Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rate of leucine incorporation into brain proteins was studied in rats with experimental brain tumors produced by intracerebral transplantation of the glioma clone F98. Incorporation was measured with [14C]leucine using a controlled infusion technique for maintaining constant specific activity of [14C]leucine in plasma, followed by quantitative autoradiography and biochemical tissue analysis. After 45 min the specific activity of free [14C]leucine in plasma was 2.5-3 times higher than in brain and brain tumor, indicating that the precursor pool for protein synthesis was fueled both by exogenous (plasma-derived) and endogenous (proteolysis-derived) amino acids. Endogenous recycling of amino acids amounted to 73% of total free leucine pool in brain tumors and to 60-70% in normal brain. Taking endogenous amino acid recycling into account, leucine incorporation was 78.7 +/- 16.0 nmol/g of tissue/min in brain tumor, and 17.2 +/- 4.2 and 9.7 +/- 3.3 nmol/g/min in normal frontal cortex and striatum, respectively. Leucine incorporation within tumor tissue was markedly heterogeneous, depending on the local pattern of tumor proliferation and necrosis. Our results demonstrate that quantitative measurement of leucine incorporation into brain proteins requires estimation of recycling of amino acids derived from proteolysis and, in consequence, biochemical determination of the free amino acid precursor pool in tissue samples. With the present approach such measurements are possible and provide the quantitative basis for the evaluation of therapeutic interventions.
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PMID:Biochemical and autoradiographical determination of protein synthesis in experimental brain tumors of rats. 161 98

The transport of the amino acid amide N-[3H]sarcosinamide (methyl glycinamide) was investigated in human glioma SK-MG-1 cells. Sarcosinamide uptake was found to be temperature dependent, sodium independent, and linear up to 1 min at 22 degrees C. Equilibrium was reached after 10 min at 22 degrees C with accumulation slightly above unity. Sarcosinamide was not metabolized in the cells as shown by thin layer chromatography. The uptake of sarcosinamide was significantly decreased when the extracellular pH was lowered from 7.5 to 6.0 and significantly enhanced at pH values above 7.5. The latter effect may be due mainly to increased cell permeability at high pH. The uptake of the labeled sarcosinamide was trans-stimulated by excess cold sarcosinamide. Sarcosinamide uptake over a 200-fold range of concentrations followed Michaelis-Menten kinetics with a Km of 0.284 +/- 0.041 mM and a Vmax of 0.154 +/- 0.024 nmol/10(6) cells/min. The uptake of sarcosinamide was significantly reduced by iodoacetate but not by the metabolic poisons NaF, ouabain, or dinitrophenyl, suggesting that the uptake is not dependent on energy, rather it proceeds by facilitated diffusion. Several naturally occurring substrates were unable to inhibit the uptake of sarcosinamide. Leucine significantly reduced the uptake of sarcosinamide, while sarcosinamide was a weak inhibitor of leucine transport. 2-Aminobicyclo[2,2,1]heptane-2-carboxylic acid a specific substrate for the sodium-independent, 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid-sensitive amino acid system L failed to inhibit the uptake of sarcosinamide. Epinephrine reduced the uptake of sarcosinamide and sarcosinamide was equally potent as an inhibitor of epinephrine transport. Dixon plot analysis demonstrated that epinephrine (Km = 0.270 mM) inhibits the uptake of sarcosinamide competitively (Ki = 0.260 mM). These results indicate that sarcosinamide is a substrate for the catecholamine transporter. The alkylating agent, sarcosinamide chloroethylnitrosourea, was tested for its ability to inhibit the uptake of sarcosinamide. The results of Dixon plot analysis were consistent with competitive inhibition of sarcosinamide uptake and the inhibition constant Ki for SarCNU was found to be 3.26 +/- 0.57 mM. The steady-state intracellular concentration of SarCNU was found to be significantly higher (cell:medium ratio of 1.03 +/- 0.01) than that of BCNU cell:medium ratio of 0.52 +/- 0.12). These findings indicate that SarCNU and sarcosinamide share the same carrier for uptake in SK-MG-1 cells. This transport mechanism may be responsible for the increased accumulation of SarCNU as compared to BCNU, a nitrosourea which enters cells by passive diffusion.
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PMID:Transport of amino acid amide sarcosinamide and sarcosinamide chloroethylnitrosourea in human glioma SK-MG-1 cells. 169 54

Leucine-enkephalin, methionine-enkephalin, and morphine caused a reversible block of Ca2+ channel currents in neuroblastoma-glioma hybrid cells (NG108-15). The long-lasting (type 2) component of the Ca2+ channel current was blocked by leucine-enkephalin, while the transient (type 1) component was not affected. The enkephalin-induced blocking action was antagonized by naloxone and appears to be mediated by delta-opiate receptors. Two different aspects of the blocking effect were detected, a resting block and a recovery from block during prolonged depolarizing pulses. Recovery from block was more complete, and its time course was more rapid, with depolarization to more positive potentials. The dose dependence of the type 2 channel block at rest indicated a one-to-one binding stoichiometry, with an apparent dissociation constant of 8.8 nM. Somatostatin exerted a similar selective blocking action on the type 2 Ca2+ channel. The time- and voltage-dependent block of type 2 Ca2+ channels may provide a mechanism underlying the enkephalinergic presynaptic inhibition of transmitter release and the somatostatin block of pituitary growth hormone release.
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PMID:Block of calcium channels by enkephalin and somatostatin in neuroblastoma-glioma hybrid NG108-15 cells. 243 4

