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)

The long and GC-rich 5'-untranslated region (5'-UTR) of the known 3.8-kb platelet-derived growth factor B (PDGF-B)/c-sis mRNA is highly conserved and inhibits its own translation. It has been thought that this 5'-UTR functions by regulating translation possibly using an internal ribosome entry site (IRES)-mediated mechanism. However, in the present study we found no evidence that the 5'-UTR sequence of PDGF-B mRNA contains any IRES activity. Instead, we found that the 5'-UTR sequence of PDGF-B functions as a promoter both constitutively and upon induction in a variety of cell lines. The 5'-UTR sequence contains two promoters (termed P1 and P2) when only the 5'-UTR sequence is analyzed. In the presence of the upstream TATA-box-containing promoter (P0), P1 and P0 promoters are integrated into one promoter, whereas the P2 promoter still functions. The full promoter with combined P0, P1, and P2 produced two transcripts, with the major one having the full-length 5'-UTR and the minor one the short 5'-UTR. The integrated P0/P1 promoter and P2 promoter are likely responsible for producing the endogenous 3.8- and 2.8-kb PDGF-B mRNAs that are detected in cultured human renal microvascular endothelial cells, a few tumor cells, and rat brain tissues. Furthermore, we detected the 2.8-kb PDGF-B mRNA in erythroleukemia K562 cells upon 12-O-tetradecanoylphorbol-13-acetate-induced differentiation. Considering that the 5'-UTR in the 3.8-kb mRNA contains no IRES activity and inhibits cap-dependent translation, we believe that the endogenous 2.8-kb mRNA produced from the 5'-UTR promoter is likely the major template responsible for protein production both constitutively and upon induction. We also found that the transcription from the 5'-UTR P2 promoter might be coordinated by the major upstream P0 promoter upon stimulation. Based on these observations, we propose that the TATA-containing P0 promoter and the 5'-UTR promoter work together to tightly control the expression of PDGF-B.
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PMID:Tight control of platelet-derived growth factor B/c-sis expression by interplay between the 5'-untranslated region sequence and the major upstream promoter. 1296 Jan 51

Prohibitin is a candidate tumor suppressor gene located on human chromosome 17q21, a region of frequent loss of heterozygosity in breast cancers. We showed previously that microinjection of RNA encoded by the prohibitin gene 3'untranslated region (3'UTR) blocks the G(1)-S transition causing cell cycle arrest in several human cancer cell lines, including MCF7. Two allelic forms (C versus T) of the prohibitin 3'UTR exist, and carriers of the less common variant (Tallele) with a family history of breast cancer exhibited an increased risk of breast cancer. In the present study, we examined the tumor suppressor activity of the prohibitin 3'UTR in human breast cancer cells. Stable clones of MCF7 cells expressing either the C allele or the T allele RNA under the control of the cytomegalovirus promoter were isolated and compared with empty vector clones. Clones expressing the C allele RNA (UTR/C) exhibited significant suppression of growth in cell proliferation assays, inhibition of colony formation in soft agar assays, and suppression of xenograft tumor growth when implanted on nude mice, compared with either T allele expressing or empty vector clones. Immunohistochemical analyses with Ki67 staining confirmed a significant reduction in proliferation of UTR/C tumors. Thus, the C allele of prohibitin 3'UTR produces a functional RNA, whereas a single nucleotide polymorphism creates a null allele (T allele) of which the RNA product has lost activity. Our data demonstrate for the first time that an RNA molecule functions as a tumor suppressor in human breast cancer.
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PMID:Tumor suppression by the prohibitin gene 3'untranslated region RNA in human breast cancer. 1450 Mar 55

Germline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease-causing mutations of MSH6 may or may not exhibit MSI. We used D-HPLC to screen for germline mutations in the promoter region, the coding region and the 3'-UTR of MSH6. Eighty-four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC-like families), were tested for MMR gene mutations; 27 families had a disease-causing mutation in MLH1 or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein-truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early-onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease-causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease-causing germline mutations of MSH6 are rare in HNPCC and HNPCC-like families.
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PMID:MSH6 germline mutations are rare in colorectal cancer families. 1452 Jun 94

