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)

The p53 protein accumulates rapidly through post-transcriptional mechanisms following cellular exposure to DNA damaging agents and is also activated as a transcription factor leading to growth arrest or apoptosis. Phosphorylation of p53 occurs after DNA damage thereby modulating its activity and impeding the interaction of p53 with its negative regulator oncogene Mdm2. The serines 15 and 37 present in the amino terminal region of p53 are phosphorylated by the DNA-dependent protein kinase (DNA-PK) in response to DNA damage. In order to verify if specific p53 mutations occur in the multi-drug resistance phenotype, we analysed the p53 gene in two T-lymphoblastoid cell lines, CCRF-CEM and its multi-drug-resistant clone CCRF-CEM VLB100, selected for resistance to vinblastine sulfate and cross-resistant to other cytotoxic drugs. Both cell lines showed two heterozygous mutations in the DNA binding domain at codons 175 and 248. The multi-drug resistant cell line, CCRF-CEM VLB100, showed an additional mutation that involves the serine 37 whose phosphorylation is important to modulate the protein activity in response to DNA damage. The effects of these mutations on p53 transactivation capacity were evaluated. The activity of p53 on pro-apoptotic genes expression in response to DNA damage induced by (-irradiation, was affected in the vinblastine (VLB) resistant cell line but not in CCRF-CEM sensitive cell line resulting in a much reduced apoptotic cell death of the multi-drug resistant cells.
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PMID:A serine 37 mutation associated with two missense mutations at highly conserved regions of p53 affect pro-apoptotic genes expression in a T-lymphoblastoid drug resistant cell line. 1104 98

The ATP-binding cassette transmembrane proteins play an important role in transport of drugs as well as of biologically active endogenous substances. The human multidrug resistance-associated protein (MRP) subfamily consists of at least six members, exhibiting a wide spectrum of biological functions. MRP1 operates as an ATP-dependent primary active transporter for substrates conjugated with glucuronide, sulfate or glutathione. Leukotriene C4 is an important endogenous substrate for MRP1. Glutathione serves as a cofactor in MRP1-mediated drug transport as well. Genes encoding both MRP1 and the catalytic subunit of gamma-glutamylcysteine synthetase (gamma-GCS) are coordinately regulated in cultured cancer cell lines as well as colorectal cancer tissues from colon cancer patients. The induction of MRP1 and gamma-GCS expression by oxidative stress varies among different cell lines, and p53 mutations are associated with elevated levels of induction. To modulate the transport function of MRP1, we have synthesized novel glutathione derivatives as photoreactive biochemical probes targeting the transporter protein. GIF-0019 restored the cellular sensitivity of MRP1-overexpressing drug-resistant cancer cells to anticancer prostaglandins in vitro, which was characterized by enhanced mRNA levels of the cyclin-dependent kinase inhibitor p21, suppressed c-myc expression and G1 arrest.
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PMID:The human multidrug resistance-associated protein (MRP) gene family: from biological function to drug molecular design. 1109 46

The p53 tumor suppressor is a transcription factor that upon activation by DNA-damaging agents induces growth arrest or apoptosis mainly through transactivation and transrepression of its downstream target genes. Two additional p53 family members, p73 and p51/p63, were recently identified and characterized. Although the three family members share some similarities in transcription activation and apoptosis induction, each of them appears to play a distinct role in development and tumor suppression. We have previously identified a nuclear protein, p53CP (p53 competing protein), that is not p53 but binds to the p53 consensus sequence. Here we report the partial purification of p53CP from HeLa cells by ammonium sulfate precipitation, followed by a series of chromatography steps through heparin-agarose, Mono S ion exchange and DNA affinity columns, coupled with a gel shift assay. Although p53CP activity is readily detectable in HeLa cells by gel shift assay, only a trace amount of p53CP protein was partially purified, which was not sufficient for direct protein sequencing. Using a monoclonal antibody (4A4) specific for all p51/p63 isoforms or a polyclonal antibody (N-18) recognizing the N-terminus-containing p51/p63 isoforms we detected a significant enrichment of p51/p63 protein in p53CP-containing fractions following each step of purification. Significantly, p51/p63 was detected only in the DNA affinity column fractions that contain p53CP activity. Thus, p53CP appears to be p51/p63, the third member of the p53 gene family.
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PMID:p53CP is p51/p63, the third member of the p53 gene family: partial purification and characterization. 1118 51

