Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The isolation and characterization of the rat genomic clone encoding the cholesterogenic enzyme farnesyl diphosphate (FPP) synthase is reported. The gene is localized on a 15-kilobase (kb) genomic fragment, spans approximately 12 kb and contains eight exons. Sequences containing from 3.9 kb to 132 base pairs (bp) of the putative promoter were joined to the coding region of the bacterial reporter gene chloramphenicol acetyltransferase (CAT). The CAT activities or CAT mRNA levels of the hybrid genes were determined following either transient transfections into human hepatoma HepG2 cells or stable transfections into Chinese hamster ovary cells. The transient transfections identified a 319-bp fragment that was required for a 4-fold induction in the absence of sterols. Sequence analysis of this region showed it contained five potential copies of the sterol regulatory element (SRE-1) (Smith, J.R., Osborne, T.F., Brown, M.S., Goldstein, J.L., and Gil, G. (1988) J. Biol. Chem. 263, 18480-18487) previously identified in the promoters of the 3-hydroxy-3-methyl-coenzyme A (HMG-CoA) reductase, HMG-CoA synthase, and low density lipoprotein receptor genes. Further mutational and deletion analysis of the FPP synthase promoter-CAT constructs followed by stable transfection and primer extension of the CAT mRNA levels indicated that these potential SRE-1 regulatory elements were not involved in the sterol-mediated transcriptional regulation of the gene. Our analyses have identified a 115-bp region that is required for the transcriptional induction of FPP synthase in the absence of sterols. These results suggest that the FPP synthase gene may be regulated at the transcriptional level by a different mechanism than other sterol regulated genes.
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PMID:Molecular cloning and promoter analysis of the rat liver farnesyl diphosphate synthase gene. 132 Nov 49

We compared liver tumor frequencies, and age and length characteristics of brown bullheads (Ictalurus nebulosus) of greater than 250 mm total length from two Lake Erie tributaries. Bullheads taken from Old Woman Creek (n = 144) had no grossly observable liver tumors, while those collected in the highly industrialized Black River (n = 532) had a 30% frequency of grossly visible liver tumors during 1981-1982. Liver lesions diagnosed histologically in a randomly collected sample (n = 125) of brown bullheads from the Black River included both biliary and hepatic lesions, with cancerous neoplasms occurring in 38.4% of the fish. Black River bullheads of combined ages 4 and 5 had a significantly (p less than or equal to 0.05) greater prevalence of biliary carcinomas (35.5%) than those of ages 2 and 3 combined (18.4%). Biliary carcinoma was significantly more prevalent than hepatocellular carcinoma in age 4 fish (sexes combined) and in males of ages 3 and 4. The prevalence of hepatocellular carcinoma was significantly higher in females than in males. Age distributions of bullheads differed significantly between the two sites, while length distributions were similar. No brown bullheads of ages 6 or 7 were collected in the Black River, while these age groups composed 18% of the catch in Old Woman Creek. Brown bullheads of age 5 were almost six times more numerous in the Old Woman Creek than in Black River collections. These age and length distributions are consistent with the hypothesis that brown bullheads in the Black River were subjected to an age-selective mortality associated with high prevalences of liver carcinoma.
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PMID:Relationship between liver tumors and age in brown bullhead populations from two Lake Erie tributaries. 236 40

