible NO synthase by incubation of cells with a combination of lipopolysaccharide and interferon-gamma produced internucleosomal DNA fragmentation and morphological alterations, i.e., chromatin condensation, indicative of apoptotic cell death. These alterations, reflecting the production of NO, were prevented by an inhibitor of NO synthase, NG-monomethyl-L-arginine. Moreover, NO derived from endogenous or exogenous sources caused accumulation of the tumor suppressor gene p53. Proposing a link between NO generation and DNA fragmentation, we investigated interfering biochemical signaling pathways. Therefore, we tested the ability of four NO-releasing compounds [sodium nitroprusside (SNP), 3-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), and S-nitrosoglutathione (GSNO)] to cause specific DNA fragmentation. All NO donors induced DNA fragmentation in a time- and concentration-dependent manner. However, substance-specific differences became obvious. After an 8-hr incubation period, GSNO proved to be the strongest apoptotic inducer, whereas SIN-1 was much less active. Apoptosis was rapid with GSNO and SNP, yielding specific DNA fragments after 4 hr and 5 hr, respectively. In contrast, SNAP and SIN-1 produced DNA fragmentation after considerable lag times of 9 hr and 14 hr, respectively. Furthermore, an inhibitory effect of protein kinase C (PKC) and cAMP-dependent protein kinase became apparent. 12-O-Tetradecanoylphorbol-13-acetate, an activator of PKC, inhibited DNA fragmentation by all four NO donors, whereas PKC inhibitors such as staurosporine and calphostin C sensitized macrophages to apoptosis induced by SNP and GSNO. Lipophilic cAMP analogues suppressed SNP-, SIN-1, and SNAP-induced DNA fragmentation. Thus, our study suggests the existence of specific down-modulatory mechanisms related to NO-induced apoptotic DNA fragmentation.
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PMID:Nitric oxide-induced apoptosis in RAW 264.7 macrophages is antagonized by protein kinase C- and protein kinase A-activating compounds. 772 36

To examine the hypothesis that nutritional signals regulate trophoblast cell function, JEG-3 choriocarcinoma cells were treated with drugs that stimulate peroxisome proliferator-activated receptors (PPARs). These receptors are thought to mediate in part the effects of lipidic nutrients on gene expression. Because PPARs are modulated by interactions with retinoid-X receptors, we also examined the actions of the peroxisome proliferators in the presence of retinoids. Clofibric acid, a known peroxisome proliferator, suppressed JEG-3 cell growth in association with increases in the tumor suppressor p53 protein and its messenger RNA (mRNA). It reduced CG secretion and CG alpha and CG beta mRNAs in growing cells. However, clofibric acid did not induce peroxisome proliferation in the JEG-3 cells, as assessed by electron microscopy and immunostaining for catalase, a peroxisomal enzyme, or alter levels of mRNAs for peroxisomal proteins, sterol carrier protein-X/sterol carrier protein-2 and acyl-Coenzyme-A oxidase. The mitochondrial cholesterol side-chain cleavage enzyme, cytochrome P450scc, was modestly increased in some experiments. All-trans-retinoic acid and 9-cis-retinoic acid increased CG secretion and CG alpha and CG beta mRNAs, but clofibric acid blunted these stimulatory effects. WY 14,643, another peroxisome proliferator, also reduced CG gene expression without increasing mRNAs encoding peroxisomal proteins or altering P450scc mRNA. The mRNA for a human PPAR, NUC1, was demonstrated in JEG-3 cells, and NUC1 mRNA was shown to be upregulated by 8-bromo-cAMP. We conclude 1) that JEG-3 cells express a PPAR and are subject to regulation by PPAR stimulators; 2) that PPAR stimulation in JEG-3 cells does not promote peroxisome proliferation; and 3) that peroxisome proliferators and retinoids differentially regulate JEG-3 cell endocrine activities. We suggest from these findings that JEG-3 cells possess mechanisms to respond to nutrient cues.
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PMID:Peroxisome proliferators and retinoids affect JEG-3 choriocarcinoma cell function. 807 Mar 57


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