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 tumor suppressor p53 plays a central role in the cellular responses to genotoxic stress. Besides its well known role in activation of the G1 checkpoint after exposure to agents like ionizing radiation and its role in apoptosis, the possibility exists that p53 may have additional roles, such as in DNA repair. For example, p53, is known to bind to single strand DNA such as would occur during repair events, and the proteins encoded by two p53-regulated genes have previously been found to bind to at least one protein involved in DNA damage processing including nucleotide excision repair (NER). NER is an important and versatile DNA repair mechanism, which is the major pathway for repair of u.v.-type lesions and damage by a variety of important carcinogens and mutagens. If components of the p53 pathway are involved in NER, then disruption of p53 function by mutations or expression of certain viral proteins could have important implications in carcinogenesis and cancer treatment. In the present study we show that disruption of normal p53 function in human colon carcinoma RKO cells with either the human papillomavirus E6 oncoprotein or a dominant-negative mutant p53 transgene results in reduced repair of u.v.-induced DNA damage. The E6 and mutant p53-containing cell lines demonstrated reduced repair of u.v.-induced DNA lesions in host cell reactivation experiments with reporter plasmids, and reduced repair in in vitro DNA repair assays. With this in vitro assay, extracts from the E6- and mutant p53-containing lines also showed loss of induced repair following cellular u.v.-irradiation. The reduced DNA repair activity of the transfected cell lines also correlated with reduced clonogenic survival following u.v.-irradiation. These results indicate that p53 and/or p53-regulated gene products function in the NER pathway and that this process is inducible by DNA damage.
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PMID:Involvement of the p53 tumor suppressor in repair of u.v.-type DNA damage. 770 Jun 29

The possibility that appropriately designed chemotherapy could act selectively against p53-defective tumor cells was explored in MCF-7 human breast cancer cells. These cells were chosen because they have normal p53 function but are representative of a tumor cell type that does not readily undergo p53-dependent apoptosis. Two sublines (MCF-7/E6 and MCF-7/mu-p53) were established in which p53 function was disrupted by transfection with either the human papillomavirus type-16 E6 gene or a dominant-negative mutant p53 gene. p53 function in MCF-7/E6 and MCF-7/mu-p53 cells was defective relative to control cells in that there were no increases in p53 or p21Waf1/Cip1 protein levels and no G1 arrest following exposure to ionizing radiation. Survival assays showed that p53 disruption sensitized MCF-7 cells to cisplatin (CDDP) but not to several other DNA-damaging agents. CDDP sensitization was not limited to MCF-7 cells since p53 disruption in human colon carcinoma RKO cells also enhanced sensitivity to CDDP. Contrary to the other DNA-damaging agents tested, CDDP-induced DNA lesions are repaired extensively by nucleotide excision, and in agreement with a defect in this process, MCF-7/E6 and MCF-7/mu-p53 cells exhibited a reduced ability to repair a CDDP-damaged chloramphenicol acetyltransferase-reporter plasmid transfected into the cells. Therefore, we attributed the increased CDDP sensitivity of MCF-7 cells with disrupted p53 to defects in G1 checkpoint control, nucleotide excision repair, or both. The G2 checkpoint inhibitor pentoxifylline exhibited synergism with CDDP in killing MCF-7/E6 cells but did not affect sensitivity of the control cells. Moreover, pentoxifylline inhibited G2 checkpoint function to a greater extent in MCF-7/E6 than in the parental cells. These results suggested that, in the absence of p53 function, cancer cells are more vulnerable to G2 checkpoint abrogators. Our results show that a combination of CDDP and pentoxifylline is capable of synergistic and preferential killing of p53-defective tumor cells that do not readily undergo apoptosis.
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PMID:Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. 771 69

