Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To further investigate the role of p53 gene inactivation in gastric tumorigenesis, the mutational status of the p53 gene in primary human gastric cancer samples was examined. Reverse transcriptase polymerase chain reaction and subsequent direct sequencing of the p53 gene from gastric cancer samples revealed frequent point mutations of the p53 gene: some of these coincided with those previously identified in gastric cancer cell lines. In addition, both allelic deletion analysis using pYNZ 22 and polymerase chain reaction-restriction fragment length polymorphism analysis demonstrated an allelic deletion of the p53 gene in cancer tissue which contained a point mutation of the p53 gene in the remaining allele. Transfection of the wild-type or mutant p53 genes into gastric cancer cells showed that the wild-type but none of the mutated p53 genes suppressed the colony formation of gastric cancer cells. Furthermore, the incorporation of thymidine into DNA was reduced in cancer cells expressing the wild-type p53 gene. The glutathione S-transferase-wild type p53 fusion protein bound to simian virus 40 large T antigen in COS-1 cell lysate. None of the p53 fusion proteins containing mutations at codons 143, 175, 248, or 273 bound to simian virus 40 large T antigen. By contrast, two different mutant p53 fusion proteins containing mutations specifically observed in gastric cancer bound to simian virus 40 large T antigen. These results indicate that inactivation of the p53 gene through mutations and the allelic deletion may play an important role in gastric tumorigenesis. These mutations may cause a conformational change in the p53 protein resulting in the loss of the suppression by p53 of the growth of gastric cells, partly through disruption of the association of p53 protein with a cellular component.
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PMID:p53 gene mutations in human gastric cancer: wild-type p53 but not mutant p53 suppresses growth of human gastric cancer cells. 132 85

To investigate the molecular pathogenesis of human gastric cancers the p53 gene, a suppressor oncogene, was analyzed in 12 human gastric cell lines. Southern blot and Northern blot analysis revealed a total deletion of p53 gene in KATO-III cells but no major abnormality of p53 gene in other cell lines. By the use of the reverse-transcriptase polymerase chain reaction and direct sequencing 7 cell lines showed point mutations of p53 gene resulting in amino-acid substitutions. Most of them were rare mutations which had not been observed in other types of cancers. One of these mutations was also detected through the use of PCR and oligomer-specific hybridization. Six out of 7 cell lines with mutations of p53 gene also lost one allele of chromosome 17p. Immunoblotting of cell lysates with an antibody specific to p53 demonstrated the absence of p53 protein in KATO-III cell. By contrast, the high levels of the p53 protein were observed in 5 cell lines all of which contained mutations of p53 gene. These results further suggest that the inactivation of p53 gene may play an important role in the transformation of gastric cells to the malignant phenotype. KATO-III cells might be a good model for studying the significance of the loss of p53 gene in cellular transformation.
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PMID:Missense mutations and a deletion of the p53 gene in human gastric cancer. 137 Jun 12

Polyomavirus large T-antigen transgenic mice develop cardiac hypertrophy characterized by an increase in atrial natriuretic factor and beta-myosin heavy chain isoform expression. The aim of this study was to examine changes in proto-oncogene expression in hypertrophied hearts from the transgenic mice. Expression of early growth response-1 (Egr-1) mRNA was detected in hearts from all 15 transgenic mice, but was not detectable in 13 control mice. Reverse transcriptase-polymerase chain reaction experiments using Egr-1-specific primers confirmed the increase in Egr-1 mRNA in enlarged hearts from the transgenic mice. Expression of c-jun, junD and Ha-ras mRNAs was increased in the transgenic hearts 3, 17 and 2.8-fold respectively. Western blots showed an increase in c-myc, c-jun and ras protein in hypertrophied transgenic hearts. Immunofluorescence analyses confirmed an increase in Egr-1 and c-jun protein in transgenic cardiomyocytes. Proliferating cell nuclear antigen, Ki-ras and HSP 90 mRNAs were decreased 22, 2.7 and 3-fold, respectively in the transgenic hearts. Not altered in most hypertrophied hearts was expression of c-fos, junB, p53, c-neu, c-myc, HSP70, HSP27, TGF-beta or IGF 1 mRNAs. Proto-oncogene and growth factor gene expression in hypertrophy induced by PVLT expression is modulated with some proto-oncogenes increased and others decreased in expression.
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PMID:Molecular remodelling in hypertrophied hearts from polyomavirus large T-antigen transgenic mice. 875 Nov 59