The mechanism of isoproterenol and N6,O2'-dibutyryl adenosine 3':5'-monophosphate (dibutyryl cAMP) induction of lactate dehydrogenase (EC 1.1.1.27) was investigated in the C6 rat glioma cell line. [3H]Leucine-labeled lactate dehydrogenase in noninduced and induced cells was quantitatively immunoprecipitated with rabbit anti-rat lactate dehydrogenase-5 antiserum. The immunoprecipitates were analyzed for 3H-labeled lactate dehydrogenase by electrophoresis on sodium dodecyl sulfate-polyacrylamide gels and isoelectrofocusing. Using this technique, it was shown that isoproterenol + 3-isobutyl-1-methylxanthine and dibutyryl cAMP cause an increase of the [3H]leucine incorporation into glioma cell lactate dehydrogenase. Analysis of the kinetics of induction and deinduction revealed no change in the rate of degradation of lactate dehydrogenase in the presence and absence of inducing agent, indicating that the induction was due to an increase in the rate of synthesis of the enzyme. The increased rate of synthesis was prevented by actinomycin D. Isoproterenol + 3-isobutyl-1-methylxanthine increased only the specific rate of synthesis of lactate dehydrogenase-5 isozyme and of the M subunit. The mechanism was further studied by assaying the level of functional mRNA coding for lactate dehydrogenase in a reticulocyte cell-free protein-synthesizing system using glioma cell poly(A)-containing RNA isolated from either isoproterenol or dibutyryl cAMP-induced cells. Analysis of the immunoprecipitated translation product by isoelectrofocusing revealed that isoproterenol or dibutyryl cAMP produced an approximately 8-fold stimulation of the poly(A) + RNA-directed synthesis of the lactate dehydrogenase M subunit. These data demonstrate that isoproterenol and dibutyryl cAMP control the level of functionally active lactate dehydrogenase mRNA in glioma cells which, in turn, determines the extent of synthesis of the lactate dehydrogenase M subunit.
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PMID:Cyclic AMP regulation of lactate dehydrogenase. Isoproterenol and N6,O2'-dibutyryl cyclic AMP increase the levels of lactate dehydrogenase-5 isozyme and its messenger RNA in rat C6 glioma cells. 616 Jan 45

Loss of heterozygosity for 10q23-26 is seen in over 80% of glioblastoma multiforme tumors. We have used a positional cloning strategy to isolate a novel gene, LGI1 (Leucine-rich gene-Glioma Inactivated), which is rearranged as a result of the t(10;19)(q24;q13) balanced translocation in the T98G glioblastoma cell line lacking any normal chromosome 10. Rearrangement of the LGI1 gene was also detected in the A172 glioblastoma cell line and several glioblastoma tumors. These rearrangements lead to a complete absence of LGI1 expression in glioblastoma cells. The LGI1 gene encodes a protein with a calculated molecular mass of 60 kD and contains 3.5 leucine-rich repeats (LRR) with conserved flanking sequences. In the LRR domain, LGI1 has the highest homology with a number of transmembrane and extracellular proteins which function as receptors and adhesion proteins. LGI1 is predominantly expressed in neural tissues, especially in brain; its expression is reduced in low grade brain tumors and it is significantly reduced or absent in malignant gliomas. Its localization to the 10q24 region, and rearrangements or inactivation in malignant brain tumors, suggest that LGI1 is a candidate tumor suppressor gene involved in progression of glial tumors.
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PMID:A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. 987 93

Autosomal dominant lateral temporal lobe epilepsy previously has been linked to chromosome 10q22-q24, and recently mutations in the LGI1 gene (Leucine-rich gene, Glioma Inactivated) have been found in some autosomal dominant lateral temporal lobe epilepsy families. We have now identified a missense mutation affecting a conserved cysteine residue in the extracellular region of the LGI1 protein. The C46R mutation is associated with autosomal dominant lateral temporal lobe epilepsy in a large Norwegian family showing unusual clinical features like short-lasting sensory aphasia and auditory symptoms.
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PMID:LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures. 1220 52

The Leucine-rich Glioma Inactivated-1 (LGI1) gene is supposed to be a tumor suppressor gene involved in glial tumors. Mutations in this gene were recently found to cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). We have now analysed the comorbidity in a large Norwegian ADLTE family. No evidence was found that LGI1 is a high-penetrance tumor suppressor gene associated with a serious risk for malignancies in ADLTE families.
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PMID:No evidence for a seriously increased malignancy risk in LGI1-caused epilepsy. 1464 4

