Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte/macrophage colony stimulating factor (GM-CSF) is a hematopoietic growth factor that stimulates a wide range of myeloid hematopoietic cells; RNAs coding for many oncogenes and cytokines including GM-CSF have a very short half-life. The motif of AUUUA is a highly conserved sequence in the 3'untranslated regions (3'UTR) of these transcripts and is repeated a number of times in these short-lived cytokines and oncogenes. These sequences play a major role in controlling stability of these transcripts. Human cancer cells were transfected with a chimeric rabbit beta-globin gene linked to either a 58 bp sequence of the AT-rich region from GM-CSF or a control sequence. We have found that irradiation stimulates accumulation of GM-CSF, interleukin-6 (IL-6), and IL-1 beta RNAs. In addition, this accumulation of GM-CSF was at least, in part, a result of increased stabilization of GM-CSF transcripts. Further experiments showed that irradiation increased levels of the chimeric beta-globin transcripts containing AUUUA sequences from GM-CSF, but not those containing the control sequences. Our results suggest that irradiation increases expression of GM-CSF RNA and that posttranscriptional stabilization requiring AUUUA sequences probably is in part one of the mechanisms producing the increased levels of GM-CSF RNA by irradiation.
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PMID:Irradiation increases levels of GM-CSF through RNA stabilization which requires an AU-rich region in cancer cells. 147 71

The mRNAs for two key enzymes in polyamine biosynthesis, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), both long 5' untranslated regions (5'UTRs) that could be important in the regulation of enzyme levels by affecting the translation of these mRNAs. In order to test this hypothesis, ODC and AdoMetDC activities were measured in 3T3 cells and in 3T3 cells overexpressing eIF-4E (P2 cells). eIF-4E has been reported to be a limiting factor in the translation of mRNAs with extensive secondary structures in the 5'UTR. AdoMetDC activity was not greatly different in the two cell lines, but ODC activity was much greater in the P2 cells. These results were confirmed by transfecting these cells with plasmids containing a luciferase complementary DNA fused to follow the 5'UTR from ODC or AdoMetDC. The ODC 5'UTR construct produced a higher luciferase activity in the P2 cells. The high level of expression of ODC may be a critical factor in the transformed phenotype of the P2 cells since the ability of these cells to grow in soft agar was blocked by levels of the ODC inhibitor, alpha-difluoromethylornithine, that reduced the ODC activity to values comparable to those of the parent 3T3 cells. These results provide more evidence for a critical role of ODC activity in neoplastic transformation and for the importance of its translational regulation in cell growth and transformation.
Cancer Res 1994 May 01
PMID:Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. 816 72

pMV7-4E cells (4E-P2), derived from NIH-3T3 cells, overexpress eIF-4E and exhibit characteristics of transformation, possibly due to translational relief of mRNAs encoding proteins that regulate cell growth. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, is induced in 4E-P2 cells, and this induction appears to be related to the transformed phenotype of these cells. ODC mRNA contains extensive secondary structure in its 5' untranslated region (5'UTR) and may be regulated by eIF-4E, which melts mRNA secondary structure. To better understand this regulation, cDNA constructs containing the wild-type 5'UTR of ODC or deletion mutants inserted ahead of the luciferase gene were transfected into 4E-P2 and 3T3 cells. Expression of luciferase was higher in 4E-P2 cells in all cases, suggesting that the secondary structure of the ODC 5'UTR inhibits expression in 3T3 cells, and this inhibition is overcome by the high eIF-4E levels in 4E-P2 cells. When a small open reading frame present in the 5'UTR of ODC was destroyed by a point mutation, this luciferase construct was expressed about 6-fold over that containing the wild-type 5'UTR in both cell lines, although both of these 5'UTRs contain the same predicted secondary structure. Thus, factors in addition to eIF-4E may be involved in the regulation of ODC. To examine the differences in ODC regulation by polyamines in normal and transformed cells, the effect of N1,N12-bis(ethyl)spermine (BE-3-4-3) on the synthesis and degradation of ODC was examined. ODC activity in 4E-P2 cells was 10 times less sensitive to reduction by BE-3-4-3 compared to 3T3 cells, suggesting that high ODC levels in eIF-4E-overexpressing cells are the result of decreased regulation by polyamines as well as relief of translational regulation by eIF-4E.
Cancer Res 1996 Jul 15
PMID:Regulation of ornithine decarboxylase in a transformed cell line that overexpresses translation initiation factor eIF-4E. 876 19