Digital image analysis provides objective measurements of tissue and cell analytes previously interpreted subjectively. Both analyte concentration determination and morphometric analyses are possible. Calibration of the instrument and the use of standards and controls are essential for precise and reproducible quantitation of the analyte. Multi-tissue blocks ensure reproducible staining of the batch in quantitative immunohistochemical assays such as breast cancer estrogen and progesterone receptors. These multi-tissue blocks can be shared among laboratories to reduce interlaboratory variation and to objectively quantitate estrogen and progesterone receptors in clinical trials. In colon carcinoma, p53 can be quantitated objectively by image analysis. In prostate carcinoma, morphometric analysis of nuclear shape, nuclear roundness factor, and variations in nuclear size are objective measurements which constitute the pathologist's nuclear grade. Developments in instrumentation have now made it possible to combine analyte determination (such as DNA ploidy) and morphologic analysis of tumors, a diagnostic improvement over either method alone. A study employing image analysis to detect and quantitate androgen receptors and p53 in formalin-fixed, paraffin-embedded prostate cancer biopsies is underway to determine the utility of androgen receptors in predicting response to hormonal therapy. Histopathological features such as nuclear size, shape, and pleomorphism must be converted to image features such as area, shape factor, and variance of the area; this feature vector must be correlated with the pathologist's expert opinion or diagnosis. Other applications of image analysis include quantitation of immunofluorescent assays such as anti-nuclear antigen or anti-cytoplasmic nuclear antigen. Fluorescent image analysis provides more precision and greater reproducibility, as well as reduced test costs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Quantitation and morphometric analysis of tumors by image analysis. 782 83

Human colon cancer development is associated with the accumulation of mutations and deletions in the suppressor genes DCC, APC and p53 and mutations in the dominant oncogene K-ras, with loss of wild type alleles. In earlier studies we had observed that about half of the resected human colon cancers placed into primary culture were growth stimulated by TGF beta 1. This group included the more advanced cancers which were either poorly differentiated primary-site cancers or metastases. In contract, the more differentiated colon cancers were inhibited or unaffected by TGF beta 1, indicating that a switch in response to TGF beta 1 occurs during colon cancer progression. Different sublines of the HT29 colon carcinoma cell line model the resected cancers, responding to TGF beta 1 by proliferation, inhibition or no growth modulation. The current study shows that while the poorly differentiated, TGF beta 1-stimulated sublines are most tumorigenic, all the sublines have the same spectrum of mutations: truncating mutations in both APC (adenomatous polyposis coli) alleles, no activated ras genes, mutated and thus overexpressed p53, and very low expression of DCC compared to normal colon cells. Genes other than the four already implicated in colon carcinoma evolution are responsible for the mitogenic response to TGF beta 1 found in the more advanced cancers.
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PMID:The capacity for growth stimulation by TGF beta 1 seen only in advanced colon cancers cannot be ascribed to mutations in APC, DCC, p53 or ras. 797 Jul 29

Immunohistochemical demonstration of p53 is thought to reflect mutations of the p53 gene. Although p53 expression or mutation has been investigated in a variety of carcinomas, it has not been examined in intrahepatic cholangiocarcinoma (CC). We investigated expression of p53 in formalin-fixed, paraffin-embedded archival specimens of 40 CCs (22 autopsy cases and 18 surgical cases) by immunohistochemistry using four antibodies (PAb1801, DO-7, BP53-12, CM1). We also attempted to enhance p53 expression by pretreatments of tissue sections by pepsin digestion as well as by microwave oven heating. Formalin-fixed, paraffin-embedded archival surgical specimens of 15 colon carcinomas were used as controls. In surgical cases, p53 expression was abolished by pepsin predigestion, although it was greatly enhanced by pretreatment of microwave oven heating in all immunostainings (PAb1801, DO-7, BP53-12, CM1). In surgical cases immunostained with microwave oven heating, DO-7, BP53-12, and CM1 showed frequent p53 expression (22% in CC; 60-67% in colon carcinoma), whereas PAb1801 showed low p53 expression (0% in CC; 13% in colon carcinoma). In contrast to the surgical cases, all 22 CCs of autopsy cases showed no p53 expression by any antibodies as well as by any pretreatments. These results shows that a pretreatment of tissue sections by microwave oven heating is a very good method for demonstrating p53 protein in formalin-fixed, paraffin-embedded archival materials and that DO-7, BP53-12, and CM1 are useful antibodies for detection of p53 in formalin-fixed, paraffin-embedded archival materials. No expression of p53 in autopsy cases of CC suggests that p53 antigenicity is lost during autopsy procedure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Methods in pathology. p53 expression in formalin-fixed, paraffin-embedded archival specimens of intrahepatic cholangiocarcinoma: retrieval of p53 antigenicity by microwave oven heating of tissue sections. 800 49