At least two genetically distinct glucose transporters (GTs) coexist in adipose cells, one cloned from human hepatoma cells and rat brain (HepG2/brain) and another from rat skeletal muscle, heart, and adipose cells (adipose cell/muscle). Here we demonstrate differential regulation of these two GTs in adipose cells of diabetic and insulin-treated diabetic rats and compare changes in the expression of each GT with marked alterations in insulin-stimulated glucose transport activity. Adipose cell/muscle GTs detected by immunoblotting with the monoclonal antiserum 1F8 (James, D. E., R. Brown, J. Navarro, and P. F. Pilch. 1988. Nature (Lond.). 333:183-185), which reacts with the protein product of the newly cloned adipose cell/muscle GT cDNA, decrease 87% with diabetes and increase to 8.5-fold diabetic levels with insulin treatment. These changes concur qualitatively with previous detection of GTs by cytochalasin B binding and with insulin-stimulated 3-O-methylglucose transport. Northern blotting reveals that the adipose/muscle GT mRNA decreases 50% with diabetes and increases to 6.8-fold control (13-fold diabetic) levels with insulin treatment. In contrast, GTs detected with antisera to the carboxyl terminus of the HepG2 GT or to the human erythrocyte GT show no significant change with diabetes or insulin treatment. The HepG2/brain GT mRNA is unchanged with diabetes and increases threefold with insulin treatment. These results suggest that (a) altered expression of the adipose cell/muscle GT forms the molecular basis for the dysregulated glucose transport response to insulin characteristic of diabetes, (b) the expression of two types of GTs in rat adipose cells is regulated independently, and (c) alterations in mRNA levels are only part of the mechanism for in vivo regulation of the expression of either GT species.
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PMID:Differential regulation of two glucose transporters in adipose cells from diabetic and insulin-treated diabetic rats. 266 32

A hepatocellular carcinoma which was predominately black was surgically excised from a noncirrhotic, asymptomatic 62-year-old white man. Brown-black, pigment granules, found only in the tumor cells, were histochemically and ultrastructurally identical to the hepatocellular pigment found in Dubin-Johnson syndrome. The latter pigment is thought to accumulate as a consequence of a genetically determined abnormality in the excretion of catecholamines and related substances. It is postulated that the pigment formation in this tumor developed via a similar, though epigenetic, mechanism. This occurrence has not been previously described. Unusual PAS-negative, globular cytoplasmic inclusions were also found in the tumor cells and these proved to be Mallory bodies by electron microscopy.
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PMID:A black hepatocellular carcinoma with Dubin-Johnson-like pigment and Mallory bodies: a histochemical and ultrastructural study. 628 73

6-p-Dimethylaminophenylazobenzothiazole (6BT) administered at a dose of 10 mg/kg by gavage to Sprague-Dawley and Wistar-derived rats for 2 months produced marked cellular changes in the liver, including proliferation of oval cells and the formation of regenerative/hyperplastic nodules. Cellular change continued after stopping dosing at 2 months such that liver tumours were first observed after only 4 months into the study, and animals examined between 4 months and termination at 6 months showed a 75% and 85% incidence of hepatocellular carcinoma for the Sprague-Dawley and Wistar strains, respectively. This study establishes 6BT as a potent hepatocarcinogen in the rat when administered by gavage, and confirms and extends an initial brief report by Brown and Sanchorawala in 1968 of its carcinogenicity following dietary administration.
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PMID:6-p-Dimethylaminophenylazobenzothiazole: a potent hepatocarcinogen in the rat. 641 66

Transfectants that express membrane-bound (MB) or secrete soluble truncated (TR) rat class I RT1.Aa major histocompatibility (MHC) antigens induce alloimmunity in vivo. The MB-RT1.Aa was produced by transfecting the full-length RT1.Aa cDNA, including the alpha 1, alpha 2, and alpha 3, transmembrane and intracellular domains. The TR-RT1.Aa cDNA insert included only the extracellular alpha 1, alpha 2, and alpha 3 domains; a stop codon was placed in front of the transmembrane domain. Following full-length sequencing, MB-RT1.Aa and TR-RT1.Aa cDNAs were translated in vitro into glycosylated MB-RT1.Aa (45 kDa) and TR-RT1.Aa (36 kDa) proteins, respectively. Each cDNA construct was individually subcloned into the pSG5 vector before transfection into Buffalo (BUF; RT1b) hepatoma cells. FACscan analysis with anti-RT1.Aa-specific R2/15S monoclonal antibody (MAb) confirmed surface expression of RT1.Aa molecules on the MB-RT1.Aa, but not on the TR-RT1.Aa, transfectants. In contrast, enzyme-linked immunoadsorbent assays documented the presence of soluble RT1.Aa molecules in supernates from cells transfected with the TR-RT1.Aa, but not from cells transfected with the MB-RT1.Aa, cDNA. Subcutaneous injection of MB-RT1.Aa or TR-RT1.Aa transfectants to BUF or Wistar Furth (WF; RT1u) rats induced accelerated rejection of ACI (RT1a) but not third-party Brown Norway (RT1n) heart allografts. Furthermore, supernates of TR-RT1.Aa, but not of MB-RT1.Aa, transfectants immunized WF hosts toward ACI hearts. Thus, both intact MB-RT1.Aa and soluble TR-RT1.Aa class I alloantigens induce potent sensitization against alloantigens.
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PMID:Membrane-bound or soluble truncated RT1.Aa rat class I major histocompatibility antigens induce specific alloimmunity. 757 Sep 58

