Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retinoblastoma-predisposition gene, RB1, segregates as an autosomal dominant trait with high (90%) penetrance. Certain families, however, show an unusual low-penetrance phenotype with many individuals being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors. We have used single-strand conformation polymorphism analysis and PCR sequencing to study two such families. Mutations were found in exon 20 of RB1 in both cases. In one family a C----T transition in codon 661 converts an arginine (CGG) to a tryptophan (TGG) codon. In this family, incomplete penetrance and mild phenotypic expression were observed in virtually all patients, possibly indicating that single amino acid changes may modify protein structure/function such that tumorigenesis is not inevitable. In the second family the mutation in codon 675 is a G----T transversion that converts a glutamine (GAA) to a stop (TAA) codon. However, this mutation also occurs near a potential cryptic splice acceptor site, raising the possibility of alternative splicing resulting in a less severely disrupted protein.
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PMID:Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype. 135 83

The effect of methapyrilene (MP), a mitochondrial proliferator and presumed nongenotoxic carcinogen, has been examined in rodent liver by means of high-resolution two-dimensional electrophoretic analysis of total proteins. Using this approach, we have discovered protein modifications in rat liver resulting from 1 week MP treatment that suggest the involvement of a reactive drug metabolite. The restriction of these molecular charge modifications to mitochondrial proteins indicates that such a reactive metabolite must be generated and confined within the mitochondrion. Quantitative changes in numerous nonmitochondrial proteins are also observed. Following a 4-week recovery period, almost all the 1-week treatment changes are reversed, reestablishing a protein pattern close to that of the controls. At the end of a 10-week exposure, the mitochondrial protein modifications are increased and are accompanied by a variety of quantitative protein changes indicative of a large shift in gene expression and/or cell type composition. When a 4-week untreated recovery period follows the 10-week treatment, small quantitative changes persist. In the mouse, where MP appears not to induce mitochondrial proliferation or tumorigenesis, 1 week treatment nevertheless produces mitochondrial protein changes in vivo consistent with attack by a reactive metabolite, but at a level substantially lower than that seen in the rat. Features of the mitochondrial protein modification indicate that it is covalent, does not involve cysteine or tryptophan, and results from binding of a negatively charged adduct. The possibility that the putative reactive metabolite could also attack mitochondrial (but not nuclear) DNA suggests that MP could be genotoxic in an unconventional way. Detection of protein modification by two-dimensional gel analysis appears to offer a general method for the detection and characterization of processes generating reactive metabolites.
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PMID:Covalent protein modifications and gene expression changes in rodent liver following administration of methapyrilene: a study using two-dimensional electrophoresis. 152 69

A total of 45 chemicals, including two aromatic hydrocarbons, five aromatic amines, three azo dyes, ten nitroso compounds, three steroids, four tryptophan metabolites and their related compounds, four naturally occurring substances, four pyrolysates of amino acids and ten miscellaneous compounds, were tested for newborn mouse tumorigenesis assay (NMTA). The results of the NMTA were compared with data from 'Survey of Compounds Which Have Been Tested for Carcinogenic Activity', NIH, NCI, USA (SCWHBTCA), and also with data from the IARC Monographs (Vols 1-41), Lyon, France (IARC). Of the 45 chemicals tested by the NMTA, 28 chemicals showed positive results in the NMTA, and the remaining 17 chemicals were found to be negative for tumor development. The correlation of the results between the NMTA and the mouse and/or rat carcinogenesis test starting at young adult age reported in the SCWHBTCA and in the IARC were compared with 37 chemicals tested; the remaining eight chemicals were found only in our NMTA results. It can be concluded that 31 out of 37 chemicals (83.8%) tested by the NMTA showed similar carcinogenic or non-carcinogenic results obtained in either adult mouse and/or rat carcinogenesis tests. The remaining six chemicals showed contradictory results between the NMTA and either adult mouse and/or rat carcinogenesis tests. Those six chemicals were N-hydroxy-4-acetylaminobiphenyl, estradiol, 3-hydroxyanthranilic acid, 3-hydroxy-L-kynurenine, isonicotinic acid hydrazide and phenobarbital. Among the 37 chemicals, 34 were comparable with the results of the adult mouse carcinogenesis test and those of the NMTA. Twenty-nine out of 34 chemicals (85.3%) showed similar results to the adult mouse carcinogenesis test. Contradictory results were obtained with the following five chemicals: N-hydroxy-acetylaminobiphenyl, 3-hydroxy-anthranilic acid, 3-hydroxy-L-kynurenine, isonicotinic acid hydrazide and phenobarbital. There were 35 chemicals which were comparable with the results of the adult rat carcinogenesis test, and 32 chemicals showed the same results as the NMTA (91.4%). Dissimilar results were obtained with the following three chemicals: estradiol, 3-hydroxy-anthranilic acid and phenobarbital. Based on the results presented in this report, it is reasonable to conclude that the NMTA is one of the most useful and reliable methods for detecting tumorigenic or non-tumorigenic chemicals, when a small amount of chemical is available for rodent carcinogenesis test and the duration of the study is limited to 1 year.
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PMID:Evaluation of the newborn mouse model for chemical tumorigenesis. 186 Jan 62

