Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer secretory protein profiles were shown to be different from normals by a microcomputer-assisted analysis of isoelectric focusing patterns. Two acidic protein band regions (pI 3.0 and 4.5) of the pancreatic carcinoma profiles were significantly increased, and eight protein bands (pI 3.7, 5.0, 5.5, 6.5, 6.9, 7.3, 8.0, greater than 10.0) were significantly decreased. Highly significant decreases occurred at pH 7.3 (chymotrypsinogen) and at pH 5.0 (procarboxypeptidase Al, DNase I) in nonactivated specimens. The ratio between the absorbance points at 2.08 and 2.63 cm from the anode in each protein pattern differentiated the pancreas cancer specimens from the control group. Profiles found for the control group gave pI values similar to those found in the literature. The potential value of these findings in the search for tumor markers warrants further investigation as to whether these specimens can be differentiated from those from chronic pancreatitis patients.
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PMID:Human pancreatic secretory protein profiles in the search for tumor markers. 688 65

We show that a new rat chondrosarcoma (RCS) cell line established in long-term culture from the Swarm tumor displayed a stable differentiated chondrocyte-like phenotype. Indeed, these cells produced the collagen types II, IX, and XI and alcian blue-stainable cartilage-specific proteoglycans, but no type I or type III collagen. To functionally characterize their chondrocytic nature, the cells were stably transfected with a type II collagen/beta geo chimeric gene which confers essentially perfect chondrocyte-specific expression in transgenic mice. RCS cells expressed both beta-galactosidase and G418 resistance, in comparison with similarly transfected 10T1/2 and NIH/3T3 fibroblasts which did not. These cells were then used to perform a systematic deletion analysis of the first intron of the mouse type II collagen gene (Col2a1) using transient expression experiments to determine which segments stimulated expression of a luciferase reporter gene in RCS cells but not in 10T1/2 fibroblasts. Cloning of two tandem copies of a 156-base pair (bp) intron 1 fragment (+2188 to +2343) in a construction containing a 314-bp Col2a1 promoter caused an almost 200-fold increase in promoter activity in RCS cells but no increase in 10T1/2 cells. DNase I footprint analysis over this 156-bp fragment revealed two adjacent protected regions, FP1 and FP2, located in the 3'-half of this segment, but no differences were seen with nuclear extracts of RCS cells and 10T1/2 fibroblasts. Deletion of FP2 to leave a 119-bp segment decreased enhancer activity by severalfold, but RCS cell specificity was maintained. Further deletions indicated that sequences both in the 5' part of the 119-bp fragment and in FP1 were needed simultaneously for RCS cell-specific enhancer activity. A series of deletions in the promoter region of the mouse Col2a1 gene progressively reduced activity when these promoters were tested by themselves in transient expression experiments. However, these promoter deletions were all activated to a similar level in RCS cells by a 231-bp intron 1 fragment that included the 156-bp enhancer. The RCS cell-specific activity persisted even if the Col2a1 promoter was replaced by a minimal adenovirus major late promoter. This 231-bp intron 1 fragment also had strong enhancing activity in transiently transfected mouse primary chondrocytes. Our experiments establish the usefulness of RCS cells as an experimental system for studies of the control of chondrocyte-specific genes, provide an extensive delineation of segments in the Col2a1 first intron involved in chondrocyte-specific activity, and show that promoter sequences are dispensable for chondrocyte specificity.
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PMID:Use of a new rat chondrosarcoma cell line to delineate a 119-base pair chondrocyte-specific enhancer element and to define active promoter segments in the mouse pro-alpha 1(II) collagen gene. 749 38

The C4-I cell line derived from a non-keratinizing squamous cell carcinoma of the uterine cervix contains integrated human papillomavirus-18 DNA. Fluorescence in situ hybridization of C4-I cells demonstrated a single viral integration site at 8q22.1 on a derivative chromosome originating from an 8q;12q translocation. 8q22 is a site of chromosome fragility and is also recombinogenic in several human malignancies. DNase I hypersensitivity of the integration site was studied with a cellular flanking probe. A hypersensitive site was detected within 3 kb from viral DNA. The integration sites are undermethylated in C4-I and HeLa cells and fully methylated in tumor cell lines of other origin, such as lymphoid cells.
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PMID:Integration site of human papillomavirus type-18 DNA in chromosome band 8q22.1 of C4-I cervical carcinoma: DNase I hypersensitivity and methylation of cellular flanking sequences. 750 97