We have cloned and characterized the 5'-flanking region of the gene encoding human squalene synthase. We report here the promoter activity of successively 5'-truncated sections of a 1 kilobase of this region by fusing it to the coding region of a luciferase reporter gene. DNA segments of 200 base pairs (bp) 5' to the transcription start site, as determined by primer extension analysis, show a strong promoter effect on the expression of the luciferase chimeric gene and a high response to the presence of sterols when transiently transfected into the human hepatoma cell line HepG2 or to the hamster-derived CHO-K1 cells. An approximately 50-fold induction of luciferase activity, in the absence of sterols, was observed in transiently transfected HepG2 cells for fusion constructs containing sections of 200, 459, and 934 bp of the putative human squalene synthase promoter. Loss of promoter activity and response to sterols was localized to a 69-bp section located 131 nucleotides 5' to the transcription start site. Sequence analysis of this region showed that it contained a sterol regulatory element 1 (SRE-1) previously identified in other sterol regulated genes (Smith, J. R., Osborne, T. F., Brown, M. S., Goldstein, J. L., and Gil, G. (1988). J. Biol. Chem. 263, 18480-18487) and two potential NF-1 binding sites. Additional CCAAT box, SRE-1 element, and two Sp1 sites were identified 3' to this section. Sequences within this 69-bp DNA, including the SRE-1 cis-acting element, show strong binding to the purified nuclear transcription factor ADD1 (Tonzonoz, P., Kim, J. B., Graves, R. A., and Spiegelman B. M. (1993) Mol. Cell Biol. 13, 4753-4759) by mobility shift assay and footprinting analyses.
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PMID:Molecular cloning and functional analysis of the promoter of the human squalene synthase gene. 766 18

Coagulation factor Xa is a plasma serine protease that catalyzes prothrombin to thrombin conversion, which, in turn, leads to the generation of the fibrin clot. Of the several parameters that govern the plasma level of factor Xa, control of its catabolism is of crucial importance. However, little is known regarding the mechanisms by which factor Xa is catabolized. In the present study we examine the cellular basis for the uptake and degradation of factor Xa. 125I-Factor Xa was degraded by hepatoma cells and embryonic fibroblasts via a process which required cell surface-bound tissue factor pathway inhibitor (TFPI), a potent inhibitor of factor Xa. Uptake and degradation of cell surface-bound 125I-TFPI was also markedly stimulated in response to factor Xa binding. The intracellular kinetics of 125I-factor Xa and cell surface-bound 125I-TFPI display a strikingly similar pattern, suggesting that factor Xa and cell surface-bound TFPI are taken up as a bimolecular complex. Using cell lines either deficient in low density lipoprotein receptor-related protein, an endocytic receptor that mediates the degradation of uncomplexed TFPI (Warshawsky, I., Broze, G.J., Jr., and Schwartz, A.L. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 6664-6668), or deficient in tissue factor (TF), an integral membrane protein capable of forming quarternary complexes with factor Xa, TFPI, and factor VIIa, we demonstrated that the receptor that mediates the uptake and degradation of factor Xa-TFPI complex was neither low density lipoprotein receptor-related protein nor TF. As the vascular endothelial cell surface retains a substantial pool of TFPI (Sandset, P.M., Alildgaard, U., and Larsen, M.L. (1988) Thromb. Res. 50, 803-813; Novotny, W.F., Brown, S.G., Miletich, J.P., Rader, D.J., and Broze, G.J., Jr. (1991) Blood 78, 387-393), our data suggest that endothelial cell surface TFPI may be actively involved in the clearance of factor Xa from the circulation via mediated uptake and degradation.
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PMID:Receptor-mediated endocytosis of coagulation factor Xa requires cell surface-bound tissue factor pathway inhibitor. 862 21