p21(WAF1/CIP1) is a universal cyclin-dependent kinase (cdk) inhibitor, the expression of which is regulated by p53-dependent and p53-independent pathways. We examined p21(WAF1/CIP1) expression in and p53 status of 21 primary hepatocellular carcinomas (HCCs) by reverse-transcriptase polymerase chain reaction (RT-PCR) and by PCR single-strand conformation polymorphism (PCR-SSCP) analysis. p21(WAF1/CIP1) messenger RNA expression was reduced markedly in 8 of 21 HCCs (38.1%) and 5 of these 8 HCCs bore p53 mutations. The relative p21(WAF1/CIP1) messenger RNA expression value of HCCs with p53 mutations (.73 +/- .13 U, n = 6) was significantly lower than that of HCCs with wild-type p53 (1.00 +/- 0.21 U, n = 14; P < .01). The p21(WAF1/CIP1) expression levels in cancerous tissues (.73 +/- .13 U) were significantly reduced in comparison with those in noncancerous tissues (.97 +/- .13 U) (P < .01) in the 6 cases with p53 mutations. These data indicate that p21(WAF1/CIP1) expression in HCCs is predominantly regulated by dependence on p53 and that reduced p21(WAF1/CIP1 expression may participate in hepatocarcinogenesis.
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PMID:Reduced p21(WAF1/CIP1) expression and p53 mutation in hepatocellular carcinomas. 904 1

Leukemia in the soft-shell clam, Mya arenaria, is characterized by tumor cells which are detected initially in the hemolymph. This disease is much more common in clams inhabiting polluted waters, suggesting an environmental component to its pathogenesis. In this study, leukemia cells were identified using a murine monoclonal antibody, 1E10, which recognizes a leukemia-specific protein expressed by tumor cells. Mutant p53 protein was detected using a murine monoclonal antibody (PAb 240) which reacts with mutant p53. Using immunofluorescence, the reactivity of clam cells to the 1E10 antibody was evaluated along with mutant p53 protein reactivity. Reverse transcriptase-polymerase chain reactions followed by sequence analyses were utilized to examine clams with hemocytes reacting with the p53 antibody for possible p53 gene mutations. Mutant p53 protein was expressed by tumor cells from five animals with advanced disease (in which greater than 90% of cells reacted with 1E10). A C-->G transversion was detected at the end of exon 6 from two of the five animals that reacted with both the mutant p53 antibody and 1E10. This substitution changes the amino acid of this codon from proline to alanine. Overall, our results suggest that environmentally induced alterations in p53 can contribute to the pathogenesis of leukemia in soft-shell clams inhabiting polluted water and/or sediment.
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PMID:Detection of mutant p53 in clam leukemia cells. 916 98

The association of increased metallothionein (MT) gene expression in breast cancer with metastasis and poor prognosis has led us to investigate the hypothesis that inhibition of MT gene expression may elicit antiproliferative effects in breast carcinoma MCF7 cells. To monitor the effect of downregulation of MT protein on growth, MCF7 cells were transiently transfected by electroporation with an 18-mer MT antisense phosphorothioate oligomer (AO) or an 18-mer random oligomer (RO). The MT-AO is complementary to the region 7 bases downstream from the AUG translational start site of the hMT-IIA gene. Transfection of MCE7 cells with the AO inhibited cell growth by 50-60% at 72 hours when compared to control cells or the cells transfected with RO. The AO-induced growth inhibition was associated with alterations in morphology suggestive of apoptotic cell death. This was further confirmed by DNA linker cleavage into oligonucleosomal fragments and decreased bcl-2 protein levels in AO-transfected cells as opposed to the RO-transfected cells. Reverse transcriptase polymerase chain reaction analysis showed that AO induced a 2-fold increase in the levels of c-fos and p53 transcripts in comparison to RO which had no significant effect. Conversely, c-myc transcripts were decreased by 2.5-fold in the AO-transfected cells when compared to the controls. Furthermore, MCF7 cells transfected with an expression plasmid pBAcNEO-sMT-IIA encompassing human MT-IIA cDNA, constitutively driven by beta-actin promotor, caused a 2.5-fold increase in intracellular levels of MT, as judged by PCR and western blot analysis, in comparison to the cells transfected with pBAcNEO plasmid. In contrast to the AO-induced growth inhibition, overexpression of cytoplasmic MT increased the cell multiplication by 2-fold compared with control cells or the cells transfected with the control plasmid 72 hours post-transfection. Moreover, the effects of AO on oncogene expression were reversed on increased expression of MT. These data suggest that overexpression of MT potentiates the growth of MCF7 cells, whereas downregulation of MT elicits antiproliferative effects.
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PMID:Antisense down-regulation of metallothionein induces growth arrest and apoptosis in human breast carcinoma cells. 917 39

