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

We immortalized oral keratinocytes by transfection with recombinant human papillomavirus type 16 (HPV-16) DNA and established two cell lines, human oral keratinocytes-16A (HOK-16A) and -16B (HOK-16B). These cell lines were morphologically different from the normal counterpart, contained HPV-16 DNA as integrated form and expressed numerous viral genes. However, these cells proliferated only in culture medium containing low calcium (0.15 mM) and are not tumorigenic in nude mice. To test the hypothesis that tumors can be developed by sequential combined effect of human papillomavirus and chemical carcinogens in the oral cavity, these immortalized cell lines were chemically transformed by exposure to either benzo[a]pyrene or methanesulfonic acid ethyl ester. Such transformants proliferated in medium containing physiological calcium levels (1.5 mM) and demonstrated enhanced growth potential in nude mice, whereas primary human oral keratinocytes treated with these chemical carcinogens failed to show any evidence of transformation. Chemically transformed cells contained integrated, intact HPV-16 sequences and transcribed significantly higher amount of HPV-16 E6/E7 messages and transforming growth factor-alpha (TGF-alpha) compared with the immortalized oral keratinocytes. Like the HPV-immortalized cell lines, the chemically transformed oral keratinocytes contained lower levels of newly synthesized, wild-type p53 proteins compared to normal cells, and expressed wild-type c-Ha-ras. These results indicate that this in vitro system is useful for investigating the mechanisms of multistep oral carcinogenesis.
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PMID:Sequential combined tumorigenic effect of HPV-16 and chemical carcinogens. 133 Mar 48

We report here that the negative cell cycle regulator protein p53 is an in vivo and in vitro substrate for protein kinase C, a cellular receptor for the tumor-promoter phorbol esters. We also demonstrate that p53 interacts in a calcium-dependent manner with S100b, a member of the S100 protein family involved in cell cycle progression and cell differentiation, and that such an interaction inhibits in vitro p53 phosphorylation by protein kinase C. The interaction between p53 and S100b was utilized for the purification of cellular and recombinant murine p53 by affinity chromatography with S100b-Sepharose. Furthermore, and of particular interest, we have shown that purified p53 undergoes temperature-dependent oligomerization and that the interaction between S100b and p53 not only induces total inhibition of p53 oligomerization but also promotes disassembly of the p53 oligomers. We suggest that these effects result from the binding of S100b to the multifunctional basic C-terminal domain of p53 and propose that p53 may be a cellular target for the S100 protein family members involved in the control of the cell cycle at the G0-G1/S boundary.
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PMID:Characterization of the tumor suppressor protein p53 as a protein kinase C substrate and a S100b-binding protein. 145 55

Mutation of the p53 gene is a key element in the development of several human cancers. Intron 4, a noncoding region of the p53 gene, is required for optimal expression of that gene. We have previously shown that nuclear protein binds intron 4 and have defined the protein-binding site. In this paper we address the question, "Does the mutant p53 gene's ability to transform cells to the malignant phenotype depend on protein binding to intron 4?" Using an in vitro assay in which the mutant p53 gene and Ha-ras oncogene cooperate in transformation of cells to the malignant phenotype, we determined the ability of mutant mouse p53 gene constructs, with and without two base pair substitutions at the intron 4 protein-binding site, to participate in malignant transformation. On Day 1, 5 x 10(5) rat embryo fibroblasts were transfected by the calcium phosphate procedure with 10 micrograms of both a mutant p53 gene construct and Ha-ras oncogene. Malignant transformation was evidenced by the formation of discrete foci of heaped-up cells. After 14 days of incubation at 37 degrees C in DMEM and 10% fetal calf serum (8% CO2), the cells were stained with cresyl violet and the foci counted. In three separate experiments, the presence of two base pair substitutions at the intron 4 protein-binding site caused a significant decrease in the number of foci formed (P less than 0.05).
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PMID:Inhibition of the mutant p53 gene in transformation assays. 159 78

A number of proteins have been identified whose expression or activity is regulated by cell growth. We have produced a monoclonal antibody against a new cell-growth regulated protein found in normal human fibroblasts. We have shown that this antibody recognizes a 51/52-kDa doublet (p51/52) found mainly in normal cells. This doublet is sensitive to degradation by the calcium-activated protease, calpain, breaking down to a 37/38-kDa doublet. The relative amount of the two members of the 51/52-kDa doublet changes when serum-starved cells reenter the cell cycle. Quiescent cells express mainly the 51-kDa form; the 52-kDa form becomes more abundant upon refeeding serum-starved cells. Transformed cells express either very small amounts of this doublet, and then predominantly the 52-kDa form, or no detectable amount of either form. These characteristics distinguish this molecule from several other known growth-regulated proteins such as statin and the anti-oncogene p53.
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PMID:Characterization of p51/52, a cell-growth regulated protein of WI-38 cells. 170 23