The Epstein-Barr Virus (EBV) latency C promoter (Cp) is the origin of transcripts for six viral proteins. The promoter is active in lymphoblastoid B-cell lines but silent in many EBV-associated tumors and tumor cell lines. In these latter cell lines, the viral episome is hypermethylated in the vicinity of this promoter. We show that in such a cell line (Rael, a Burkitt's lymphoma line), 5-azacytidine inhibits DNA methyltransferase, brings about demethylation of EBV genomes, activates Cp transcription, and induces the expression of EBNA-2. Investigation of the phenomenon demonstrates the importance of the methylation status of a particular CpG site for the regulation of the Cp: (i) genomic sequencing shows that this site is methylated when the Cp is inactive and is not methylated when the promoter is active; (ii) methylation or transition mutation at this site abolishes complex formation with a cellular binding activity (CBF2) as determined by electrophoretic mobility shift analyses, competition binding analyses, and DNase I footprinting; and (iii) a single C --> T transition mutation at this site is associated with a marked reduction (> 50-fold) of transcriptional activity in a reporter plasmid. Thus, the CBF2 binding activity is shown to be methylation sensitive and crucial to EBNA-2-mediated activation of the Cp.
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PMID:Transcriptional activation of the Epstein-Barr virus latency C promoter after 5-azacytidine treatment: evidence that demethylation at a single CpG site is crucial. 756 67

We have studied the effect of poly(ADP-ribose) synthetase on the interferon-gamma (IFN-gamma)-inducible expression of major histocompatibility complex (MHC) class II molecules. We constructed an expression plasmid capable of expressing either a sense RNA (MT-ARS) or an antisense RNA (pAS-FL or pAS-5') for poly(ADP-ribose) synthetase. We transfected the plasmid into mouse or human macrophage tumor cells and examined the effect on the expression of MHC class II molecules. The IFN-gamma-inducible expression of MHC class II gene was considerably reduced in transformant clones (A-2, B-2), in which the synthetase was highly expressed, whereas the depletion of the synthetase due to the expression of antisense RNA for the synthetase amplified the expression of MHC class II molecules. The results indicate that the level of the synthetase critically regulates the IFN-gamma-inducible MHC class II molecules. Next, we analyzed DNase I hypersensitive sites (DHS) of mouse MHC class II, I-A beta gene and found two sites, one in the promoter region and the other one in the first intron. The DHS in first intron was less sensitive towards DNase I attack in transformant clones (A-2, B-2) in which the synthetase was synthesized in a large quantity. Thus we constructed two beta-galactosidase reporter genes, one (A beta 2.0kb-lac z) containing the promoter region to a part of the second exon of the class II gene, and the other (A beta pro-lac z) containing the promoter region of the class II gene alone. The expression of the reporter gene was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and found that the expression of A beta 2.0kb-lac z was suppressed in the transformant clones (A-2, B-2) relevant to control cells but the expression of A beta pro-lac z was the same level among those cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of poly(ADP-ribose) synthetase on the expression of major histocompatibility complex (MHC) class II genes. 757 32

E-cadherin has been identified as a tumor (invasion) suppressor gene, which is mutated in 50% of diffuse-type human gastric carcinomas. In other carcinomas, the expression of E-cadherin is down-regulated in the poorly differentiated cells such as from breast, bladder, lung and colon. We have here examined the in vivo properties of the genomic E-cadherin promoter in well and poorly differentiated carcinoma cell lines in order to gain insights into the mechanisms of E-cadherin down-regulation in tumors. In vivo footprinting analysis revealed that positive regulatory elements of the E-cadherin promoter (a GC-rich region, the CCAAT-box and a palindromic element) are specifically bound by transcription factors in E-cadherin-expressing but not in non-expressing cells. The tested cell systems include more than a dozen carcinomas cell lines as well as mammary epithelial cells where E-cadherin expression can be switched off by activation of a Fos-estrogen receptor fusion protein and rhabdomyosarcoma cells where E-cadherin expression was induced by transfection with E1A. Mapping of DNase I hypersensitive sites showed that the chromatin structure in the promoter region is loosened in expressing but condensed in non-expressing cells. Furthermore, the endogenous E-cadherin promoter is specifically methylated at CpG sites in the undifferentiated cells. We also show that the in vivo properties of the promoter in E-caherin-negative carcinoma cells are similar as in mesenchymal cells, i.e. fibroblasts or sarcoma cells. These data suggest that silencing of the E-cadherin promoter during epithelialmesenchymal transition and tumor progression is due to a loss of factor binding in vivo and to chromatin rearrangement in the regulatory region.
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PMID:Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo. 763 Jun 31

By comparing two subsequent human tumor stages we previously described calcyclin as a new potential melanoma associated neoplastic progression marker positively linked with metastasis. In this study the calcyclin expression levels in a representative panel of human melanoma cell lines were correlated with the occurrence of DNase I hypersensitive (DH) regions and potential enhancer elements in a 6 kb genomic fragment spanning the human calcyclin gene. Examination of the chromatin structure of the transcription unit revealed no qualitative differences in DH sites within the panel of tested human melanoma cells, but especially the sequences around the transcription start site and a 1.5 kb upstream region appeared more accessible to the nuclease in frequently (BLM, MV3) as compared to poorly (530, 1F6) metastasizing cells. The genomic fragments that harbor one or more DH sites were subjected to functional analysis by luciferase reporter gene assays. Thus, an enhancer element was detected between 361 and 167 bp upstream of the transcription start site. This enhancer displayed equal activating potential (2-3 fold) both in weakly and in frequently metastasizing cells and was apparently recognized by transcription factors present in both types of human melanoma cells lines. We conclude that, in addition to a slight amplification of the encoding gene, the elevated calcyclin mRNA levels are only reflected in a selectively increased accessibility of the chromatin structure to DNaseI in metastasizing melanoma cells.
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PMID:Functional analysis of the human calcyclin gene promoter in a panel of human melanoma cell lines. 765 29

