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)

We examined the effect of amino acid substitutions of the GPGR (glycine-proline-glycine-arginine) tip sequence at the V3 domain of the Env protein of human immunodeficiency virus type 1 (HIV-1) on its cell tropism and coreceptor use. We changed the GPGR sequence of a T-cell line (T)- and macrophage (M)-tropic (R5-R3-X4) HIV-1 strain, GUN-1wt, to GA(alanine)GR (the resulting mutant was designated GUN-1/A), GL(leucine)GR (GUN-1/L), GP(proline)GR (GUN-1/P), GR(arginine)GR (GUN-1/R), GS(serine)GR (GUN-1/S), or GT(threonine)GR (GUN-1/T). GUN-1/A, GUN-1/S, and GUN-1/T mutants infected brain-derived cells such as a CD4-transduced glioma cell line, U87/CD4, and a brain-derived primary cell strain, BT-20/N, as well as T-cell lines in a CD4-dependent manner, although the plating of these mutants onto macrophages was inhibited. GUN-1/L, GUN-1/P, and GUN-1/R mutants showed both T- and M-tropism, but did not plate onto the brain-derived cells. A CCR3, CCR5, CCR8, or CXCR4 gene was introduced into a CD4-positive glioma cell line, NP-2/CD4, which demonstrated complete resistance to various HIV-1 strains. Not only HIV-1 strains, which were infectious to macrophages, such as GUN-1wt, GUN-1v, GUN-1/L, and GUN-1/P, but also an HIV-1 strain, GUN-1v, which was hardly infectious to macrophages, grew well in NP-2/CD4 cells expressing CCR3 or CCR5. However, the M-tropic GUN-1/R mutant could not efficiently use CCR5 nor CCR3. No point mutants, except GUN-1/L, grew well in NP-2/CD4 cells expressing CCR8. These findings indicate that the cell tropism of HIV-1 to macrophages and brain-derived cells and their use of the coreceptors were markedly, though not always concomitantly, affected by the tip sequence of the V3 domain.
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PMID:Changes in and discrepancies between cell tropisms and coreceptor uses of human immunodeficiency virus type 1 induced by single point mutations at the V3 tip of the env protein. 1038 57

Mxi1 is thought to negatively regulate Myc function and may therefore be a potential tumor suppressor gene. Little effort has yet been made to find alterations involving this gene in human solid tumors. We screened 31 human gastric cancers, 7 esophageal cancers, 85 bone and soft tissue tumors of various types, including 4 neurofibrosarcomas. We also examined 29 human tumor cell lines consisting of 12 esophageal cancers, 7 glioma/glioblastomas and 10 others for Mxi1 mutations in exons 1, 2, 4 (HLH domain), 5 and 6. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and subsequent sequencing revealed three distinct polymorphisms in the intron-exon boundary upstream from exon 6. We discovered a missense mutation, GCA to GTA (Ala 54 Val), in exon 2 in a neurofibrosarcoma patient (case 1), two missense mutations, AAA to CAA (Lys 118 Gln) and GAA to GGA (Glu 154 Gly) in exon 5 of another neurofibrosarcoma patient (case 2), and 3 amino acid substitutions, GTG to GCG (Val 179 Ala), GTT to GCT (Val 181 Ala) and TTC to CTC (Phe 186 Leu), in a third neurofibrosarcoma patient (case 3). In case 3, loss of heterozygosity was also demonstrated by informative (TTC)3/(TTC)2 polymorphism. Our data demonstrate that mutations occur in the Mxi1 gene in neurofibrosarcoma. Missense mutations in the functional domain of Mxi1 in these cases may be involved in the pathogenesis of neurofibrosarcoma.
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PMID:Mxi1 mutations in human neurofibrosarcomas. 1047 Feb 86

Investigations of D(1) receptor regulation have suggested a role for cAMP-dependent protein kinase (PKA) in agonist-induced desensitization and down-regulation of receptor expression. Given the presence of at least four possible consensus recognition sites for PKA on the D(1) receptor protein, a reasonable hypothesis is that some of these PKA-mediated effects are caused by phosphorylation of the receptor. As an initial test of this hypothesis, we used site-directed mutagenesis to create a mutant D(1) receptor with substitutions at each of its four potential PKA phosphorylation sites. The modified amino acids are as follows: Thr135 to Val, Ser229 to Ala, Thr268 to Val, and Ser380 to Ala. Characterization of the wild-type and mutant receptors stably expressed in C6 glioma cells suggests that the mutations have no effect on receptor expression, antagonist or agonist affinities, or on functional coupling with respect to cAMP generation. Similarly, dopamine preincubation of the stably transfected C6 cells expressing either the wild-type or mutated D(1) receptors results in an agonist-induced loss of ligand binding activity (down-regulation) in an identical fashion. In contrast, the time of onset of dopamine-induced desensitization is greatly attenuated in the quadruple mutant receptor. After 1 h of dopamine pretreatment, the wild-type receptor exhibits approximately 80% desensitization of the cAMP response, whereas the mutant receptor is desensitized by only approximately 20%. Further analyses of single mutated receptors, in which only one of the four putative phosphorylation sites is modified, reveals that Thr268 in the third cytoplasmic loop of the receptor protein is primarily responsible for regulating the desensitization kinetics. These results are consistent with the hypothesis that phosphorylation of the D(1) receptor on Thr268 is important for rapid agonist-induced homologous desensitization.
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PMID:Regulation of D(1) dopamine receptors with mutations of protein kinase phosphorylation sites: attenuation of the rate of agonist-induced desensitization. 1049 49