The proviral DNA of human T-lymphotropic virus type I (HTLV-I) was examined in 8 patients with adult T-cell leukemia/lymphoma (ATL/L) by Southern blot analysis. Judging from the number of bands containing viral DNA sequences in tumor cells, one and three copies of proviral genome were detected in 7 and 1 cases, respectively. The proviral genome in 1 case contained variant PstI sites and a single defective provirus which lost 5' LTR, gag and a part of pol genes was found in 2 cases. However, the pX region was detected in both of 2 latter cases by using the polymerase chain reaction. The results indicate that not all tumor cells from ATL/L yield infectious viruses and also support that the product of pX region may contribute to the tumorigenesis of HTLV-I.
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PMID:Human T-lymphotropic virus type I genome in adult T-cell leukemia/lymphoma. 193 71

A cDNA clone of human transforming growth factor alpha (TGF-alpha) was introduced into two different retroviral vectors under the transcriptional control of either the viral LTR, vector 1520, or an internal mouse metallothionein-1 promoter, vector 1522. Infection of normal rat kidney fibroblasts (NRK-49F) and mouse mammary epithelial cells (NOG-8), followed by selection, allowed isolation of individual colonies expressing human TGF-alpha. NRK-49F and NOG-8 1520 infectants conditioned their media with equivalent amounts of TGF-alpha protein but responded differently to autocrine stimulation. NOG-8 infectants formed colonies in soft agar and tumors in nude mice. However, while the NRK-49F infectants proliferated in the presence of transforming growth factor beta (TGF-beta), a response that requires epidermal growth factor (EGF) or TGF-alpha, they exhibited neither anchorage independent growth nor tumorigenicity. NRK-49F cells infected with the 1522 vector produced five-fold more TGF-alpha than the 1520 infectants. Increasing the level of TGF-alpha production by the NRK-49F cells in this way was sufficient to promote agar growth of the cells in the presence of TGF-beta but insufficient to promote tumorigenesis. The EGF receptor level is approximately ten-fold higher on the NOG-8 epithelial cells than on the NRK-49F fibroblast. This fact, in conjunction with the experimental results, suggest that the target cell type and its ability to respond to TGF-alpha is as critical for autocrine stimulation as the amount of growth factor produced by the cells.
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PMID:Infection with a TGF-alpha retroviral vector transforms normal mouse mammary epithelial cells but not normal rat fibroblasts. 281 79

The organization and expression of endogenous mouse mammary tumor virus (MMTV) proviruses in normal and neoplastic C3Hf/Ki tissues were examined. MMTV-containing EcoRI, HindIII, BamHI and PstI restriction fragments of C3Hf/Ki DNA were identical to those of C3H/StWi DNA. The full-length endogenous MMTV Units Ia (Mtv-7), II (Mtv-8), III (Mtv-9) and IV (Mtv-10), in addition to the subgenomic endogenous MMTV Units I (Mtv-6) and IX (Mtv-14), were germinally transmitted in C3Hf/Ki DNA. The previously uncharacterized Mtv-7 was contained in EcoRI fragments of 16.7 and 11.7 kbp. The endogenous MMTV Unit V (Mtv-1), which is responsible for virus production and mammary tumorigenesis in C3Hf/He mice, was absent from C3Hf/Ki DNA. The 9.0 kb gag-pol, the 3.8 kb env and the 1.7 kb LTR MMTV RNA transcripts were present in C3Hf/Ki mammary glands. MMTV proviruses, in addition to the endogenous C3Hf/Ki MMTV complement, were not detected in C3Hf/Ki mammary tumor DNA. The DNA organization and RNA expression of the putative mammary proto-oncogene regions int-1 and int-2 were also examined in C3Hf/Ki mammary tumors. The int-1 and int-2 regions did not appear rearranged, amplified, or expressed in C3Hf/Ki mammary tumors. These studies indicate that MMTV proviral activation of the int proto-oncogenes is not necessary for C3Hf/Ki mammary tumorigenesis.
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PMID:Mammary tumorigenesis in C3Hf/Ki mice: examination of germinal mouse mammary tumor viruses and the int-1 and int-2 putative proto-oncogenes. 298 29