To analyze direct intracellular interactions of CR2 in normal human B lymphocytes, we used polyclonal anti-Id anti-CR2 antibodies (Ab2) prepared against the highly purified CR2 molecule (gp140) as original immunogen. We previously demonstrated that this Ab2 contained specificities that mimicked extracellular and intracellular domains of CR2 and was helpful for identifying CR2-specific ligands. Indeed, some Ab2 specificities recognized human C3d and EBV, two extracellular CR2 ligands. In addition, other Ab2 specificities interacted directly, as CR2, with the intracellular p53 antioncoprotein that is expressed in transformed cells and not in normal cells. We demonstrate herein that Ab2 detected in normal B lymphocytes a 68-kDa protein, p68, that was not expressed in transformed B cells. p68 was localized in purified plasma membranes and cytosol fractions. Direct interaction of purified CR2 with purified p68 was demonstrated. Competitive studies supported that CR2 and Ab2 interacted with identical sites on p68. These interactions were calcium dependent. p68 was identified as a calcium-binding protein by its ability to be solubilized from B lymphocyte membranes by EGTA, a calcium-chelating agent, to bind specifically on phenothiazine-Sepharose in a calcium-dependent interaction, and to be recognized by specific antibodies directed against human p68, a calcium-binding protein of the annexin VI family. Thus, demonstration of different intracellular interactions of CR2 with distinct regulatory proteins, such as p53, the antioncoprotein, and p68, a calcium-binding protein, supports involvement of two regulatory pathways of signal transduction through CR2, depending on the normal or transformed state of human B lymphocytes.
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PMID:Intracellular interaction of EBV/C3d receptor (CR2) with p68, a calcium-binding protein present in normal but not in transformed B lymphocytes. 183 Dec 22

We have activated resting human T lymphocytes to study the roles of the putative cell cycle control gene products, retinoblastoma susceptibility gene product (Rb) and p53, in regulating cell proliferation. After stimulation with phorbol, 12,13, dibutyrate and the calcium ionophore, ionomycin, which triggers a rapid entry of cells into G1 phase, we demonstrated Rb phosphorylation 24 h later, well before the onset of DNA synthesis. This finding, in contrast to reports using proliferating cell lines, implies that Rb phosphorylation is not a proximal event regulating the G1 to S transition. The production of p53 became detectable 3 to 6 h after addition of phorbol, 12,13,-dibutyrate and ionomycin, and peaked at 30 to 42 h. To further delineate the relationship of the synthesis and metabolism of the proteins to cell cycle progression, we used three agents to arrest progression of activated T cells at various points in the cell cycle. Aphidicolin arrested the cells at the G1/S boundary, whereas deferoxamine, an iron chelator, arrested the cells at an earlier stage of the cell cycle. Cyclosporin A blocked T cell activation at the earliest point in the cell cycle. In the presence of aphidicolin, Rb phosphorylation and p53 production proceeded normally whereas cyclosporin A inhibited both events. Although deferoxamine completely prevented Rb phosphorylation, p53 production was unaffected, suggesting a differential regulation of the two molecules. Our results place Rb phosphorylation and p53 production in the hierarchy of genetic events that are thought to regulate T lymphocyte progression through the cell cycle.
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PMID:Differential regulation of the tumor suppressor molecules, retinoblastoma susceptibility gene product (Rb) and p53, during cell cycle progression of normal human T cells. 190 3

Hexamethylene bisacetamide (HMBA) is a most effective compound as an inducer of MELC differentiation. HMBA-mediated terminal differentiation of MELC is a multistep process. There is a latent period during which a number of changes occur including the appearance of Ca2+ and phospholipid independent PKC activity in the cytosol, and modulation in expression of several genes, including c-myc, c-myb, c-fos and the p53 genes. During this latent period there is neither detectable commitment to terminal differentiation (including terminal cell division) or increased transcription of the globin genes. HMBA-mediated commitment to terminal differentiation is first detected at about 12 hr and increases in a stochastic fashion, until over 95% of the population has been recruited to terminal differentiation by 48 to 60 hr. Commitment is associated with persistent HMBA-mediated suppression of c-myb gene expression. By 36 to 48 hr, transcription of the globin genes has increased by 10 to 30 fold, whereas transcription of rRNA genes is suppressed. The steroid, dexamethasone, and the tumor promotor, phorbol-12-myristate-13-acetate, suppress HMBA-induced MEL cell terminal differentiation. The evidence indicates that these agents act at a late step during the latent period. Recently, we showed that MELC variants selected for resistance to vincristine have a marked increased sensitivity to HMBA. Compared to the parental MELC strains, vincristine resistant MELC are: A) responsive to 1/5 to 1/10 the concentration of HMBA; B) induced to terminal differentiation without a latent period and C) resistant to inhibition of HMBA induced terminal differentiation by dexamethasone or tumor promotor. The vincristine resistant MELC have characteristics of the multidrug resistant phenotype. A number of independently derived vincristine resistant MELC lines show similar altered response to HMBA. These findings suggest that vincristine resistance leads to a constitutive expression of a factor or factors induced by HMBA in vincristine sensitive (wild type) MELC during the latent period and which are essential to the transition to terminal differentiation.
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PMID:Induced differentiation of murine erythroleukemia cells (MELC) by polar compounds: marked increased sensitivity of vincristine resistant MELC. 261 74