The objective of this study was to develop an animal model to evaluate the biology of hepatocellular carcinoma (HCC) recurrence after liver transplantation. HCC was induced in Brown Norway (BN) rats (n = 45) by diet-hylnitrosamine (DEN) administered continuously through the drinking water. Starting from day 14, rats were sequentially autopsied or syngeneically transplanted according to Kamada's cuff technique. After 74 days of DEN administration, neoplastic liver lesions appeared and after a mean of 102 days (SD +/- 6) the animals died of abdominal haemorrhage from liver tumours. At this time lung metastases were present in three-fifths animals. Transplantation success was dependent on the DEN consumption and thereby the tumour stadium. After 74 days of DEN administration BN rats could no longer be transplanted because of anaesthetic problems or technical problems due to tumour adhesion to surrounding tissues. No recurrence was found in the transplants. In conclusion, we believe that timing of the operation in this HCC model is essential because the physical condition of the animals prohibits orthotopic liver transplantation in an advanced tumour stage. With a different DEN dosage scheme this problem may be solved.
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PMID:Hepatocellular carcinoma and liver transplantation: an animal model. 966 79

A chimeric yellow fever-dengue 1 (ChimeriVax-DEN1) virus was produced by the transfection of Vero cells with chimeric in vitro RNA transcripts. The cell culture supernatant was subjected to plaque purification for the identification of a vaccine candidate without mutations. Of 10 plaque-purified clones, 1 containing no mutation (clone J) was selected for production of the vaccine virus. During subsequent cell culture passaging of this clone for vaccine production, a single amino acid substitution (K to R) occurred in the envelope (E) protein at residue 204 (E204) (F. Guirakhoo, K. Pugachev, Z. Zhang, G. Myers, I. Levenbook, K. Draper, J. Lang, S. Ocran, F. Mitchell, M. Parsons, N. Brown, S. Brandler, C. Fournier, B. Barrere, F. Rizvi, A. Travassos, R. Nichols, D. Trent, and T. Monath, J. Virol. 78:4761-4775, 2004). The same mutation was observed in another clone (clone E). This mutation attenuated the virus in 4-day-old suckling mice inoculated by the intracerebral (i.c.) route and led to reduced viremia in monkeys inoculated by the subcutaneous or i.c. route. The histopathology scores of lesions in the brain tissue of monkeys inoculated with either the E204K or E204R virus were reduced compared to those for monkeys inoculated with the reference virus, a commercial yellow fever 17D vaccine (YF-VAX). Both viruses grew to significantly lower titers than YF-VAX in HepG2, a human hepatoma cell line. After intrathoracic inoculation into mosquitoes, both viruses grew to a similar level as YF-VAX, which was significantly lower than that of their wild-type DEN1 parent virus. A comparison of the E-protein structures of nonmutant and mutant viruses suggested the appearance of new intramolecular bonds between residues 204R, 261H, and 257E in the mutant virus. These changes may be responsible for virus attenuation through a change in the pH threshold for virus envelope fusion with the host cell membrane.
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PMID:A single amino acid substitution in the envelope protein of chimeric yellow fever-dengue 1 vaccine virus reduces neurovirulence for suckling mice and viremia/viscerotropism for monkeys. 1533 33


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