Mammalian ribonucleotide reductase is rate limiting for the synthesis of DNA. The active enzyme is composed of two dissimilar components called R1 and R2, encoded by different genes. The 3' untranslated regions (3' UTRs) of R1 and R2 messages contain sequences that are important in regulating gene expression through changes in message stability. We have constructed expression plasmids containing the R1 or R2 mRNA 3' UTRs, and we show that transfection of these plasmids into highly malignant mouse 10 T1/2 cells significantly suppresses the tumorigenic properties of these cells in syngeneic mice when compared with cells transfected with the same plasmid lacking R1 or R2 3' UTR sequences or when compared with cells transfected with the same plasmid expressing a heterologous sequence as a control. Furthermore, cells expressing the R2 3' UTR exhibit significantly reduced potential to disseminate to the lungs of syngeneic animals in experimental metastasis assays. The tumor-suppressive effects of the mouse R1 and R2 3' UTRs were not confined to mouse cells, because human HeLa cells transfected with expression plasmids containing either RI or R2 3' UTRs were also significantly less tumorigenic in assays using BALB/c nu/nu mice. These studies demonstrate that the untranslated regions of ribonucleotide reductase mRNAs can function as modifiers of tumor cell development and for the more complex process of tumor dissemination. We propose that these malignancy-suppressive effects are mediated through RNA interactions with cellular components involved in growth regulation through mechanisms of posttranscriptional control of gene expression. In addition, these observations emphasize the enormous potential of untranslated RNA to act directly as modifiers of biological characteristics relevant to mechanisms of malignancy.
Cancer Res 1996 Oct 01
PMID:Suppression of malignancy by the 3' untranslated regions of ribonucleotide reductase R1 and R2 messenger RNAs. 881 26

Recently, human chromosome band 3p21.3 was shown to undergo overlapping homozygous deletions in several small cell lung cancer lines further defining a putative tumor suppressor gene(s) region. We report the cloning and mutational analysis of a novel human gene, SKMc15, from the commonly homozygously deleted region in three small cell lung cancer lines (NCI-H1450, NCI-H740, GLC20). It has 11 exons ranging in size from 50 to 541 bp with an open reading frame of 442 amino acids. The gene covers 7 to 10 kb of genomic DNA; the message of 1.8 to 2 kb is expressed in all analyzed fetal and adult human and mouse tissues including heart, brain, placenta, lung liver, skeletal muscle, kidney, testis and pancreas and in small cell and non-small cell cancer lines. The intron/exon boundaries were used to analyze the gene for mutations by exon PCR-SSCP sequencing in 60 small cell lung cancer cell lines. No loss-of-function mutations were detected. The cDNA sequence has high homology, 75% at the protein level, to the rat early response gene PC4 and its murine homolog TIS7. In addition, the known partial sequence of the putative mouse interferon beta2 (64 amino acids) gene is highly conserved in PC4/TIS7 (94%) and in SKMc15 (83%) at the amino acid level. The sequence TAAAT, which is thought to be involved in mRNA degradation, is present in the 3' UTR of SKMc15 and in the 3' UTR of PC4 and TIS7 genes.
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PMID:The human homolog of the rodent immediate early response genes, PC4 and TIS7, resides in the lung cancer tumor suppressor gene region on chromosome 3p21. 905 Sep 19

In order to evaluate the role of inherited BRCA2 mutations in American families--particularly the appearance in America of European founder mutations--the BRCA2 coding sequence, 5' UTR, and 3' UTR were screened in 22 Caucasian American kindreds with four or more cases of breast or ovarian cancer. Six mutations were found that cause a premature-termination codon; four of them have been reported elsewhere, and two are novel. In the four families with previously seen mutations, the distinct lineages at high risk of cancer were of Dutch, German, Irish, and Ashkenazi Jewish ancestry; mutations in Europe reflect these ancestries. The families with novel mutations were Puerto Rican Hispanic (exon 9 deletion 995delCAAAT) and Ashkenazi Jewish (exon 11 deletion 6425delTT). Among female BRCA2-mutation carriers, risks of breast cancer were 32% by age 50 years, 67% by age 70 years, and 80% by age 90 years, yielding a lifetime risk similar to that for BRCA1 but an older distribution of ages at onset. BRCA2 families also included multiple cases of cancers of the male breast (six cases), ovary (three cases), fallopian tube (two cases), pancreas (three cases), bladder (two cases), and prostate (two cases). Among 17 Ashkenazi Jewish families with four or more breast or ovarian cancers, 9 families (including 3 with ovarian cancer and 1 with male breast cancer) carried none of the three ancient mutations in BRCA1 or BRCA2. To date, both BRCA2 and BRCA1 have been screened by SSCA, supplemented by the protein-truncation test, in 48 families with four or more breast or ovarian cancers. Mutations have been detected in BRCA1 in 33 families, in BRCA2 in 6 families, and in neither gene in 9 families, suggesting both the probable cryptic nature of some mutations and the likelihood of at least one other BRCA gene.
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PMID:BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. 915 Jan 48