Ribonucleotide reductase consists of two non-identical protein subunits that are required for enzyme activity. These subunits are encoded by different genes and are not expressed coordinately as the cells pass through the cell cycle. Using specific cDNAs for the non-heme iron (NHI) and the effector-binding (EB) subunits the levels of the mRNAs for these two subunits were determined in leukemia L1210 cells during the transition from the G0/G1 phase to the S and G2/M phases of the cell cycle. Synchronized populations of L1210 cells were obtained either by ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) treatment or by enrichment by elutriation centrifugation. The changes in the levels of the mRNAs for NHI and EB subunits were compared with the changes in the levels of the mRNAs for actin, p53, c-myc, thymidine incorporation into DNA, and DNA content by flow cytometric measurements. Synchronization of the cells by the two methods resulted in quantitative differences in the responses. The EGTA synchronized L1210 cells showed maximal increases of 9.3- and 5.7-fold in the mRNAs for the NHI and EB subunits, respectively. The peak level of the NHI mRNA was observed at 12 hr after the addition of calcium ions. The peak increase in the level of the mRNA for the EB subunit was observed between 12 and 15 hr after the addition of calcium ions. The rate of increase for the mRNA for c-myc was greater than the increase in the mRNA for the NHI subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in messenger RNA levels for the subunits of ribonucleotide reductase during the cell cycle of leukemia L1210 cells. 270 Sep 14

We have tested the ability of chrysotile asbestos fibers to introduce plasmid DNA into monkey COS-7 cells and the ability of this DNA to function in both replication and gene expression. Chrysotile fibers are at least as effective as calcium phosphate in standard transfection assays at optimal ratios of asbestos to DNA. After transfection with chrysotile, a minor percentage of introduced plasmid DNA bearing a simian virus 40 origin of replication replicates after 24 hr. Fragmentation of entering DNA is more prominent with asbestos than with calcium phosphate, and after 72 hr most DNA introduced by asbestos is associated with chromosomal DNA. Cells transfected with plasmid p11-4, bearing the p53 protooncogene, express this gene. Cells transfected with pSV2-neo express a gene conferring resistance of antibiotic G418, allowing isolation of colonies of transformed cells after 18 days. The introduction of exogenous DNA into eukaryotic cells could cause mutations in several ways and thus contribute to asbestos-induced oncogenesis.
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PMID:Asbestos fibers mediate transformation of monkey cells by exogenous plasmid DNA. 284 18

Hexamethylene bisacetamide (HMBA), a highly polar compound, induces murine erythroleukemia (MEL) cells to express the erythroid phenotype, including cessation of proliferation. Inducer-mediated differentiation of MEL (DS19) cells is a multistep process characterized by a latent period during which a number of changes occur including alterations in ion flux, an increase in membrane-bound protein kinase C (PKC) activity, the appearance of Ca2+ and phospholipid-independent PKC activity in the cytosol, and modulation in expression of a number of genes such as c-myc, c-myb, c-fos and the p53 genes. HMBA-mediated commitment to terminal differentiation is first detected at about 12 hours and increases in a stochastic fashion until over 95% of the population is recruited to terminal differentiation by 48 to 60 hours. Commitment is associated with persistent suppression of c-myb gene expression. By 36 to 48 hours, transcription of the globin genes has increased 10 to 30 fold, whereas transcription from rRNA genes is suppressed. The steroid, dexamethasone, or the tumor promoter, phorbol-12-myristate-13-acetate (TPA), suppress HMBA-induced MEL cell terminal differentiation. These agents appear to act at a late step during the latent period. MEL cell lines derived from DS19 by selection for resistance to vincristine are: 1) induced to commit without a detectable latent period, 2) markedly more sensitive to HMBA, and 3) resistant to dexamethasone or TPA inhibition of HMBA-induced commitment. The data suggests that vincristine-resistant MEL cells express a factor which circumvents essential HMBA-mediated early events. In vitro studies with HMBA provide a basis for the application of HMBA to clinical therapy of human cancers. Clinical trials with HMBA have been initiated.
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PMID:Hexamethylene bisacetamide-induced differentiation of transformed cells: molecular and cellular effects and therapeutic application. 304 66


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