Reactive species generated by chemicals and UV radiation can cause sequence-specific DNA damage and play important roles in mutagenesis, carcinogenesis and aging. We have investigated sequence specificity of oxidative stress-mediated DNA damage by using 32P-labeled DNA fragments obtained from the human c-Ha-ras-1 and p53 genes. Free hydroxyl radical causes DNA damage with no marked site specificity. Reactive nitrogen species, sulfate radicals, nitrogen-centered radicals, benzoyloxyl radical and alkoxyl radical show different sequence specificity. Benzoyloxyl radical specifically causes damage to the 5'-G in GG sequence. UVA radiation also causes DNA damage at this site through electron transfer in the presence of certain photosensitizers. The 5'-G in GG sequence is easily oxidized because a large part of the highest occupied molecular orbital is distributed on this site. On the basis of these findings, the sequence specificity of DNA damage is presumably determined by (a) redox potential of reactive species; (b) ionization potential of DNA bases; and (c) site-specific binding of metal ion to DNA. Here we discuss the mechanisms of sequence-specific DNA damage in relation to carcinogenesis and aging.
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PMID:Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging. 1122 5

In coastal locations, marine invertebrates, primarily molluscs, develop fatal leukemias in their blood or hemolymph. In the clam Mya arenaria, non-adhesive, mitotic, spherical leukemia cells replace adhesive, motile, normal hemocytes as leukemia progresses. End-stage leukemia cells express a unique antigen, IE10, while normal cells express the 2A4 marker. The goals of this work were to further differentiate the normal and leukemia specific antigens relative to protein structure, determine if other protein distinctions exist, and examine p53 gene family expression in both cell types. Recognized by the monoclonal antibody 2A4, normal cells express a 185-kDa glycoprotein that may have multiple forms. Detected by the monoclonal antibody 1E10, leukemic cells express a very hydrophobic 252-kDa glycoprotein that is likely to be a transmembrane protein with spectrin/dystrophin-like characteristics. After normalization to the major cytoskeletal protein actin, sodium dodecyl sulfate-polyacrylamide gel electrophoresis reveals major distinguishing protein and glycoprotein differences between the two cell types. Most obvious is the near-absence of tubulin in the non-mitotic normal hemocytes. We have also characterized the expression of p53 gene family members in normal and end-stage leukemia cells, finding shifts in expression of the p53 gene homologues p73 and p97 coincident with leukemia-specific protein synthesis.
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PMID:Multiple protein differences distinguish clam leukemia cells from normal hemocytes: evidence for the involvement of p53 homologues. 1148 30

Occupational exposure to beryllium (Be) and Be compounds occurs in a wide range of industrial processes. A large number of workers are potentially exposed to this metal during manufacturing and processing, so there is a concern regarding the potential carcinogenic hazard of Be. Studies were performed to determine the carcinogenic potential of beryllium sulfate (BeSO4) in cultured mammalian cells. BALB/c-3T3 cells were treated with varying concentrations of BeSO4 for 72 h and the transformation frequency was determined after 4 weeks of culturing. Concentrations from 50-200 microg BeSO4/ml, caused a concentration-dependent increase (9-41 fold) in transformation frequency. Non-transformed BALB/c-3T3 cells and cells from transformed foci induced by BeSO4 were injected into both axillary regions of nude mice. All ten Be-induced transformed cell lines injected into nude mice produced fibrosarcomas within 50 days after cell injection. No tumors were found in nude mice receiving non-transformed BALB/c-3T3 cells 90 days post-injection. Gene amplification was investigated in K-ras, c-myc, c-fos, c-jun, c-sis, erb-B2 and p53 using differential PCR while random amplified polymorphic DNA fingerprinting was employed to detect genomic instability. Gene amplification was found in K-ras and c-jun, however no change in gene expression or protein level was observed in any of the genes by Western blotting. Five of the 10 transformed cell lines showed genetic instability using different random primers. In conclusion, these results indicate that BeSO4 is capable of inducing morphological cell transformation in mammalian cells and that transformed cells induced by BeSO4 are potentially tumorigenic. Also, cell transformation induced by BeSO4 may be attributed, in part, to the gene amplification of K-ras and c-jun and some BeSO4-induced transformed cells possess neoplastic potential resulting from genomic instability.
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PMID:Carcinogenic potential and genomic instability of beryllium sulphate in BALB/c-3T3 cells. 1167 13