Leucine-rich glioma inactivated 3 (LGI3) is a member of LGI/epitempin family of which the first member, LGI1/epitempin, was shown to be mutated in glioma and autosomal dominant lateral temporal epilepsy. Similar to LGI1, LGI3 is expressed predominantly in brain and its function is unknown. In this study, we examined the expression of mouse LGI3 (mLGI3) in adult and developing brain and analyzed the 5'-upstream transcriptional regulatory regions of mLGI3 gene. In situ hybridization showed that mLGI3 was expressed in widespread areas with selective regional variation in adult brain. In developing brain, mLGI3 mRNA was expressed at low level during embryo stages and markedly increased in broad areas after birth. Analysis of the 5'- and 3'-ends of mLGI3 mRNA identified a single transcription start site and two alternative 3'-ends. Luciferase reporter analysis using Neuro-2a cells and electrophoretic mobility shift assays identified a neuronal restrictive silencer element (NRSE; -2573 approximately -2553) and a phorbol ester-sensitive AP-2 element with repressor activity (-44 approximately -33) among multiple positive and negative regulatory regions. Since NRSE and AP-2 are implicated in neuron-specific gene expression and developmental regulation of many genes in brain, respectively, these results suggested that NRSE and AP-2 might play important roles in regulation of mLGI3 expression in brain.
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PMID:Mouse LGI3 gene: expression in brain and promoter analysis. 1654 24

Leucine-rich repeat C4 (LRRC4) has been shown to inhibit glioma cell proliferation, however, little is known about the mechanism(s) underlying the action of LRRC4. Here, we show that two glioblstoma U251 cell clones stably expressing LRRC4 were established. LRRC4 expression significantly inhibited the expression of some cytokines and their receptors determined by microarray and Western blot assays, and dramatically reduced cytokine-induced AP-1, NF-kB, and CyclinD1 activation in glioma cells. Furthermore, LRRC4 expression in glioma cells significantly downregulated spontaneous and cytokine-induced expression of K-RAS and phosphorylation of c-Raf, ERK, AKT, NF-kBp65, p70S6K, and PKC, suggesting that LRRC4 inhibited receptor tyrosine kinase (RTK) signaling pathways. Moreover, treatment with bFGF, IGF1, or IGF2 stimulated LRRC4(-/-), but not the LRRC4(+), glioma cell proliferation, indicating that LRRC4 mitigated cytokine-stimulated proliferation in glioma cells. In addition, treatment of LRRC4(-/-) glioma cells with EGF, IGF2, or PDGF promoted long distance mobilization, but induced little migration in LRRC4(+) glioma cells, suggesting that LRRC4 retarded cytokine-promoted glioma cell migration in vitro. Finally, human vessel endothelial cells (ECV304) treated with VEGF grew, aligned and formed hollow tube-like structures in vitro. In contrast, LRRC4(+) ECV304 treated with VEGF failed to form vessel-tube structures. Collectively, LRRC4 expression inhibited the expression of some growth factors, cytokines and their receptors, and the capacity of glioma cells responding to cytokine stimulation, leading to inhibition of glioma cell proliferation. Conceivably, induction of LRRC4 expression may provide new intervention for human glioma in the clinic.
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PMID:LRRC4 inhibits glioblastoma cell proliferation, migration, and angiogenesis by downregulating pleiotropic cytokine expression and responses. 1754 39

Gliomas take a number of different genetic routes in the progression to glioblastoma multiforme, a highly invasive variant that is mostly unresponsive to current therapies. The alpha-chemokine stromal cell-derived factor (SDF)-1 alpha binds to the seven transmembrane G-protein-coupled CXCR-4 receptor and acts to modulate cell migration and proliferation by activating multiple signal transduction pathways. Leucine-rich repeats containing 4 (LRRC4), a putative glioma suppressive gene, inhibits glioblastoma cells tumorigenesis in vivo and cell proliferation and invasion in vitro. We also previously demonstrated that LRRC4 controlled glioblastoma cells proliferation by ERK/AKT/NF-kappa B signaling pathway. In the present study, we demonstrate that CXC chemokine receptor 4 (CXCR4) is expressed in human glioblastoma U251 cell line, and that SDF-1 alpha increases the proliferation, chemotaxis, and invasion in CXCR4+ glioblastoma U251 cells through the activation of ERK1/2 and Akt. The reintroduction of LRRC4 in U251 cells inhibits the expression of CXCR4 and SDF-1 alpha/CXCR4 axis-mediated downstream intracellular pathways such as ERK1/2 and Akt leading to proliferate, chemotactic and invasive effects. Furthermore, we provide evidence for proMMP-2 activation involvement in the SDF-1 alpha/CXCR4 axis-mediated signaling pathway. LRRC4 significantly inhibits proMMP-2 activation by SDF-1 alpha/CXCR4 axis-mediated ERK1/2 and Akt signaling pathway. Collectively, these results suggest a possible important "cross-talk" between LRRC4 and SDF-1 alpha/CXCR4 axis-mediated intracellular pathways that can link signals of cell proliferation, chemotaxis and invasion in glioblastoma, and may represent a new target for development of new therapeutic strategies in glioma.
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PMID:LRRC4 inhibits human glioblastoma cells proliferation, invasion, and proMMP-2 activation by reducing SDF-1 alpha/CXCR4-mediated ERK1/2 and Akt signaling pathways. 1754 98


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