Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the acute phase response to bacterial endotoxin in rats, hepatic levels of cytochrome P450IIC12 [AH, reduced flavoprotein:oxygen oxidoreductase (RH hydroxylating), EC 1.14.14.1] (P450IIC12) apoenzyme and mRNA are suppressed. We set out to determine the effects of potential humoral mediators of inflammation on the expression of P450IIC12 in female rats. A single injection of 12,000 or 60,000 units of interleukin-1 alpha had no effect on total cytochrome P450 content or P450IIC12 mRNA measured 12 hr later, although P450IIC12 apoenzyme was slightly but significantly increased by the higher dose. In the second experiment, animals were given dexamethasone (100 micrograms/kg at -30 min), interleukin-1 alpha (30,000 units/kg at 0, 2, and 4 hr), or both and were sacrificed at 12 hr. Treatment with interleukin-1 alpha alone significantly suppressed total cytochrome P450, P450IIC12 apoenzyme, and P450IIC12 mRNA to 77, 53, and 65% of control levels, respectively; beta-actin mRNA was significantly increased (206% of control levels). Treatment with dexamethasone alone suppressed total cytochrome P450 and P450IIC12 mRNA (73% of controls) but did not significantly affect P450IIC12 apoenzyme measured 12.5 hr later. Again, beta-actin mRNA was increased. When both interleukin-1 alpha and dexamethasone were given, total cytochrome P450 and P450IIC12 mRNA (43% of controls) were suppressed, and beta-actin mRNA was significantly increased. In the third experiment, animals were injected at 0 and 12 hr with dexamethasone (83 micrograms/kg), interleukin-6 (33 micrograms/kg), or both. Interleukin-6 alone did not significantly affect total cytochrome P450 or P450IIC12 apoenzyme or mRNA. Dexamethasone alone suppressed P450IIC12 apoenzyme and mRNA (to 52 and 41%, respectively, of controls). Treatment with both interleukin-6 and dexamethasone significantly suppressed total cytochrome P450 and P450IIC12 apoenzyme and mRNA; suppression of P450IIC12 mRNA (to 16% of controls) was greater than with dexamethasone alone. No change in the transcription rate of CYP2C12 was observed 24 hr after initiation of treatment with dexamethasone (83 micrograms/kg at 0 and 12 hr) or 12 hr after initiation of treatment with interleukin-1 alpha (30,000 units/kg at 0, 2, and 4 hr). We conclude that, in this model, interleukin-1 alpha and glucocorticoids are important mediators of the suppression of hepatic P450IIC12 expression during inflammation. Interleukin-6 was not as potent, but it did potentiate the effects of dexamethasone. Suppression of P450IIC12 expression by dexamethasone and interleukin-1 alpha appeared to be mediated at a pretranslational level, but the possibility of a transcriptional effect needs to be further investigated.
Mol Pharmacol 1991 Apr
PMID:Regulation of cytochrome P450IIC12 expression by interleukin-1 alpha, interleukin-6, and dexamethasone. 201 47

We have developed a limiting dilution clonal assay for determining the frequency of 6-thioguanine-resistant (TGr) lymphocytes produced in rats by in vivo exposure to genotoxic agents. Spleen lymphocytes were isolated from female Fischer 344 rats and were cultured with 1 microgram/ml of phytohemagglutinin (PHA) for 40 hr. Northern blot analysis revealed that this procedure resulted in increased hprt and beta-actin mRNA synthesis. Conditions for optimum cloning were established by culturing four PHA-primed lymphocytes/well in 96-well round-bottom microtiter plates containing a medium supplemented with interleukin-2. These cultures also contained autologous and/or TK6 feeder cells inactivated with different doses of irradiation. Lymphocyte cloning efficiencies (CEs) were highest in plates containing both irradiated TK6 cells (5 x 10(3) cells/well; 90 Gy) and irradiated autologous feeder cells (5 x 10(4) cells/well; 50 Gy). CE did not depend on the number of primed lymphocytes/well when four or fewer target cells/well were cloned. To measure the effects of chemical mutagens on the frequency of TGr lymphocytes, rats were given a single i.p. injection of 0-150 mg/kg of N-ethyl-N-nitrosourea (ENU), a direct-acting alkylating agent, or 0-50 mg/kg of cyclophosphamide (CP), an indirect acting alkylating agent. Lymphocytes were isolated, primed, and cloned at 4 weeks after CP treatment and at 1, 2, 4 and 6 weeks after ENU treatment. CE in these cultures ranged from 12% to 27%. Cultures were also established for measuring CE in the presence of 6-thioguanine (TG) and these contained 5 x 10(3) irradiated TK6 cells and 5 x 10(4) primed rat lymphocytes/well. The frequency of TGr lymphocytes was calculated by correcting the CE in the presence of TG with the CE measured in its absence. ENU exposure produced a higher frequency of TGr lymphocytes than CP, but both chemicals produced a dose-dependent increase in TGr cells. In addition, the frequency of ENU-induced TGr lymphocytes increased with time after treatment. The TGr cells are presumed to be hprt mutants, but further analysis at the DNA level is required to establish this. The dose-dependent responses obtained with both ENU and CP treatments suggest that rat lymphocytes are sensitive to direct- and indirect-acting alkylating agents administered in vivo and that the rat lymphocyte assay is a useful complement to the in vivo/in vitro mouse assay for determining the mutagenicity of environmental toxicants.
Environ Mol Mutagen 1991
PMID:Induction of 6-thioguanine-resistant lymphocytes in Fischer 344 rats following in vivo exposure to N-ethyl-N-nitrosourea and cyclophosphamide. 202 92