The mechanisms underlying the frequent development of colorectal carcinomas in patients with ulcerative colitis (UC) are still not understood. This study was conducted to investigate whether p53 and p21 protein expressions contribute to carcinogenesis in an experimental model with dextran sulfate sodium (DSS) treatment, and to establish if this colitis model is suitable for study of cancer development in UC. A total of 40 mice were subjected to four administration cycles of 4% DSS for 7 days followed by plain water for the subsequent 14 days. The 33-surviving mice were sacrificed to examine the malignant transformation of colonic mucosa morphologically and to determine p53 and p21 expressions immunohistochemically. After DSS treatment periods, there were marked irregularities in the mucosal layer, the thickness of the entire bowel wall and the shortness of the colon. Histologically, tumors were found in 13 out of 33 (39.4%) mice. These 13 cases included 9 with a solitary lesion and 4 with double tumors. There were occurrences of invasive carcinomas in 8 lesions, high-grade dysplasia in 3 lesions and low-grade-dysplasia in 6 lesions. One presented with a polypoid tumor, 5 mm in diameter, while 16 had small flat lesions. There were 13 tumors on the left-sided colon, as opposed to 4 on the right-sided colon. Histological differentiation of invading carcinomas revealed that 6 out of 8 lesions were comprised of well differentiated adenocarcinomas, while 2 were moderately differentiated adenocarcinomas. Overexpression of p53 protein was found in 4 out of 8 invasive carcinomas, 2 out of 3 high-grade dysplasia cases and 2 out of 6 low-grade dysplasia cases, whereas only 1 out of 8 with invasive carcinoma was positive for p21. This experimental colitis model suggests that p53 and p21 protein expressions may contribute to carcinogenesis in DSS-induced colitis in mice and appears suitable to study cancer development in UC.
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PMID:Development of colonic neoplasms and expressions of p53 and p21 proteins in experimental colitis of mice induced by dextran sulfate sodium. 1171 23

This study focuses on the effects of simulated microgravity (0g) on the human follicular thyroid carcinoma cell line ML-1. Cultured on a three-dimensional clinostat, ML-1 cells formed three-dimensional MCTSs (MCTS diameter: 0.3 +/- 0.01 mm). After 24 and 48 h of clinorotation, the cells significantly decreased fT3 and fT4 secretion but up-regulated the thyroid-stimulating hormone-receptor expression as well as the production of vimentin, vinculin, and extracellular matrix proteins (collagen I and III, laminin, fibronectin, chondroitin sulfate) compared with controls. Furthermore, ML-1 cells grown on the clinostat showed elevated amounts of the apoptosis-associated Fas protein, of p53, and of bax but showed reduced quantities of bcl-2. In addition, signs of apoptosis became detectable, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling, 4', 6-diamidino-2-phenylindole staining, DNA laddering, and 85-kDa apoptosis-related cleavage fragments. These fragments resulted from enhanced 116-kDa poly(ADP-ribose)polymerase (PARP) activity and apoptosis. These observations suggest that clinorotation elevates intermediate filaments, cell adhesion molecules, and extracellular matrix proteins and simultaneously induces apoptosis in follicular thyroid cancer cells. In conclusion, our experiments could provide a regulatory basis for the finding that astronauts show low thyroid hormone levels after space flight, which may be explained by the increase of apoptosis in thyrocytes as a result of simulated 0g.
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PMID:Simulated microgravity alters differentiation and increases apoptosis in human follicular thyroid carcinoma cells. 1191 68

A complex of the DNA-binding domain of the tumour suppressor p53 bound to the BRCT domains of the p53-binding protein (53BP1) has been prepared and purified. Single crystals have been obtained using the microbatch technique with polyethylene glycol 4 kDa and ammonium sulfate. Crystals diffract X-rays to beyond 2.3 A and belong to the space group P2(1)2(1)2(1). Several complete data sets have been collected from a number of crystals, each with different unit-cell parameters. Partial structures have been produced by successful placement of two copies of the p53 core region into the asymmetric unit. There is clear evidence for the binding protein and a complete structure determination is under way.
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PMID:Purification, crystallization and preliminary X-ray analysis of the BRCT domains of human 53BP1 bound to the p53 tumour suppressor. 1235 27

The migrating position of green fluorescent protein (GFP)-fused polypeptide varied on an SDS/urea gel by a single amino acid change in the fused polypeptide segment. An easy detection method for a single amino acid change based on this observation was called "GFP-display." Using various target polypeptides, staphylococcal protein A (SpA), Ras, p53, and human beta3 adrenergic receptor (AR), and their mobility-shift patterns resulting from the single amino acid changes, several important properties of GFP-display were revealed as follows: (i). since the binding of dodecyl sulfate ions to acidic or hydrophilic amino acids is weaker than that to basic or hydrophobic amino acids, the ions bound weakly to the fused polypeptide segment are forced to come off by high concentrations of urea prior to the ions bound strongly, resulting in the mobility shift, (ii). the mobility shift is estimated to a certain extent using a new parameter called the "GD value" calculated from the isoelectric point, hydrophilicity, and number of fused amino acids, and (iii). the fluorescence intensity of GFP-fused polypeptide tends to increase with the average hydrophilicity of the fused polypeptide segment. GFP-display will be a helpful technique for many kinds of gene or protein studies related to amino acid substitutions such as the random mutagenesis in a gene of interest.
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PMID:General properties of GFP-display, an electrophoretic analysis for single amino acid changes in target polypeptides. 1272 7


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