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.
Cancer Genet Cytogenet 1997 Jun
PMID:Molecular characterization of a complex chromosomal rearrangement in a pleomorphic salivary gland adenoma involving the 3'-UTR of HMGIC. 916 41

In a previous large scale screen for differentially expressed genes in pancreatic cancer, we identified a gene highly overexpressed in cancer encoding a novel protein with four K-homologous (KH) domains. KH-domains are found in a subset of RNA-binding proteins, including pre-mRNA-binding (hnRNP) K protein and the fragile X mental retardation gene product (FMR1). By fluorescence in situ hybridization (FISH) the identified gene named koc (KH domain containing protein overexpressed in cancer) was assigned to chromosome 7p11.5. Two pseudogenes were localised on chromosome 6 and 11. The cloned koc cDNA has a 250 bp 5'-UTR, a 1740 bp ORF and a 2168 bp 3'-UTR. The AU-rich 3'-untranslated region of koc contains eight AUUUA and four AUUUUUA reiterated motifs. The deduced koc protein with 580 amino-acids has a relative molecular mass (Mr) of approximately 65,000 (65 K). The koc transcript is highly overexpressed in pancreatic cancer cell lines and in pancreatic cancer tissue as compared to both, normal pancreas and chronic pancreatitis tissue. High levels of expression were as well found in tissue samples of other human tumours. As the KH domain has been shown to be involved in the regulation of RNA synthesis and metabolism, we speculate that koc may assume a role in the regulation of tumour cell proliferation by interfering with transcriptional and or posttranscriptional processes. However, the precise role of koc in human tumour cells is unknown and remains to be elucidated.
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PMID:Cloning of a gene highly overexpressed in cancer coding for a novel KH-domain containing protein. 917 71

Clonal rearrangements of the Ig heavy chain (IGH) locus consisting of either intrachromosomal (VDJ) rearrangements or interchromosomal translocations are a consistent feature of all B-cell malignancies and may be used both diagnostically and to monitor response to therapy. Many of these rearrangements are targeted to the IGHJ segments, but only some can be amplified with regular polymerase chain reaction (PCR) techniques. To permit PCR amplification of potentially all IGHJ rearrangements, we have devised a method incorporating self-ligation of restriction endonuclease-digested DNA fragments with long-distance PCR (long-distance, inverse PCR [LDI-PCR]). We show here, using only 4 nested oligonucleotide primers, the successful amplification and DNA sequencing of all IGHJ rearrangements up to 5.4 kb in length from a panel of 13 cases and cell lines of various types of B-cell malignancy. In all cases, both VDJ and DJ IGH rearrangements and translocation breakpoints were amplified. Six cases exhibited t(14;18)(q32;q21). All translocation breakpoints were cloned and sequenced. Three cases exhibited a rearrangement to the BCL2 major breakpoint region (MBR). However, 2 other cases exhibited rearrangements between the MBR and the minor cluster region (mcr). These 2 cases broke within 44 bp of each other, confirming the presence of an additional 3' BCL2 breakpoint cluster region. The final case fell immediately 3' of the 3' UTR of the BCL2 gene adjacent to an Alu repeat. No other BCL2 breakpoints within this region have been reported. Four cases exhibited t(11;14)(q13;q32). All 3 cases with translocations targeted to the IGHJ segments were successfully amplified and sequenced, including 1 case in which the BCL1 translocation could not be detected by DNA blot using the currently available probes. All three translocation breakpointsfell outside the BCL1 major translocation cluster between 20 and 40 kb telomeric and showed no clustering. Two of the three fell within or adjacent to Alu repeat regions. LDI-PCR is a simple and robust technique that allows PCR amplification of nearly all IGHJ rearrangements.
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PMID:Rapid molecular cloning of rearrangements of the IGHJ locus using long-distance inverse polymerase chain reaction. 931 Apr 98

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


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