We report that the concentration of phosphoenolpyruvate carboxykinase (PEPCK) mRNA increased 5- to 10-fold when H4IIEC3 rat hepatoma cells were cultured at high compared to low density. The magnitude and direction of this response were mRNA specific, as the mRNAs encoding tyrosine aminotransferase and albumin increased approximately 20%, whereas the mRNAs encoding beta-actin and alpha-tubulin decreased 40% and 20%, respectively. Paracrine or autocrine mechanisms were not responsible for the density effect, since conditioned medium or frequent medium changes had only a modest effect on the abundance of PEPCK mRNA. Culture of H4IIEC3 cells at low density or on collagen promoted a flattened morphology and low PEPCK mRNA levels. At high density, cells assumed a cuboidal shape on both plastic and collagen and expressed high PEPCK mRNA levels. Induction of PEPCK mRNA by high density culture did not involve increased intracellular cAMP, since treatment with 8-(4-chlorophenylthio)-cAMP was synergistic with density. High cell density increased PEPCK run-on transcription approximately 3-fold, while PEPCK mRNA increased more than 6-fold. These observations suggest that high culture density increases PEPCK mRNA by increasing its transcription and possibly stabilizing PEPCK mRNA. The response could be coupled to the regulation of cell shape, as a close relationship between cell shape and gene expression has previously been shown to be important in the development and maintenance of tissues and organs. The PEPCK gene in H4IIEC3 cells could provide a useful model in which to study the poorly understood mechanisms involved in coordinating form and function.
Mol Endocrinol 1991 May
PMID:Culture at high density increases phosphoenolpyruvate carboxykinase messenger RNA in H4IIEC3 hepatoma cells. 207 26

Although it is generally accepted that actin and myosin isoforms adapt to their functional requirements, the sequence of expression of these proteins in hearts developing abnormally is unknown. In the chick embryo it is possible to change various aspects of heart development without direct manipulation of the cardiovascular system, by removing various regions of the neural crest from early embryos. The neural crest provides both neural (sympathetic and parasympathetic) and ectomesenchymal components to the heart, and selective removal of various areas results in embryos with sympathetically aneural hearts, or persistent truncus arteriosus with or without parasympathetic denervation. Myosin isoform expression was studied in each of these types of hearts using an array of myosin antibodies specific for atrium, ventricle or the conduction system. Myosin expression in experimental hearts was found to follow the normal pattern of development using these antibodies. Actin expression was studied using cDNA probes for the 3' untranslated region of actin mRNA of the alpha-skeletal, alpha-cardiac and beta-actin isoforms. Using slot-blot hybridization analysis, the pattern of actin expression in atrium and ventricle was followed throughout the period of incubation in normal hearts. The pattern of actin expression was found to be abnormal in hearts which were sympathetically aneural and those which had persistent truncus arteriosus combined with parasympathetic denervation. ATPase activity was increased only in atria of hearts with persistent truncus arteriosus. It appears from these experiments that actin isoform expression is influenced in the chick heart by autonomic innervation.
J Mol Cell Cardiol 1990 Sep
PMID:Actin and myosin isoforms in aneural and malformed chick hearts. 214 50

