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: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two transformants of NIH 3T3 cells, obtained by the transfection of human colon cancer and normal colon DNAs, contained activated c-raf-1. In both the activated c-raf-1, the 5' half of the c-raf-1 sequence was replaced by sequences other than c-raf-1 as a result of recombinations which occurred at the intron between exons 7 and 8. It was suggested, however, that these recombinations, which conferred the transforming activity on the c-raf-1, occurred during the transfection. In one case analyzed, characteristic sequences were found near the breakpoint and these may be involved in the recombination. It was found, upon analysing the structure of the cDNA derived from one of the activated c-raf-1, that fused mRNA had been transcribed from the recombined gene comprising the non-raf gene and c-raf-1. The mRNA possibly encodes a fused protein. One cDNA clone was derived from alternatively spliced mRNA, although its physiological role is unclear. On comparing the structure of the two human activated c-raf-1 and the rat activated c-raf which we have reported previously, it was revealed that, in these three cases, the sequences joined to the truncated c-raf(-1)1 were different. It was suggested from data which we and others have previously reported that various sequences could be capable of activating c-raf(-1) by replacing its 5' half.
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PMID:Activation of human c-raf-1 by replacing the N-terminal region with different sequences. 295 85

Colon cancers commonly have allelic losses of chromosome 22q, which suggests the presence of a tumor suppressor gene on 22q. The candidate tumor suppressor gene on 22q is the neurofibromatosis 2 (NF2) gene. Using single strand conformation polymorphism (SSCP) analysis, we screened 24 pairs of colorectal cancer and adjacent normal mucosa, as well as 10 colon cancer cell lines from non-NF2 patients, for mutations in the coding sequence of the NF2 gene. Two SSCP variants, one in exon 14 and another one in exon 16, were detected in two of the sporadic colorectal cancers, but not in adjacent normal mucosa samples. Sequencing of these variants in one tumor detected an A-to-G transition in bp 1459 of the NF2 cDNA, resulting in the change of Ile to Val at codon 487 of merlin, the NF2 protein product. The other tumor showed a 2-bp (CT) deletion in the intronic sequence of the alternatively spliced exon 16. These results suggest that the NF2 gene is probably involved in some colorectal tumors, but is not the critical chromosome 22q tumor suppressor gene involved in colon tumorigenesis.
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PMID:Neurofibromatosis 2 gene in human colorectal cancer. 749 38

Screening of fetal brain and fetal retina complementary DNA (cDNA) libraries and exon-connection experiments using brain cDNA have identified three exons 5' to exon 1 of the adenomatous polyposis coli gene. The exons are termed (from 5'-3') 0.3, 0.1, and 0.2; exons 0.1 and 0.2 are contiguous genomically. Library screening revealed alternatively spliced cDNAs containing the following combinations of 5'-exons: 0.3 + 1 + 2, 0.3 + 2, 0.1 + 0.2 + 1 + 2, and 0.1 + 1 + 2. Exon-connection experiments also identified these four forms in mRNAs from tissues and cultured cell lines, along with two additional forms, 0.1 + 0.2 + 2 and 0.1 + 2. The multiple splice forms may lead to proteins of differing activity; for example, products derived from cDNAs without exon 1 will lack most of a heptad-repeat domain that supports formation of homodimers. No mRNA species combining 0.3 with either 0.1 or 0.2 were identified. The existence of two apparently separate 5'-ends of APC suggests the possibility of two independent promoters. The genomic sequence adjacent to exon 0.3 confers promotor activity when cloned in a chloramphenicol acetyltransferase expression vector and transfected into a colon cancer cell line.
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PMID:Demonstration of promoter activity and alternative splicing in the region 5' to exon 1 of the APC gene. 818 87