ALV-induced erythroblastosis results from the specific interruption of the host oncogene, c-erbB, by the insertion of an intact provirus. Integrated proviruses are oriented in the same transcriptional direction as c-erbB, and expression of truncated c-erbB transcripts is observed. Evidence, including sequence analysis of cDNA clones, indicates that transcription of truncated c-erbB mRNA is initiated in the 5' LTR of the integrated provirus. This transcript is processed through a series of remarkable splicing reactions to yield viral gag and env sequences fused to erbB sequences. These results establish a novel pathway of promoter insertion oncogenesis that stands in contrast to the pathways used in the activation of c-myc in B lymphomas.
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PMID:c-erbB activation in ALV-induced erythroblastosis: novel RNA processing and promoter insertion result in expression of an amino-truncated EGF receptor. 298 84

Retrovirus without oncogenes often exert their neoplastic potential as insertional mutagens of cellular proto-oncogenes. This may be associated with the production of chimaeric viral-host transcripts; in these cases; activated cellular genes can be identified by obtaining cDNA clones of bipartite RNAs. This approach was used in the analysis of chicken nephroblastomas induced by myeloblastosis-associated virus (MAV). One tumor contained a novel mRNA species initiated within a MAV LTR. cDNA cloning revealed that this mRNA encodes a protein of 189 amino acids, identical to that of normal human Ha-ras-1 at 185 positions, including positions implicated in oncogenic activation of ras proto-oncogenes; there are no differences between the coding sequences of presumably normal Ha-ras cDNA clones from chicken lymphoma RNA and the tumor-derived cDNAs. The chimaeric mRNA in the nephroblastoma is at least 25-fold more abundant than c-Ha-ras mRNA in normal kidney tissue, and a 21-kd ras-related protein is present in relatively large amounts in the tumor. We conclude that a quantitative change in c-Ha-ras gene expression results from an upstream insertion mutation and presumably contributes to tumorigenesis in this single case. Little or no increase in c-Ha-ras RNA or protein was observed in other nephroblastomas.
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PMID:Identification of a provirally activated c-Ha-ras oncogene in an avian nephroblastoma via a novel procedure: cDNA cloning of a chimaeric viral-host transcript. 301 1

This paper reviews some of the earlier experimental studies concerning the role that tryptophan plays in enhancing tumorigenesis induced by selected chemical carcinogens. For many years, tryptophan has been implicated in carcinogenesis of the bladder. The evidence regarding tryptophan's effect on hepatic tumorigenesis is conflicting; an enhancing effect has been reported by some investigators, but a reduction in tumorigenesis has been reported by other workers. Some of the unique effects that tryptophan exerts upon the liver are reviewed. Also, experimental studies from our laboratory are reported in which we observed a potentiating effect of increased dietary tryptophan on the induction of gamma-glutamyltranspeptidase-positive foci in liver when rats were fed a choline-supplemented diet but no potentiation was found when rats were fed a choline-deficient diet for 10 weeks. The results suggest that increased dietary tryptophan has a promoting effect on liver carcinogenesis as measured by the induction of gamma-glutamyltranspeptidase-positive foci in the livers of rats exposed to diethylnitrosamine. The possible significance of these findings is reviewed.
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PMID:Role of tryptophan in carcinogenesis. 359 19

Data from the long-term projects sponsored by the Food and Nutrition Board to determine the requirements for thiamin, riboflavin, niacin-tryptophan, and vitamin E are utilized to effect an opinion regarding the recommended dietary allowances for these vitamins. Based upon data obtained during these and subsequent research projects, comments on balance studies, changes in tissue lipids, and the requirements for vitamin B-6 are included. The possibility that antioxidants may have an effect on delaying oncogenesis is discussed.
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PMID:Interpretations of requirements for thiamin, riboflavin, niacin-tryptophan, and vitamin E plus comments on balance studies and vitamin B-6. 378 44


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