4-Aminopyrazolopyrimidine (4-APP) treatments to rats for 3 days induced 2-fold increase of circulating ACTH and 11-fold increase of adrenal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA compared to NaCl-treated controls. This in vivo model was used to study the effect of the suppression of ACTH secretion on the adrenal HMG-CoA reductase mRNA level. Dexamethasone (Dex) administration to 4-APP-treated rats caused a rapid and parallel decline of the levels of plasma ACTH and adrenal HMG-CoA reductase mRNA to 50% within 2.5 h, whereas the free and esterified cholesterol content was increased 5 and 9.4 times respectively. These changes could be counteracted by the co-administration of ACTH with Dex. Aminoglutethimide (AG) administration to 4-APP-treated rats, which increased the adrenal esterified cholesterol content (7.5 times), decreased the HMG-CoA reductase mRNA level (44%), despite plasma ACTH level remaining elevated. Moreover, the participation of newly synthesized protein(s) in the lowering of adrenal HMG-CoA reductase mRNA level induced by ACTH suppression is suggested by the fact that cycloheximide (Cyclo), when co-administered with AG, completely blocked the decrease of HMG-CoA reductase mRNA level, despite the plasma ACTH level decreasing by 68% and the free and esterified cholesterol content increasing 3.9 and 12.3 times, compared to 4-APP-treated rats. Furthermore, the specificity of these effects was established by the fact that the beta-actin mRNA level was not affected by the administration of either Dex, AG, Cyclo, or AG + Cyclo to 4-APP-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1990 Feb 12
PMID:Effect of ACTH suppression on adrenal 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA in 4-aminopyrazolopyrimidine-treated rats. 215 16

Phospholipase C activity is necessary for transcriptional c-fos activation by providing diacylglycerol as an activator of protein kinase C. We found that transcriptional activation of c-fos and the phosphorylation of its major transcription factor were inhibited by tricyclodecan-9-yl xanthogenate, which blocks phospholipase C-type reactions. Transcription of the c-ras and beta-actin genes in the same cells remained unaffected.
Mol Cell Biol 1990 Oct
PMID:Inhibition of c-fos transcription and phosphorylation of the serum response factor by an inhibitor of phospholipase C-type reactions. 216 25

Following destruction of entorhinal cortical (EC) input to the dentate gyrus there is an increase in protein synthesis within the denervated dendritic laminae. The present study utilized in situ hybridization to determine whether there were increases in the messenger RNAs (mRNAs) for beta-actin and beta-tubulin within the denervated neuropil of the dentate gyrus during the time of increased protein synthesis. Animals were prepared for in situ hybridization 2-21 days after a unilateral lesion of the EC. Brain sections were hybridized with either 3H or 35S-labeled riboprobes prepared from chick beta-actin and chick beta-tubulin mRNA. Analysis of light microscopic autoradiograms revealed increases in the mRNAs for beta-actin and beta-tubulin within the denervated neuropil between 6 and 8 days postlesion when compared to the intact dentate gyrus of the contralateral side. Labeling over the granule cell body layer was comparable on the two sides for both probes. Increases in both mRNAs were also observed in the scar tissue at the lesion site. These results suggest that local protein synthesis within the denervated neuropil of the dentate gyrus involves, in part, an increase in the production of actin and tubulin.
Brain Res Mol Brain Res 1990 Aug
PMID:Increases in mRNA for cytoskeletal proteins in the denervated neuropil of the dentate gyrus: an in situ hybridization study using riboprobes for beta-actin and beta-tubulin. 217 Aug 3

Calbindin-D28k (CaBP28k) protein and gene expression were examined in the mouse cerebellum during development and aging utilizing slot and Northern blot hybridization analyses for mRNA levels, Western blot analysis and radioimmunoassay (RIA) for protein levels, and by in situ studies using immunocytochemistry and hybridization cytochemistry on prepared tissue sections. Samples were obtained and analyzed from C57BL/6J mice aged day of birth and postnatal weeks 1, 2, 4, 8, and 120. A specific cDNA and antibody for CaBP28k were utilized in these studies. Analysis of mRNA levels showed a steady rise in CaBP28k mRNA from birth to a peak at postnatal week (3.4-fold increase) and then a decline to steady-state levels at postnatal weeks 4 and 8 (47% reduction of peak level) followed by a reduction of CaBP28k mRNA to birth levels at postnatal week 120. The specificity of the changes observed was tested by reprobing blots with beta-actin cDNA. Analysis of CaBP28k protein levels by both Western blot and RIA showed a similar pattern. In situ analysis of CaBP28k mRNA levels, based on hybridization signal (silver grains per cell), demonstrated a rise in cellular CaBP28k mRNA levels which peaked at postnatal week 2 (416.9 +/- 52.1) and then declined to steady-state levels by postnatal weeks 4 and 8 (267.4 +/- 35.8). Cellular CaBP28k mRNA levels exhibited a dramatic reduction in the aged cerebellum (postnatal week 120; 78.3 +/- 16.0). The levels of cellular CaBP28k mRNA corresponded to the intensity of immunoreactive CaBP28k localized by immunocytochemistry. The results are consistent with the hypothesis that CaBP28k may play a critical role in Purkinje cell maturation and maintenance.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1990 Oct
PMID:Calcium binding protein (calbindin-D28k) gene expression in the developing and aging mouse cerebellum. 217 7