Although LINE-1 (L1) sequences constitute the most important family of retrotransposons in the human genome, their transcriptional regulation is poorly understood. Specifically, their unusual internal promoter is incompletely characterized. Current promoter prediction programs fail to identify the promoter in the 5'UTR of the active LINE-1 element L1.2B. Experimental investigation of this promoter using reporter gene assays in various human and murine cell types confirmed that the promoter consists of two segments, and demonstrated that the distal portion is essential for cell-type-independent activity. No differences in promoter activity were found between normal and transformed cells. The complete promoter was shown to possess approximately 20% of the activity of the strong early promoter of cytomegalovirus, and to be capable of directing the expression of levels of p53 sufficient to kill normal and transformed human cells. Thus, active LINE-1 elements contain highly active promoters capable of driving cell-type-independent expression, which are of potential use in mammalian expression constructs. In vitro methylation of the promoter at HpaII sites decreased its activity independently of cell type, but this repression was alleviated in MBD2-/- cells. Surprisingly, mutation of specific HpaII sites was also found to reduce promoter activity. Thus, efficient repression of the L1.2B promoter by DNA methylation may involve MBD2 binding, but at least one HpaII site also appears to be involved specifically in transcriptional activation. Since neither promoter activity nor the efficiency of repression by methylation differed between normal and tumor cells, the re-activation of LINE-1 sequences observed in tumor cells is probably caused by hypomethylation of the promoter.
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PMID:Transcriptional regulation of the human LINE-1 retrotransposon L1.2B. 1453 Sep 63

Abnormal production of interleukin-10 (IL-10) is observed in some pathologic conditions. For example, compared with normal melanocytes, IL-10 expression is elevated in melanoma cells. IL-10 overexpression could inhibit both immune surveillance and tumor rejection. We investigated a potential posttranscriptional mechanism for IL-10 overexpression in melanoma cells. In normal melanocytes, the half-life of IL-10 mRNA is 7 min, whereas in the melanoma cell line MNT1, the half-life is 75 min. This 10-fold difference could account, at least in part, for IL-10 overexpression in MNT1 cells. Examination of the 3'-untranslated region (3'-UTR) of IL-10 mRNA revealed a suspected A + U-rich element (ARE) that might target the mRNA for rapid degradation. Transfection experiments confirmed that these sequences promote rapid degradation when inserted into a normally stable mRNA, indicating ARE functionality. As AREs act via their interactions with ARE-binding proteins, we examined cytoplasmic proteins from normal melanocytes and MNT1 cells for IL-10 ARE-binding activity. Compared with cytoplasmic extracts of normal melanocytes, cytoplasmic extracts of MNT1 cells possess substantially less ARE-binding activity, consistent with the extended half-life of IL-10 mRNA in MNT1 cells. Finally, we find that the ARE-binding protein AUF1 comprises the major ARE-binding activity in cytoplasmic extracts of normal melanocytes. By contrast, AUF1 is not detectable in cytoplasmic extracts of MNT1 cells but appears restricted to the nuclear fraction. Together, these data suggest a mechanism whereby reduced cytoplasmic levels of AUF1 in MNT1 melanoma cells may lead to IL-10 overexpression, with deleterious consequences for tumor surveillance and rejection.
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PMID:Increased interleukin-10 mRNA stability in melanoma cells is associated with decreased levels of A + U-rich element binding factor AUF1. 1458 95

The human cell lines VACO-235 and VACO-411 constitute a novel in vitro model of colon adenoma to carcinoma progression. By differential display RT-PCR we identified a transcript that is expressed in the parental nontumorigenic adenoma line (VACO-235E), but is not expressed in the tumorigenic daughter (VACO-235L) or granddaughter (VACO-411) lines. This cDNA represents a previously uncharacterized portion of the 3'UTR of human PIGR. Human PIGR mRNA was found to be highly expressed in normal colon epithelium, but was decreased in 6 of 8 colon tumors and was negligible in 8 of 10 colon tumor cell lines. We sequenced the entire 1.8 kb 3'UTR of human PIGR, and found it to contain multiple repetitive elements as well as elements that could affect the processing and stability of PIGR mRNA. We hypothesize that differential regulation of PIGR mRNA stability may contribute to its downregulation in colon cancer.
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PMID:Characterization of the human polymeric immunoglobulin receptor (PIGR) 3'UTR and differential expression of PIGR mRNA during colon tumorigenesis. 1463 Nov 19