Effects of alpha-chymotrypsin and deoxyribonuclease I (DNase I) on the early phase of blood-borne lung metastasis in rats were studied using confocal laser scanning microscopy and AH-109A cells labeled either with carboxyfluorescein diacetate succinimyl ester or with 51Cr. Intravenous administration of alpha-chymotrypsin or DNase I appeared to enhance or inhibit, respectively, the tumor cell arrest in lung microvasculature as a reflection of reduction or promotion of the tumor cell clearance in the microvasculature. These results suggest that the effects of alpha-chymotrypsin and DNase I are related to induction of tumor cell aggregation and disaggregation in the blood stream, respectively.
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PMID:Effects of serine protease and deoxyribonuclease on intravascular tumor cell arrest in rat blood-borne lung metastasis. 767 31

The P450/6 beta A (CYP3A2) gene encoding a testosterone 6 beta-hydroxylase is expressed predominantly in liver and induced by the treatment of rats with various compounds. To understand the mechanism of the basal transcriptional activation of the CYP3A2 gene, the cis-acting elements in the proximal promoter region (-165 to -73) of the CYP3A2 gene were identified in this study. Nuclear extract from rat livers interacted with three sites, 6 beta A-A (-106 to -87), 6 beta A-B (-140 to -119) and 6 beta A-C (-163 to -145). These sites were detectable by DNase I footprinting and gel mobility shift assays and found to share nucleotide sequence similarity with each other (T(A/C)(A/C)N(A/G)AAG(G/T)(C/T)CA). Direct repeats of AGTTCA (-134 to -120) and AG(G/C)TCA (-162 to -148) are also detected in 6 beta A-B and 6 beta A-C sites, respectively. To elucidate the relationship of these sites with basal transcriptional activation of the CYP3A2 gene, varying lengths of the proximal promoter region (-164 to +41) fused to a CAT reporter gene were transfected in human hepatoma (HepG2) and mouse adrenal tumor (Y-1) cells. The relative level of CAT activity in HepG2 cells was slightly increased by the deletion of the 5'-portion from -164 to -111 bp, but was reduced to 14% of the control (the construct including from -110 to +41) by the deletion from -110 to -81 including the 6 beta A-A site. On the other hand, these deletions have no clear effect on the level of the activity in Y-1 cells. Substitution mutations at two nucleotides in the 6 beta A-A site resulted in the reduction of CAT activity in HepG2 cells to 12% of the activity in the wild-type construct. The interaction of an oligonucleotide corresponding to the 6 beta A-A site (-106 to -87) with liver nuclear factors was completely inhibited by the addition of a typical oligonucleotide for hepatocyte nuclear factor-4 (HNF-4) binding site (F. M. Sladek, W. Zhong, E. Lai, and J. E. Darnell, Jr., 1990, Genes Dev. 4, 2353-2365) but not of oligonucleotides corresponding to 6 beta A-B or 6 beta A-C sites. These results suggest an essential role of the binding of HNF-4 and/or HNF-4-related nuclear factors to the 6 beta A-A site on the basal transcriptional activation of the CYP3A2 gene in liver cells.
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PMID:Transcriptional elements directing a liver-specific expression of P450/6 beta A (CYP3A2) gene-encoding testosterone 6 beta-hydroxylase. 772 76

The human UBE1L gene, for which the product may well play a role in the ubiquitin system because of its high degree of identity to the ubiquitin activating enzyme, is located at 3p21, a chromosomal region consistently showing loss of heterozygosity in lung cancer. The finding that UBE1L is well expressed in normal lung tissue, but hardly or not in lung cancer-derived cell lines, prompted us to investigate its genomic structure to find an explanation for the lack of expression in lung cancer. The gene has 22 exons distributed over 8.4 kb. Both anchored PCR experiments and mapping of DNase I-hypersensitive sites point to the region immediately upstream of exon 1 as the promoter site. Three moderately to well-informative polymorphisms were found, of which one is easily directly detectable. Cancer-specific mutations were not detected. The lack of expression in lung cancer cell lines correlated with a highly decreased sensitivity towards DNAse I of the promoter region and with an almost complete methylation of the HhaI site in the first exon. 5'-Azacytidine-induced demethylation did not result in a marked increase of the UBE1L mRNA level in the tumor cell lines. This leaves the possibility that mutation or absence of yet unknown transcription factors causes a regulatory block of the UBE1L gene.
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PMID:The genomic structure of the human UBE1L gene. 773 49


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