Survival analysis of 144 histologically confirmed cases of colon carcinoma diagnosed in a 12 year period (1971-82) at the Tampere University Hospital was performed to test the hypothesis that p53 overexpression is associated with a poor clinical outcome. Immunohistochemical staining of paraffin-embedded sections using a polyclonal antibody CM-1 against p53 protein was performed to identify aberrant expression of the p53 tumour-suppressor gene. Sixty-nine per cent of the tumours (100/144) showed overexpression of the p53 protein. The prevalence of p53 overexpression was independent of age and sex of the patient and subsite of the tumour, but was slightly, although not statistically significantly, higher in advanced than in localised tumours. Overexpression was associated with a higher S-phase fraction. Some indication of a larger proportion of aneuploid tumours among those with overexpression was also observed, although this finding did not reach statistical significance. Significantly reduced patient survival for tumours with p53 overexpression was found. Patients with p53-overexpressing tumours had a corrected 5 year survival rate of 37% compared with 58% among patients whose tumours had normal expression of p53. The corresponding 10 year rates were 34% and 54%. In the multivariate analysis using a Cox model, the survival difference was independent of age and sex of the patient, as well as of subsite and stage of the tumour. Furthermore, the effect of p53 overexpression remained after controlling for flow cytometric parameters in an analysis of a subset of tumours. Thus, p53 overexpression appears to be a useful prognostic indicator in colon carcinoma.
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PMID:Overexpression of p53 and long-term survival in colon carcinoma. 805 78

The LIM 1863 colon carcinoma cell line grows as structural organoids of goblet and columnar cells around a central lumen and provides a model for the development of stem cells in the normal colon. The organoid structure can be disrupted by removal of calcium from the medium, resulting in a suspension of single cells. Upon readdition of calcium, the cells reform the organoid structure over a period of 24 h, and ultrastructural examination of the reforming cells reveals that this involves a complex process that we have termed clutching. To determine the adhesion molecules involved in organoid formation we attempted to block this process by single cell suspensions of LIM 1863 reseeded in the presence of monoclonal antibodies. An anti-integrin antibody directed against a conformational epitope on the alpha v subunit totally inhibited organoid reformation. As a consequence of this inhibition of cell contact the colon carcinoma cells rapidly underwent apoptosis. Investigations of the apoptotic pathway involved suggested an induction mechanism since the onset of apoptosis in the contact-inhibited cells showed specific increased synthesis of 68- and 72-kD proteins. In addition, immunoblotting of cytosolic and nuclear extracts of the cells revealed the rapid translocation of the tumor suppressor gene product, p53 to the cell nucleus upon induction of apoptosis. These results suggest that cell-cell adhesion may be a vital regulator of colon development overcome in tumor cells by loss of adhesion molecules or of functional p53 protein.
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PMID:Apoptosis induced by inhibition of intercellular contact. 816 56