In the present study, we describe the human and mouse RFP2 gene structure, multiple RFP2 mRNA isoforms in the two species that have different 5' UTRs and a human-specific antisense transcript RFP2OS. Since the human RFP2 5' UTR is not conserved in mouse, these findings might indicate a different regulation of RFP2 in the two species. The predicted human and mouse RFP2 proteins are shown to contain a tripartite RING finger-B-box-coiled-coil domain (RBCC), also known as a TRIM domain, and therefore belong to a subgroup of RING finger proteins that are often involved in developmental and tumorigenic processes. Because homozygous deletions of chromosomal region 13q14.3 are found in a number of malignancies, including chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), we suggest that RFP2 might be involved in tumor development. This study provides necessary information for evaluation of the role of RFP2 in malignant transformation and other biological processes.
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PMID:Distinct organization of the candidate tumor suppressor gene RFP2 in human and mouse: multiple mRNA isoforms in both species- and human-specific antisense transcript RFP2OS. 1463 97

We developed an antisense peptide nucleic acid (PNA) targeted against a unique sequence in the terminus of the 5'-UTR of N-myc, designed for selective inhibition of NMYC in neuroblastoma cells. Fluorescent microscopy showed carrier-free delivery of the PNA to two human neuro-blastoma cell lines: GI-LI-N (N-myc-amplified) and GI-CA-N (N-myc-unamplified). Only in the former, PNA treatment determined 70% cell-viability reduction (at 48 h). In N-myc-amplified GI-LI-N cells, the PNA determined NMYC-translation inhibition (Western blotting), accumulation of cells in G1, induction of differentiation and apoptosis. Selectivity of the PNA was demonstrated by altering three point mutations. These findings should encourage development of a PNA-based tumor-specific agent for neuroblastoma (or other neoplasms) with N-myc overexpression.
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PMID:Targeted inhibition of NMYC by peptide nucleic acid in N-myc amplified human neuroblastoma cells: cell-cycle inhibition with induction of neuronal cell differentiation and apoptosis. 1471 1

Transfection of cDNA in 3'untranslated region of human nuclear factor for interleukin-6 (NF-IL6 3'UTR) induced tumor suppression in a human hepatoma cell line. cDNA array analysis was used to reveal changes in gene expression profile leading to tumor suppression The results indicate that this suppression was not due to activation of dsRNA-dependent protein kinase, nor to inactivation of oncogenes; rather, all the changes in expression of known genes, induced by NF-IL6 3'UTR cDNA may be ascribed to the suppression of cellular malignancy. Therefore, our results imply that this 3'untranslated region may have played role of a regulator of gene expression profile.
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PMID:Gene expression profile favoring phenotypic reversion: a clue for mechanism of tumor suppression by NF-IL6 3'UTR. 1472 9

We have identified the initiation factor 4A (eIF4A) in a two-dimensional protein database of Drosophila wing imaginal discs. eIF4A, a member of the DEAD-box family of RNA helicases, forms the active eIF4F complex that in the presence of eIF4B and eIF4H unwinds the secondary structure of the 5'-UTR of mRNAs during translational initiation. Two-dimensional gel electrophoresis and microsequencing allowed us to purify eIF4A, and generate specific polyclonal antibodies. A combination of immunoblotting and labelling with [(35)S]methionine + [(35)S]cysteine revealed the existence of a single eIF4A isoform encoded by a previously reported gene that maps to chromosome 2L at 26A7-9. Expression of this gene yields two mRNA species, generated by alternative splicing in the 3'-untranslated region. The two mRNAs contain the same open reading frame and produce the identical eIF4A protein. No expression was detected of the eIF4A-related gene CG7483. We detected eIF4A protein expression in the wing imaginal discs of several Drosophila species, and in haltere, leg 1, leg 2, leg 3, and eye-antenna imaginal discs of D. melanogaster. Examination of eIF4A in tumor suppressor mutants showed significantly increased (> 50%) expression in the wing imaginal discs of these larvae. We observed ubiquitous expression of eIF4A mRNA and protein during Drosophila embryogenesis. Yeast two-hybrid analysis demonstrated the in vivo interaction of Drosophila eIF4G with the N-terminal third of eIF4A.
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PMID:Identification and characterization of the expression of the translation initiation factor 4A (eIF4A) from Drosophila melanogaster. 1476 Jul 1


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