Tumor stroma is a specialized form of tissue that is associated with epithelial neoplasms. Recent evidence indicates that significant changes in proteoglycan content occur in the tumor stroma and that these alterations could support tumor progression and invasion as well as tumor growth. Our main hypothesis is that the generation of tumor stroma is under direct control of the neoplastic cells and that, via a feedback loop, altered proteoglycan gene expression would influence the behavior of tumor cells. In this review, we will focus primarily on the work from our laboratory related to the altered expression of chondroitin sulfate proteoglycan and its role in tumor development and progression. The connective tissue stroma of human colon cancer is enriched in chondroitin sulfate and the stromal cell elements, primarily colon fibroblasts and smooth muscle cells, are responsible for this biosynthetic increase. These changes can be reproduced in vitro by using either tumor metabolites or co-cultures of human colon carcinoma cells and colon mesenchymal cells. The levels of decorin, a leucine-rich proteoglycan involved in the regulation of matrix assembly and cell proliferation, are markedly elevated in the stroma of colon carcinoma. These changes correlate with a marked increase in decorin mRNA levels and a concurrent hypomethylation of decorin gene, a DNA alteration associated with enhanced gene expression. Elucidation of decorin gene structure has revealed an unexpected degree of complexity in the 5' untranslated region of the gene with two leader exons that are alternatively spliced to the second coding exon. Furthermore, a transforming growth factor beta (TGF-beta)-negative element is present in the promotor region of decorin gene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered proteoglycan gene expression and the tumor stroma. 829 47

Tumor stroma is a specialized form of tissue that is associated with epithelial neoplasms. Recent evidence indicates that significant changes in proteoglycan content occur in the tumor stroma and that these alterations could support tumor progression and invasion as well as tumor growth. Our main hypothesis is that the generation of tumor stroma is under direct control of the neoplastic cells and that, via a feedback loop, altered proteoglycan gene expression would influence the behavior of tumor cells. In this review, we will focus primarily on the work from our laboratory related to the altered expression of chondroitin sulfate proteoglycan and its role in tumor development and progression. The connective tissue stroma of human colon cancer is enriched in chondroitin sulfate and the stromal cell elements, primarily colon fibroblasts and smooth muscle cells, are responsible for this biosynthetic increase. These changes can be reproduced in vitro by using either tumor metabolites or co-cultures of human colon carcinoma cells and colon mesenchymal cells. The levels of decorin, a leucine-rich proteoglycan involved in the regulation of matrix assembly and cell proliferation, are markedly elevated in the stroma of colon carcinoma. These changes correlate with a marked increase in decorin mRNA levels and a concurrent hypomethylation of decorin gene, a DNA alteration associated with enhanced gene expression. Elucidation of decorin gene structure has revealed an unexpected degree of complexity in the 5' untranslated region of the gene with two leader exons that are alternatively spliced to the second coding exon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered proteoglycan gene expression and the tumor stroma. 850 May 99

Mutations in the APC gene are responsible for the dominantly inherited colon cancer syndrome, familial adenomatous polyposis (FAP). We have designed PCR primers which allow amplification by RT-PCR of exons 1-14 of the APC gene in six overlapping segments. The amplicons have been screened for the presence of mutations in patients affected with FAP using heteroduplex analysis. One patient has been identified with an alternatively spliced transcript involving exon 14 and a single base insertion mutation within the same exon.
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PMID:Mutation detection in exons 1-14 of the adenomatous polyposis coli gene: identification of an alternatively spliced transcript. 891 Aug 93

The interaction between the colon tumor cell surface and the endothelial cell layer is an important component of tumor intravasation, extravasation, and metastasis. Multiple studies suggest that tumor cells may bind to E-selectin expressed on endothelial cells during these processes. To identify possible E-selectin ligands on tumor cells that may participate in this mechanism, we used E-selectin-Ig chimera affinity chromatography to isolate glycoproteins from the human colon cancer cell line Colo-205. Binding of these cells to E-selectin was specific, required the presence of calcium, and could be blocked by antibodies against E-selectin. We identified LAMP-1 (lysosomal membrane glycoprotein-1), LAMP-2, and two high molecular weight glycoproteins (>400 kDa and 300 kDa) as the main E-selectin ligands on Colo-205 cells. Treatment of the cells with N-glycanase and O-sialoglycoprotease abolished their binding to E-selectin. The high MW glycoproteins contained sialyl Lewis X and/or sialyl Lewis A glycoconjugates, and appeared to be either alternatively spliced or alternatively glycosylated forms of MUC-1 (mucin-1).
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PMID:Human colon cancer cells express multiple glycoprotein ligands for E-selectin. 1063 80

