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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, the high mobility group protein gene, HMGIC, was identified as a common genetic denominator in benign tumors with chromosome 12q13-15 aberrations, such as lipomas, uterine leiomyomas, pleomorphic adenoma of the salivary glands, hamartomas of breast and lung, angiomyxomas, and endometrial polyps. In most cases, the rearrangements resulted in the separation of the three HMGIC DNA-binding motifs from the acidic carboxy-terminal tail. Here, we report about the molecular characterization of a case of pleomorphic adenoma carrying a t(1;12)(p22;q15). Studies were performed on a cell line derived from the primary tumor, i.e., cell line Ad-312/SV40. Although the chromosome 12 breakpoint was initially mapped more than 1 Mb distal to the HMGIC gene by fluorescence in situ hybridization (FISH) analysis, the present molecular studies reveal a more complex chromosomal rearrangement that directly affects the HMGIC gene. Using 3'-RACE analysis, a HMGIC fusion transcript was detected that contained the complete HMGIC, coding region but lacked the putative mRNA destabilizing AUUUA motifs that are normally present in the 3'-UTR of HMGIC. Wild-type HMGIC transcripts were also detected in the tumor cells. The results suggest that alterations in the 3'-noncoding region of HMGIC may have to be considered as pathogenetically relevant.
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PMID:Molecular characterization of a complex chromosomal rearrangement in a pleomorphic salivary gland adenoma involving the 3'-UTR of HMGIC. 916 41

The genetic alterations and molecular events mediating human prostate cancer development and progression remain to be defined. Rapid expression cloning and differential RNA display detect a putative oncogene, prostate tumor-inducing gene 1 (PTI-1), that is differentially expressed in human prostate (as well as breast, colon, and small cell lung) cancer cell lines, patient-derived prostate carcinomas, and blood from patients with metastatic prostate cancer. PTI-1 consists of a unique 5' untranslated region (5' UTR) with significant sequence homology to Mycoplasma hyopneumoniae 23S ribosomal RNA juxtaposed to a sequence that encodes a truncated and mutated human elongation factor 1alpha (Trun-EF). Stable expression of a nearly full-length 1.9-kb PTI-1 gene, but not the separate PTI-1 5' UTR or Trun-EF region, in normal rat embryo fibroblast cells, CREF-Trans 6, induces an aggressive tumorigenic phenotype in athymic nude mice. Blocking PTI-1 expression with antisense PTI-1 results in reversion of transformed PTI-1-expressing cells to a more normal cellular morphology with suppression in both anchorage-independent growth and tumorigenic potential in athymic nude mice. These findings document that PTI-1 is indeed an oncogene, and directly blocking PTI-1 expression can nullify cancer phenotypes. In these contexts, PTI-1 not only represents a gene with discriminating diagnostic properties but also may serve as a target for the gene-based therapy of human prostate and other cancers.
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PMID:Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes. 946 91

Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the COOH-terminal alpha-amidation of peptidylglycine substrates, yielding amidated products. Growing evidence suggests that the metabolism of PAM messenger RNAs (mRNAs) can be regulated within the cytoplasm. To understand the mechanisms controlling the metabolism of PAM mRNAs, we sought to identify cis elements of the 3'-untranslated region (3'-UTR) of PAM mRNA that are recognized by cytoplasmic factors. From gel retardation assays, one sequence element is shown to form a specific RNA-protein complex. The protein-binding site of the complex was determined by ribonuclease T1 mapping, by blocking the putative binding site with antisense oligonucleotide, and by competition assays. Using 3'-end-labeled RNA in gel shift and UV cross-linking analyses, we detected in the 3'-UTR a novel 20-nucleotide cis element that interacted with a widely distributed cellular cytosolic protease-sensitive factor(s) to form a 60-kDa PAM mRNA-binding protein complex. The binding activity was redox sensitive. Tissue distribution of the protein in the rat showed a marked tissue-specific expression, with ovary, testis, lung, heart septum, anterior pituitary and hypothalamus containing large amounts compared with liver, ventricle, atrium, and neurointermediate lobe. No binding activity was detectable in pancreas, intestine, or kidney extracts. Northwestern blot analysis of AtT-20 (mouse corticotrope tumor cell line) cytoplasmic extracts revealed a protein of 46 kDa. Thus, we have identified a widely distributed cellular protein that binds to a conserved domain within the 3'-UTR of PAM mRNA from many animal species. Although these data suggest that cis element-binding activity could be a cytoplasmic regulator of PAM mRNA metabolism, the functional consequences of this binding remain to be determined.
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PMID:Identification of a novel cis-element in the 3'-untranslated region of mammalian peptidylglycine alpha-amidating monooxygenase messenger ribonucleic acid. 949 18