In this study, we have mapped the intracellular alkylation sites of adozelesin and bizelesin, two potent analogs of CC-1065, in individual genes at the single-nucleotide level. Human colon carcinoma cells were treated with adozelesin and bizelesin, and the position of adducts were mapped within the PGK-1 and p53 genes by means of ligation-mediated polymerase chain reaction. The monofunctional alkylating agent adozelesin was found to alkylate genomic DNA predominantly within 5'-(A/T)(A/T)A* sequences. Additional sites of alkylation were observed within 5'-(A/T)(G/C)(A/T)A* sequences; however, these were considered to represent sites of medium to low preference. Bizelesin, a bifunctional analog capable of both DNA monofunctional alkylation and DNA interstrand cross-link formation, was also found to alkylate 5'-(A/T)(A/T)A* sequences. Putative bizelesin DNA interstrand cross-link sites indicated that AT-rich sequences are preferred in the intervening sequence between the two cross-linked adenines. Both six- and seven-nucleotide regions were identified as putative sites of DNA interstrand cross-link formation with 5'-TTTTTTA*, 5'-TTTATCA* and 5'-GTACTAA* sequences being preferred. Non-adenine bases are not observed as potential intracellular sites of either DNA interstrand cross-linking formation or monofunctional alkylation. Thus, the patterns of alkylation induced by adozelesin and bizelesin in genomic DNA are similar but not identical to that observed in purified cell-free DNA.
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PMID:Mapping of DNA alkylation sites induced by adozelesin and bizelesin in human cells by ligation-mediated polymerase chain reaction. 818 Feb 30

In areas of the world where hepatitis B and aflatoxin ingestion are common, alterations of the p53 tumor suppressor gene have frequently been reported in hepatocellular carcinoma (HCC). In particular, G-to-T transversions at codon 249 of the p53 gene have been consistently observed in hepatocellular carcinomas in China and sub-Saharan Africa. The goal of this study was to determine the frequency and relationship of p53 gene alterations and hepatitis B in formalin-fixed, paraffin-embedded HCCs resected in the United States. Since immunoreactivity for p53 correlates closely with the presence of missense mutations in the p53 gene, we performed immunohistochemical staining with the monoclonal antibody PAb1801. Only seven of 37 cases (19%) demonstrated nuclear accumulation of p53 gene product, in contrast to 10 of 20 cases (50%) of colon carcinoma metastatic to the liver. Staining was not observed in seven liver cell adenomas, 10 cases of focal nodular hyperplasia, or eight cases of cirrhosis. DNA was extracted from formalin-fixed paraffin sections for additional analysis with use of the polymerase chain reaction (PCR). G-to-T transversions of the third nucleotide of codon 249 were demonstrated in only four of 37 cases (11%), three of which had stained with PAb1801. Of 13 patients for whom there was information about a restriction fragment length polymorphism (RFLP) for BstUI within the fourth exon of the p53 gene, allelic loss of p53 was demonstrated in only two cases (15%), both of which stained with PAb1801. Because of previous reports specifically associating hepatitis B with p53 mutations in HCC, we performed nested PCR for hepatitis B virus DNA. Five of 37 cases (14%) contained hepatitis B virus DNA, two of which stained diffusely for p53 and three of which had codon 249 mutations. Our findings indicate that alterations in the p53 gene, particularly at codon 249, are uncommon in HCCs in the United States, and when present are associated with hepatitis B. Since hepatitis B is infrequently associated with HCC in our patient population, the role of p53 alterations in hepatocellular carcinogenesis may not be as significant as in other parts of the world where hepatitis B and aflatoxin are more prevalent.
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PMID:Hepatitis B and alterations of the p53 tumor suppressor gene in hepatocellular carcinoma. 823 31

Colorectal carcinogenesis is a multistep process that is accompanied by accumulation of changes in proto-oncogenes and tumor-suppressor genes. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes, as well as other genomic alterations appear at characteristic stages of tumor development and are observed in most neoplasms. However, consideration of each of these abnormalities leaves many unanswered questions. The striking data on recurrent amplification of the RB tumor-suppressor gene as well as suppressive activities of protein kinase C and activated RAS genes, at least in some colon carcinoma cell lines, suggest the unusual effects of some signalling pathways in colonic epithelial cells. The results obtained to date indicate that distinct sets of genetic changes may underlie the development of colorectal tumors.
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PMID:Genetic events responsible for colorectal tumorigenesis: achievements and challenges. 824 74


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