The levels of hepatic mRNAs for several enzymes involved in drug metabolism were measured following administration to rats of either phenobarbitone or 2-allyl-2-isopropylacetamide. There was a substantial elevation in the mRNA levels for cytochromes P450 IIB1, IIB2, and IIIA1, epoxide hydrolase, glutathione-S-transferase Ya/Yc subunit, UDP-glucuronosyltransferase isoenzyme (UDPGTr-2), NADPH-cytochrome P450 oxidoreductase, and 5-aminolevulinate synthase. When rats were treated with hemin, together with inducing drug, there was a marked reduction in the induced levels of these mRNAs, with decreases in the range of 55-95%. Basal levels of these mRNAs in the noninduced rat liver were also lowered by hemin administration. Nuclear run-on transcriptional experiments showed that hemin administration substantially lowered both the basal and drug-induced transcriptional activities of the genes for cytochrome P450IIB1/IIB2 and 5-aminolevulinate synthase. In contrast, the mRNA for heme oxygenase was elevated by hemin treatment, whereas the mRNA levels of beta-actin, albumin, and ornithine transcarbamylase, used as controls, were not affected. Treatment of rats with clofibrate resulted in increased levels of mRNA for cytochrome IVA1 and, in addition, those for cytochromes P450IIB1 and P450IIB2. Hemin administration repressed the induction of mRNA levels for cytochromes P450IIB1 and IIB2 but not that for cytochrome P450 IVA1. Additionally, the induction of P450IAI by beta-naphthoflavone was not affected by hemin. The results suggest that heme may negatively control the induction of cytochromes P450IIB1 and IIB2 and other hepatic enzymes by phenobarbitone and phenobarbitone-like drugs and perhaps play a role in regulating drug metabolism. There is, however, no evidence at present as to whether heme has a direct role in such a mechanism or whether injected hemin promotes a secondary response.
Mol Pharmacol 1990 Oct
PMID:Hemin administration to rats reduces levels of hepatic mRNAs for phenobarbitone-inducible enzymes. 223 90

To elucidate how the neuropeptide Y (NPY) gene is regulated by physiological/pharmacological changes in neural functions, the expression and regulation of the NPY gene were studied by measuring changes in the abundances of NPY and NPY mRNA in the adrenal gland and brain regions of rats in vivo and in PC12 rat pheochromocytoma cells after reserpine treatment. Long term treatment with reserpine in vivo, which causes hypotension and increased splanchnic nerve activity, induced prolonged increases in the abundance of NPY mRNA and putative NPY pre-mRNA, with concomitant increases in NPY, in the adrenal gland in a tissue-dependent manner but caused no changes in the abundance of beta-actin mRNA. Transection of the splanchnic nerves almost completely (76%) prevented the reserpine-induced increases in the abundance of NPY mRNA and NPY pre-mRNA, but denervation alone did not affect their steady state levels. These results suggested that increased activity of the splanchnic nerves regulates NPY gene expression positively in the adrenal gland, probably at the level of transcription. In PC12 cells, reserpine decreased the abundance of NPY mRNA directly, but nicotinic receptor activation increased its abundance transiently and the persistent membrane depolarization increased its abundance markedly. Thus, NPY gene expression is positively regulated by membrane depolarization via increased transsynaptic activation with reserpine.
Mol Pharmacol 1990 Nov
PMID:Long lasting increase in neuropeptide Y gene expression in rat adrenal gland with reserpine treatment: positive regulation of transsynaptic activation and membrane depolarization. 223 98


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