We analysed 50 gastric carcinomas (GCs) to verify whether mutations at coding repeats were associated with microsatellite instability (MSI). The tumors included: ten cases with no MSI, 14 cases with MSI = 1 locus, 13 cases with MSI = two loci and 13 cases with MSI > or = 3 loci. We investigated coding repeats within the TGF-beta RII, IGFIIR, BAX, hMSH6, hMSH3 and BRCA2 genes. The TGF-beta RII, IGFIIR, BAX, hMSH6 and hMSH3 repeats were altered in 11 (22%), five (10%), four (8%), 16 (32%) and five (10%) cases respectively. Mutations occurred only in MSI-positive (MSI+) tumors and correlated with increasing MSI levels. No alterations of the BRCA2 repeat were found. Mutations in genes other than hMSH6 were strongly associated to hMSH6 mutations, suggesting a key role of this gene. The non-coding BAT-26 and E-Cadherin 3' UTR poly(A)8/(T)15 repeats were analysed in 44 of the 50 cases. Novel tumor-associated alleles were observed only in MSI-positive GCs and were in most cases associated with mutations at coding repeats. Further investigations with BAT-40 confirmed that four cases manifested mononucleotide repeat alterations restricted to hMSH6 and one case to TGF-beta RII. A subset of tumors with MSI at two or more dinucleotide loci resulted negative for mutations at coding and non-coding mononucleotide repeats.
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PMID:Mutations at coding mononucleotide repeats in gastric cancer with the microsatellite mutator phenotype. 965 43

Vascular Endothelial Growth Factor (VEGF) is a very potent angiogenic agent that has a central role in normal physiological angiogenesis as well as in tumor angiogenesis. VEGF expression is induced by hypoxia and hypoglycemia, and thus was suggested to promote neovascularization during tumor outgrowth. Yet, the molecular mechanism that governs VEGF expression is not fully characterized. VEGF induction is attributed in part to increased levels of transcription and RNA stability. Previously, we demonstrated that the 5' Untranslated Region (5' UTR) of VEGF has an important regulatory role in its expression. VEGF has an exceptionally long 5' UTR (1038 bp) which is highly rich in G+C nucleotides. This suggests that secondary structures in the 5' UTR might be essential for VEGF expression through transcriptional and post-transcriptional control mechanisms, as demonstrated for other growth factors. In this communication, we provide evidence that a computer predicted Internal Ribosome Entry Site (IRES) structure is biologically active and is located at the 3' end of the UTR. In addition, the results demonstrate that an alternative transcriptional initiation site for VEGF exists in the 5' UTR of VEGF. This alternative initiation site is 633 bp downstream of the main transcription start site and the resulting 5' UTR includes mainly the IRES structure. Therefore, our results suggest that VEGF is subjected to regulation at either translational level through a mechanism of ribosome internal initiation and/or transcriptional level through alternative initiation.
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PMID:Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription. 967 7

Expression of the protooncogene C-FOS can lead to the development of bone tumors in transgenic mice. However, recent experiments have suggested that the tumor induction is independent of the promoter chosen for the C-FOS expression construct but dependent on modifications in the 3' untranslated region (3'UTR) of the C-FOS gene. To investigate this effect, C-FOS expression constructs have been tested in transgenic mice for their ability to induce bone tumors. Removal of 3'UTR sequences known to affect the stability of C-FOS mRNA resulted in high expression in several organs but gave no detectable bone lesions. In contrast, the presence of different long terminal repeats of murine retroviruses at the 3'UTR caused the induction of bone tumors. These data suggest that the C-FOS gene can be converted into a tumor-inducing oncogene only by retroviral control elements.
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PMID:Induction of bone tumors in transgenic mice by C-FOS depends on the presence of a retroviral long terminal repeat. 972 28

Homozygous deletions of the tumor suppressor gene p16INK4A and deficiency of methylthioadenosine phosphorylase (MTAP), both located on chromosome 9p21, have been independently reported in non-small cell lung cancer (NSCLC). To determine the frequency of co-deletion of these two genes, we investigated 50 samples of primary NSCLC using a quantitative PCR-ELISA. All specimens were fixed in formalin, paraffin embedded and stored until assayed. Histologic subtypes included 25 adenocarcinomas (50%), 21 squamous cell carcinomas (42%) and four large cell carcinomas (8%). Homozygous deletions of MTAP exon 8 could be detected in 19 of 50 NSCLC samples (38%). Adenocarcinoma (11 of 25, 44%) showed a higher deletion frequency than squamous cell carcinoma (six of 21, 29%). In contrast, homozygous p16INK4A deletions were detected in only nine of 50 (18%) samples using specific primers for p16INK4A exon 1alpha. No difference between the histological subtypes and p16INK4A deletion frequency was observed. We further investigated the ten samples with MTAP deletions but intact p16INK4A exon 1alpha with primers specific for p16INK4A exon 3, the exon nearest to MTAP exon 8. Interestingly, none of the ten samples had deletion of the p16INK4A exon 3 coding region. Fine mapping analysis performed in ten samples showed a frequent breakpoint between MTAP exon 4 and exon 5. In addition, p16 protein expression could not be detected in five out of six samples with intact p16 but deleted MTAP locus. These data show a high frequency of homozygous MTAP deletions in NSCLC which is associated with detectable co-deletion of p16INK4A in only half of the cases. This result suggests the existence either of another tumor suppressor gene telomeric of p16INK4A or of deletions involving 3'-untranslated (3'-UTR) regulatory regions of p16INK4A that can interfere with its expression or function.
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PMID:Homozygous deletions of methylthioadenosine phosphorylase (MTAP) are more frequent than p16INK4A (CDKN2) homozygous deletions in primary non-small cell lung cancers (NSCLC). 984 Sep 31

