Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germline mutations of CDKN2A, at 9p21, are responsible for predisposition to melanoma in some families. However, evidence of linkage to 9p21 has been demonstrated in a significant proportion of kindreds with no detectable mutations in CDKN2A. It is possible that mutations in noncoding regions may be responsible for predisposition to melanoma in these families. We have analyzed approximately 1 kb of the CDKN2A promoter upstream of the start codon in an attempt to identify causal mutations in 107 melanoma families. Four sequence variants were detected. Two of these (A-191G and A-493T) did not segregate with disease and were present in a control population at a comparable frequency, indicating that they are unlikely to predispose to melanoma. The A-493T variant appeared to be in linkage disequilibrium with the previously described CDKN2A polymorphism Ala148Thr. The variant G-735A was detected in the control population, but segregation of this variant with melanoma within families could not be discounted. The fourth variant (G-34T), located in the 5' UTR, creates an aberrant initiation codon. This variant appeared to segregate with melanoma and was not detected in a control population. G-34T has recently been identified in a subset of Canadian melanoma families and was concluded to be associated with predisposition to melanoma. The creation of an aberrant initiation site in the 5' UTR may have an important role in carcinogenesis in a small percentage of families; however, mutations in the CDKN2A promoter appear to have a limited role in predisposition to melanoma.
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PMID:Mutation screening of the CDKN2A promoter in melanoma families. 1073 2

WNT receptors encoded by the Frizzled genes are implicated in carcinogenesis as well as in embryonic development. Human Frizzled-3 (FZD3) gene, encoding seven-transmembrane receptor with the N-terminal cysteine-rich domain, has been cloned and characterized. Expression of the FZD3 mRNAs was investigated by using three FZD3 specific probes: HF3S1, corresponding to the 5'-UTR and a part of the coding region; HF3S2, corresponding to a part of the coding region; HF3S3, corresponding to the 3'-UTR. HF3S1 and HF3S2 hybridized to the 14.0-, 9.0-, 4.0- and 1.8-kb FZD3 mRNA, while HF3S3 hybridized to the 14.0-, 9.0-, and 4.0-kb FZD3 mRNA. The 14. 0-kb FZD3 mRNA was the major transcript in fetal brain and adult cerebellum, while the 1.8-kb FZD3 mRNA was the major transcript in adult pancreas, and many cancer cell lines examined. The 1.8-kb FZD3 mRNA, alternatively polyadenylated by the internal AATAAA signal in the coding region, is predicted to encode the truncated FZD3 protein lacking the region through the second extracellular loop to the C-terminal tail, and might function as the transmembrane-type antagonist for WNTs. The FZD3 gene consists of 8 exons, and has been mapped to human chromosome 8p21.
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PMID:Molecular cloning and genomic structure of human frizzled-3 at chromosome 8p21. 1077 73

Secreted glycoprotein WNTs play important roles in carcinogenesis and development. We have previously reported molecular cloning of WNT-2B/WNT-13. Here, we have isolated a novel WNT-2B isoform (WNT-2B2), in addition to the original WNT-2B isoform (WNT-2B1). WNT-2B1 and WNT-2B2 are completely different in the 5'-UTR and in the N-terminal part of the coding region. The N-terminal hydrophobic domain is contained in WNT-2B1, but not in WNT-2B2. WNT-2B1 and WNT-2B2 share the WNT-core domain, and show 87.0% amino-acid identity. We have determined the structure of the WNT-2B gene. The WNT-2B1 mRNA consists of exons 1, 2, and 4-7, while the WNT-2B2 mRNA consists of exons 3-7. WNT-2B2 was expressed in fetal brain, fetal lung, fetal kidney, caudate nucleus, testis, glioblastoma cell lines A172, SW1783, gastric cancer cell lines MKN28, MKN74, and cervical cancer cell line HeLa S3. WNT-2B1 expression level was relatively higher in fetal brain and fetal lung than in other tissues or cell lines expressing WNT-2B2. These results indicate that the WNT-2B1 and WNT-2B2 mRNAs are transcribed due to alternative splicing with distinct expression profile. This is the first report on the WNT isoforms derived from the same gene due to alternative splicing.
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PMID:Alternative splicing of the WNT-2B/WNT-13 gene. 1094 66

The aim of this investigation was trying to identify the genes differentially expressed in esophageal cancer. By combining suppression subtractive hybridization (SSH) with reverse Northern high density blots, a gene named EC45 was obtained, which dramatically overexpressed in 70% esophageal cancer (18/26). EC45 was mapped to 3p12-3p11.2 by radiation hybrid mapping (RH mapping). The putative full length EC45 cDNA (1987 bp) was identified by cDNA libraries screening of esophageal cancer. EC45 encoded 204 amino acids, and it shared a 100% similarity with ribosomal protein L15 (635 bp, mRNA) in ORF, but no similarity in 5' UTR or 3' UTR. Northern blot panel of multiple adult human normal tissues showed EC45 distributed in almost normal tissues tested. All these data suggested that EC45, encoding ribosomal protein L15 and overexpressing in esophageal cancer might play a possible role in carcinogenesis of esophagus.
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PMID:Cloning and characterization of full-length human ribosomal protein L15 cDNA which was overexpressed in esophageal cancer. 1122 59