Chronic inflammatory states frequently lead to the increased production of nitric oxide (NO) via inducible NO synthase (NOS-2). In addition, NO may produce mutagenesis through several mechanisms such as DNA oxidation, DNA deamination, and the formation of N-nitroso compounds. As there is a strong association between human hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC), we were interested in whether human HCV hepatitis leads to induction of NOS-2 and if the mutation repair system of p53/p21 was upregulated. Reverse transcriptase-polymerase chain reaction (RT-PCR) for human NOS-2 message was performed on RNA samples from both liver biopsies and whole liver from HCV-positive and control patients (normal liver from hepatic resections for metastases). Immunohistochemistry (IHC) for p53 and Western blot analysis for p21 were also performed on the whole liver samples. From the liver biopsies, 60% of HCV-positive patients expressed NOS-2 by RT-PCR. Looking at the whole liver samples, 100% of the HCV-positive patients expressed NOS-2 vs 12.5% in the normal samples. p53 was not detected in either group but there was upregulation of p21 over baseline expression in a number of the HCV-positive patients. Human HCV hepatitis leads to consistent upregulation of hepatic NOS-2 message, but message is not predictably present in "normal" human liver. There is also induction of p21 in some patients with HCV hepatitis. Chronic expression of NO in HCV hepatitis may play a role in DNA mutagenesis and the development of HCC.
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PMID:Chronic hepatitis C virus infection in humans: induction of hepatic nitric oxide synthase and proposed mechanisms for carcinogenesis. 922

The bcl-2 family of proteins includes some important regulators of apoptosis. Among these, bcl-2 and bcl-xL prevent cells from entering apoptosis, whereas bax and bcl-xS can induce cell death. Alterations in the control of this process can lead to a decrease in cell death, thus contributing to neoplastic growth. Diminished susceptibility to chemotherapy has also been attributed, in in vitro systems, to alterations in the levels of bcl-2, bax, or bcl-x. We analyzed the expression of bcl-2, bax, bcl-xL, and bcl-xS in normal and neoplastic ovarian tissues by reverse transcriptase-PCR and Western blotting. The RNA and protein levels were significantly correlated for all genes. Interestingly, the levels of these genes in normal and neoplastic tissues were significantly different: bcl-2 was higher in normal tissue (P < 0.002), whereas bax and bcl-xL were higher in carcinoma (P < 0.018 and P < 0.030, respectively). bcl-xS was present at low levels in 83% of neoplastic samples and was undetectable in normal tissue. Reverse transcriptase-PCR analysis of 74 tumors showed no major correlation with clinicopathological parameters or with response to chemotherapy. Only bax and bcl-xL were correlated with progesterone receptor levels (n = 29, r = +0.44, P < 0.0189, and r = -0.40, P < 0.035, respectively). No correlation was found with estrogen receptor levels or with p53 immunostaining. Our data indicate that the regulation of the bcl-2 family of proteins differs between normal and neoplastic ovarian tissues. Moreover, the modulation of these genes in ovarian carcinoma is different compared to other tissues; therefore, tissue specificity is very important in regulation of the bcl-2 family of proteins.
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PMID:bcl-2, bax, bcl-XL, and bcl-XS expression in normal and neoplastic ovarian tissues. 951 44

A role for human papilloma virus (HPV) infection in the pathogenesis of head and neck neoplasms has gained support in recent years. Expression of two early-region HPV genes, E6 and E7, is widely accepted as essential for viral-induced carcinomas of the genital tract. These oncoproteins interact with the products of the cellular tumor suppressor genes, p53 and retinoblastoma, and inactivate them. Examining E6/E7 transforming gene expression is an important step toward elucidating the pathogenesis of HPV in head and neck neoplasms. We introduce nasal inverted papilloma (IP) as a novel system for evaluating viral genomic expression and transforming gene regulation of tumorigenesis by virtue of its association to HPV infection and potential for malignant progression. We describe here a reverse transcriptase-polymerase chain reaction approach for the detection of HPV E6/E7-specific transcripts in RNA extracted from IR. A primer pair flanking previously mapped HPV 6 E6/E7 splice donor/acceptor sites was used to direct amplification of cDNA. Reverse transcriptase-polymerase chain reaction experiments generated products representing the 1.2 Kb E1E4 splice transcript and a smaller unclassified fragment in IP from two patients. These results provide evidence for HPV 6 E6/E7 expression in IP with the potential to encode transforming proteins.
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PMID:The HPV 6 E6/E7 transforming genes are expressed in inverted papilloma. 952 9

A human T-acute lymphoblastic leukemia (ALL) cell line (Loucy), derived from cells from a patient with resistant ALL with a t(16:20) and 5q- chromosomal aberrations was evaluated for p53 gene alterations and expression. Western blot analysis of p53 showed elevated levels of the protein. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and direct sequencing identified a point mutation at codon 272 (GTG --> ATG) of the p53 gene. Possible molecular mechanisms underlying these alterations and their role in the establishment of this cell line and in leukemogenesis in general are discussed.
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PMID:P53 gene mutation in a T-acute lymphoblastic leukemia cell line (loucy) with t(16:20) and 5q- chromosomal aberrations. 964 74


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