Prostate cancer is a serious public health problem in many industrialized countries. Androgens appear to play a critical role in its etiology. Specifically, the active androgen in the prostate, dihydrotestosterone (DHT) which is synthesized by the enzyme steroid 5alpha-reductase from testosterone (T), acts as a mitogen. Hence androgen-deprivation is commonly used during prostate cancer therapy. Two isozymes for steroid 5alpha-reductase have been reported. The type II enzyme is prostate-specific and encoded by the SRD5A2 gene. We have investigated a polymorphic (TA)n dinucleotide repeat in the 3' UTR (untranslated region) of the SRD5A2 gene in 30 matched samples of constitutional ("germline") DNA from peripheral blood lymphocytes and microdissected, pure tumor DNA. We report here 8 LOH (loss of heterozygosity) events and 9 cases of microsatellite instability at this marker. Therefore, almost 57% of the samples examined showed evidence of somatic mutations at the 3' UTR of the SRD5A2 locus. Our data suggest that the SRD5A2 gene may be involved in prostate cancer progression and that this may have relevance for treatment of the disease.
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PMID:Somatic mutations at the SRD5A2 locus encoding prostatic steroid 5alpha-reductase during prostate cancer progression. 1008 7

HLA class I and beta-2-microglobulin (beta2m) expression in a moderately differentiated laryngeal squamous cell carcinoma appeared to be downregulated when analyzed by immunohistochemical procedures using the monomorphic anti-HLA class I monoclonal antibody (mAb; W6/32), locus-specific (HCA2 and HC10) and allele-specific (LT129.11 and KRE501) mAbs and anti-beta2m mAbs. To reveal the molecular basis of downregulated HLA class I expression, HLA-A typing was performed on DNA derived from peripheral blood lymphocytes (PBL) and the tumor. Sequencing-based typing (SBT) revealed HLA-A*02011, 31012. In addition to HLA-A*02011, 31012 alleles, the tumor contained an HLA-A*31012 allele, which lacked all introns when sequenced from the initiation codon through exon eight. The 3' UTR region was intact up to at least 200 bp downstream. The mutant HLA-A*31012 is restricted to laryngeal tumor tissue since it was not amplified in flanking tumor-free laryngeal tissue. The mutant HLA-A*31012 shares structural characteristics with processed pseudogenes, i.e., absence of introns and an intact 3' UTR. This indicates that the mutant HLA-A*31012 allele resulted from a retroposition (reverse transcription and integration) from the processed transcript of the wild-type HLA-A*31012 allele within a clonal tumor cell. Genes Chromosomes Cancer 27:26-34, 2000.
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PMID:Detection of a putative HLA-A*31012 processed (intronless) pseudogene in a laryngeal squamous cell carcinoma. 1056 83

Earlier studies have demonstrated that the genes of the human carcinoembryonic antigen (CEA) family can be divided into three subgroups, the CEA subgroup (n = 12), the pregnancy-specific glycoprotein (PSG) subgroup (n = 11), and a third subgroup (n = 6). To further characterize the CEA gene family, we have determined the genomic structures of CGM9 and CGM11, analyzed the promoter regions of all eleven PSGs, studied the CGM15-PSG13 intergenic region and the evolutionary relationships beween the CEA family genes. CGM9, a typical CEA subgroup member, was a pseudogene with the exon structure [5'UTR-L-L/N-TM-Cyt-3'UTR]. CGM11 contained a mixture of exons derived from CEA and PSG subgroup genes. The formula of the CGM11 pseudogene was [5'UTR-L-L/N-C-3'UTR]. Thus both genes lacked the IgC2-like domains typically found in CEA subfamily members. The upstream promoter regions of all eleven PSGs were characterized. All PSG promoters lacked the classical TATA and CCAAT elements, but had putative PEA3 box(es), CACCC box(es), a RARE box, and poly (dG-dT) repeats of different lengths. Five PSGs also had an SP1 site. The complete 10-kb intergenic region between CGM15 and PSG13 was sequenced. Clusters of different types of repetitive sequences were seen. The time of divergence of the CEA and PSG subfamilies was estimated to be 107.7 +/- 17.1 million years, or at about the time of human-rodent divergence. Models for the evolution of CEA and PSG and the third family subgroup genes are proposed.
Tumour Biol
PMID:Evolution of the carcinoembryonic antigen family. structures of CGM9, CGM11 and pregnancy-specific glycoprotein promoters. 1068 36


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