A novel gene, designated UROC28, was identified by an agarose gel-based differential display technique, and it was found to be up-regulated in prostate, breast, and bladder cancer. Expression of UROC28 was also up-regulated in prostate cancer cells in the presence of androgens as demonstrated by relative quantitative reverse transcription-PCR. The elevated expression of this gene was observed to increase in surgically removed tissues concomitantly with rising Gleason grade and was most elevated in metastatic tissue. UROC28 protein was detected in serum by Western slot blot analyses, and a significant higher UROC28 protein level was found in sera of prostate cancer individuals compared with normal individuals and individuals with nonmalignant prostatic hyperplasia. Northern analyses in normal tissues showed that the UROC28 cDNA hybridizes to two mRNAs at about 2.1 and 2.5 kb. Nucleic acid sequence analyses indicated that these two alternatively spliced mRNA variants differ only at the 3' untranslated region. These two mRNAs encode the same protein with 135 amino acids. Bioinformation analyses suggest that there is a possible transmembrane domain from amino acid aa34 to aa50, three protein kinase-C phosphorylation sites at aa62 (SQK), aa89 (TMK), and aa94 (SMK), and one myristylation site at aa118 (GLECCL). Genomic Southern hybridization and chromosomal mapping demonstrated that UROC28 is encoded by a single copy of gene at chromosome 6q23-24. In situ hybridization and immunohistochemistry experiments further confirmed up-regulation of this gene in prostate and breast cancers with the expression localizing to the glandular epithelium. This gene did not demonstrate increased expression in lung and colon cancer tissues.
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PMID:Cloning and characterization of UROC28, a novel gene overexpressed in prostate, breast, and bladder cancers. 1115 5

Non-steroidal anti-inflammatory drugs (NSAIDs) reduce tumour mass by increasing the rate of tumour cell apoptosis and decreasing cell proliferation. The classically recognized target for NSAID action are the two isoforms of the cyclooxygenase (COX) gene, which is responsible for prostaglandin production. In the rat, the COX-1 gene expresses an alternatively spliced mRNA COX-1 splice variant (SV) which may, at best, code for a truncated COX-1 protein. Previously, we reported that COX-1SV mRNA is differentially expressed in the ageing stomach. In this study, carcinogen treated rats were treated for 23 weeks with celecoxib, sulindac or sulindac sulfone, while untreated rats received vehicle alone. For each animal, the number and volume of tumour per animal was recorded and histology was performed. Using competitive polymerase chain reaction, we determined whether COX gene expression was altered in colorectal tumours and in regions of adjacent and distant macroscopically normal intestine, from vehicle or NSAID treated rats. In addition, we immunolocalized COX-1 and COX-2 in the same tumour and normal colonic tissue. Tumours from animals treated with vehicle or celecoxib expressed significantly elevated levels of COX-2 mRNA in comparison with the adjacent normal mucosa. In contrast, tumours from sulindac and sulindac sulfone treated rats expressed significantly less COX-2 mRNA than tumours from vehicle treated rats. The expression of COX-1 mRNA remained unchanged in all tissues examined. However, COX-1SV mRNA levels were elevated in colorectal tumours and reduced after NSAID treatment to the levels observed in normal colonic mucosa. Our results indicate that the anti-neoplastic actions of NSAIDs may be attributed to COX dependent and/or COX independent mechanisms of action. We also demonstrate the presence and differential expression of COX-1SV mRNA in colon tumours. COX-1SV mRNA represents 2% of the total COX-1 mRNA expressed and its role in colon cancer remains to be established.
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PMID:Rat colorectal tumours treated with a range of non-steroidal anti-inflammatory drugs show altered cyclooxygenase-2 and cyclooxygenase-1 splice variant mRNA expression levels. 1137 91

Hereditary nonpolyposis colorectal cancer is associated with inherited defects in DNA mismatch repair. Clinical variation even in cases with identical predisposing mutations suggests the existence of other factors contributing to the phenotype. We addressed the modifying role of the common A/G polymorphism in exon 4 and the alternatively spliced transcripts a and b of the CCND1 gene encoding cyclin D1 in a series of 146 affected carriers of 10 MLH1 and 3 MSH2 mutations. No correlation was observed between a particular allele (A versus G) and age at onset. However, the presence of the variant transcript b in blood/normal mucosa, by multiplex reverse transcription-PCR, was associated with a significantly lower age at onset of colon cancer as compared with individuals with transcript a only (35 versus 46 years; P = 0.02). Whereas our data do not support a modifying role of A versus G allele of CCND1, the results do suggest that the relative abundance of a and b transcripts may modify the age at onset of colon cancer in hereditary nonpolyposis colorectal cancer.
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PMID:CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer. 1150 50


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