Modulation of cyclooxygenase-2 (COX-2) mRNA stability plays an important role in the regulation of its expression by oncogenic Ras. Here, we evaluate COX-2 mRNA stability in response to treatment with two known endogenous promoters of gastrointestinal cancer, the bile acid (chenodeoxycholate; CD) and ceramide. Treatment with CD and ceramide resulted in a 10-fold increase in the level of COX-2 protein and a four-fold lengthening of the half-life of COX-2 mRNA. COX-2 mRNA stability was assessed by Northern blot analysis and by evaluating the AU-rich element located in the COX-2 3'-UTR. A known inhibitor of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK), PD98059, reversed the effects of CD or ceramide to stabilize COX-2 mRNA. Overexpression of a dominant-negative ERK-1 or ERK-2 protein also led to destabilization of COX-2 mRNA. Treatment with a p38 MAPK inhibitor, PD169316, or transfection with a dominant-negative p38 MAPK construct reversed the effect of CD or ceramide to stabilize COX-2 mRNA. Expression of a dominant-negative c-Jun N-terminal kinase (JNK) had no effect on COX-2 mRNA stability in cells treated with CD or ceramide. We conclude that posttranscriptional mechanisms play an important role in the regulation of COX-2 expression during carcinogenesis.
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PMID:Posttranscriptional regulation of cyclooxygenase-2 in rat intestinal epithelial cells. 1122 45

Cyclooxygenase-2 (COX-2) expression is normally tightly regulated. However, constitutive overexpression plays a key role in colon carcinogenesis. To understand the molecular nature of enhanced COX-2 expression detected in colon cancer, we examined the ability of the AU-rich element-containing (ARE-containing) 3' untranslated region (3'UTR) of COX-2 mRNA to regulate rapid mRNA decay in human colon cancer cells. In tumor cells displaying enhanced growth and tumorigenicity that is correlated with elevated COX-2, vascular endothelial growth factor (VEGF), and IL-8 protein levels, the corresponding mRNAs were transcribed constitutively and turned over slowly. The observed mRNA stabilization is owing to defective recognition of class II-type AREs present within the COX-2, VEGF, and IL-8 3'UTRs; c-myc mRNA, containing a class I ARE decayed rapidly in the same cells. Correlating with cellular defects in mRNA stability, the RNA-binding of trans-acting cellular factors was altered. In particular, we found that the RNA-stability factor HuR binds to the COX-2 ARE, and overexpression of HuR, as detected in tumors, results in elevated expression of COX-2, VEGF, and IL-8. These findings demonstrate the functional significance rapid mRNA decay plays in controlling gene expression and show that dysregulation of these trans-acting factors can lead to overexpression of COX-2 and other angiogenic proteins, as detected in neoplasia.
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PMID:Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. 1173 61

WNT signals are transduced to beta-catenin - TCF pathway, JNK pathway, or Ca2+-releasing pathway through WNT receptors. FRAT1, FRAT2, and PAR-1 are positive regulators of WNT - beta-catenin pathway. APC, AXIN, NKD1, NKD2, and Strabismus (STB1, STB2) are negative regulators of WNT - beta-catenin pathway. Here, biological significance of WNT3-WNT14B/WNT15 gene cluster (human chromosome 17q21) and WNT3A-WNT14 gene cluster (human chromosome 1q42) will be reviewed. Total-amino-acid identity between WNT3 and WNT3A is 84.2%, and that between WNT14 and WNT14B is 61.4%. WNT3A and WNT14B show reciprocal regulation by all-trans retinoic acid in NT2 cells and by beta-estradiol in MCF-7 cells. Exon-intron structures are well conserved between WNT3-WNT14B gene cluster and WNT3A-WNT14 gene cluster, except for the existence of an additional intron in 3'-UTR of WNT3. Capicua pseudogene and AK024248-related sequence are located within intergenic region of human WNT3A-WNT14 gene cluster, but not within intergenic regions of human WNT3-WNT14B gene cluster and mouse Wnt3a-Wnt14 gene cluster. Integration of mouse mammary tumor virus (MMTV) into mouse Wnt3-Wnt14b gene cluster leads to carcinogenesis. Because these WNT gene clusters might be fragile sites in the human genome, implication of WNT3 or WNT3A in cancer as well as implication of WNT14 or WNT14B in connective tissue disease and congenital joint malformation should be elucidated in the future. WNT3, WNT3A, WNT14, and WNT14B might be applicable to tissue engineering of neuron and joint in the field of regenerative medicine, and as an early diagnostic marker in the field of clinical oncology.
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PMID:WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review). 1201 73

Apobec-1 catalyzes C to U editing of apolipoprotein B (apoB) mRNA in the mammalian intestine. Rat apobec-1 is transcribed from three distinct promoters, which contain distinct 5' untranslated regions (5'UTRs) accompanied by variable numbers of in-frame upstream AUGs (uAUGs). We have observed a shift in apobec-1 promoter usage in an experimental model of colon carcinogenesis, resulting in transcripts loaded with 5'AUGs. In colon cancer, apobec-1 protein levels decreased by 90% in the cancer tissue as compared to normal tissue, suggesting an inhibitory effect of the 5'UTR on apobec-1 translation. We investigated the effects of these different 5'UTRs by site-directed mutagenesis coupled with in vitro translation studies. These studies established that the uAUGs within the 5'UTR of the alternative transcripts inhibit apobec-1 translation. This effect was independent of the length of the 5'UTR. Further analysis demonstrated that these uAUGs altered the polysome distribution, shifting the mRNA towards a denser, post-polyribosomal fraction. These findings were confirmed in transient transfection studies in vivo using HepG2 cells, where functional expression of apobec-1 was restored by mutagenesis of the uAUGs. Taken together, these data imply that rat apobec-1 gene expression is downregulated through alternative promoter usage. This dominant translational control of apobec-1 gene expression is most plausibly exerted through uAUGs.
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PMID:Apobec-1 transcription in rat colon cancer: decreased apobec-1 protein production through alterations in polysome distribution and mRNA translation associated with upstream AUGs. 1202 Aug 19

Reduced retinyl ester synthesis has been associated with several forms of cancer; we therefore proposed studying melanoma development from the perspective of this biochemical pathway. Cultures of human melanoma cells with fibroblastoid morphology showed negligible retinyl ester synthesis; in sharp contrast, those with epithelioid morphology were capable of retinol esterification. Further, isolated proliferating epidermal melanocytes (HFSC/2) esterified retinol, whereas proliferating normal skin fibroblasts (F:CCD-1121.Sk) did not. A primary site cutaneous melanoma and its metastatic match (both of epithelioid morphology) were capable of retinol esterification, while a matched fibroblastoid tumor pair did not synthesize retinyl esters; nevertheless, LRAT (lecithin:retinol acyltransferase) protein was found in microsomal fractions from all four tumors. A mutation screen in the LRAT coding region and adjacent intronic sequences revealed several novel mutations in these melanomas as well as in HFSC/2 and F:CCD-1121.Sk cells: a single nucleotide polymorphism in exon 1(37A-->G), a silent mutation in exon 2a (188 A-->G/186 G-->A), and an insertion in the 5'UTR (9-10insC). CRBP-1 basal expression was present in the HFSC/2, and in both sets of matched tumor pairs; however, steady-state levels in the fibroblastoid melanoma pair were one-third that found in the epithelioid matched tumor pair. Co-culture of human primary site epithelioid melanoma with proliferating normal human skin fibroblasts abrogated retinol esterification within 96 h and increased the expression of the active form of TGFbeta-1 by 2.4-fold. A concomitant 3.2-fold downregulation of CRBP-1 expression took place. This is the first study to (1) demonstrate an association between retinyl ester synthesis and cutaneous melanoma morphological phenotypes; (2) suggest the existence of a soluble, diffusible inhibitor of the retinol esterification pathway; (3) report the ability of the isolated, proliferating human epidermal melanocyte to esterify retinol; and (4) provide evidence of DNA variants in the coding region of LRAT.
Carcinogenesis 2002 Nov
PMID:Human melanomas of fibroblast and epithelial morphology differ widely in their ability to synthesize retinyl esters. 1241 30

A gene or genes on chromosome 8p22-23 have been implicated in prostate carcinogenesis by the observation of frequent deletions of this region in prostate cancer cells. More recently, two genetic linkage studies in hereditary prostate cancer (HPC) families suggest that germline variation in a gene in this region may influence prostate cancer susceptibility as well. DLC1 (deleted in liver cancer), a gene in this interval, has been proposed as a candidate tumor suppressor gene because of its homology (86% similarity) with rat p122 RhoGAP, which catalyzes the conversion of active GTP-bound rho complex to the inactive GDP-bound form, and thus suppresses Ras-mediated oncogenic transformation. A missense mutation and three intronic insertions/deletions in 126 primary colorectal tumors have been previously identified. However, there are no reports of DLC1 mutation screening in prostate tumors or in germ line DNA of prostate cancer patients. In this study, we report the results of the first mutation screen and association study of DLC1 in genomic DNA samples from hereditary and sporadic prostate cancer patients. The PCR products in the 5' UTR, all 14 exons, exon-intron junctions, and 3' UTR were directly sequenced in 159 HPC probands. Eight exonic nucleotide polymorphisms (SNPs) were identified, only one of which resulted in an amino acid change. Twenty-three other SNPs were identified in intronic regions. Seven informative SNPs that spanned the complete DLC1 gene were genotyped in an additional 249 sporadic cases and 222 unaffected controls. No significant difference in the allele and genotype frequencies were observed among HPC probands, sporadic cases, and unaffected controls. These results suggest that DLC1 is unlikely to play an important role in prostate cancer susceptibility.
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PMID:Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study. 1287 22


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