Activation of the A(2A) adenosine receptor (A(2A)AR) contributes to the neuromodulatory and neuroprotective effects of adenosine in the central nervous system. Here we demonstrate that, in rat C6 glioma cells stably expressing an epitope-tagged canine A(2A)AR, receptor phosphorylation on serine and threonine residues can be increased by pretreatment with either the synthetic protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) or endothelin 1, which increases PKC activity via binding to endogenous endothelin(A) receptors. Under conditions in which PMA was maximally effective, activation of other second messenger-regulated kinases was without effect. While basal and PMA-stimulated phosphorylation were unaffected by the A(2A)AR-selective antagonist ZM241385, they were both blocked by GF109203X (a selective inhibitor of conventional and novel PKC isoforms) and rottlerin (a PKCdelta-selective inhibitor) but not Go6976 (selective for conventional PKC isoforms). However, coexpression of the A(2A)AR with each of the alpha, betaI, and betaII isoforms of PKC increased basal and PMA-stimulated phosphorylation. Mutation of the three consensus PKC phosphorylation sites within the receptor (Thr298, Ser320, and Ser335) to Ala failed to inhibit either basal or PMA-stimulated phosphorylation. In addition, phosphorylation of the receptor was not associated with detectable changes in either its signaling capacity or cell surface expression. These observations suggest that multiple PKC isoforms can stimulate A(2A)AR phosphorylation via activation of one or more downstream kinases which then phosphorylate the receptor directly. In addition, it is likely that phosphorylation controls interactions with regulatory proteins distinct from those involved in the classical cAMP signaling pathway utilized by this receptor.
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PMID:Stimulation of A(2A) adenosine receptor phosphorylation by protein kinase C activation: evidence for regulation by multiple protein kinase C isoforms. 1055 65

1H-MR spectroscopy in vivo is often hampered by poor spectral resolution. Spectral overlap can be avoided with two-dimensional spectroscopic techniques. Correlation peak imaging has been implemented to measure unambiguously the distribution of several metabolites in a rat brain glioma model. Acquisition-weighted spectroscopic imaging reduced the experimental time and provided excellent spatial localization. The choice of an appropriate spectral acquisition window granted good sensitivity. Spectroscopic images presenting a full two-dimensional spectrum in every image pixel were acquired in seven rats at 7 Tesla in 195 min, with a nominal voxel volume of 75 microl. Among other metabolites, the distribution of hypotaurine, phosphoethanolamine, alanine, and even glucose could be visualized both in the C6-glioma and in the unaffected brain.
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PMID:2D-spatial/2D-spectral spectroscopic imaging of intracerebral gliomas in rat brain. 1068 Jun 84

The expression of the cyclin-dependent kinase inhibitor p15INK4B in normal cells after induction with TGF-beta1, or following overexpression from an adenovirus-encoded cDNA, appears on an SDS-polyacrylamide gel as a doublet. Here, the underlying mechanism behind the synthesis of the two species has been studied. By expressing cDNAs truncated at their 5' end, we found that the synthesis of the more slowly migrating form, called p15.5INK4B, is dependent on a sequence upstream of the first AUG codon thought to initiate translation of p15INK4B. Two potential, in frame, alternative upstream initiation codons, ACG and GUG, were individually changed to GCA encoding alanine. Analysis by in vitro translation, or immunoblotting of lysates from transfected 293 cells, showed that translation of p15.5INK4B is initiated at the GUG located 13 codons upstream of the first AUG. When this AUG was mutated, p15INK4B was no longer made. Instead, a shorter form, initiated at an in frame AUG located seven codons downstream, was synthesized. Finally, when both these AUGs were mutated, only p15.5INK4B was generated. Both p15INK4B and p15.5INK4B bound to CDK4 and CDK6, inhibited DNA synthesis, and caused replicative senescence of a human glioma cell line. We thus conclude that p15INK4B and p15.5INK4B, encoded by the CDKN2B gene, are functionally indistinguishable as based on these assays.
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PMID:Translation of p15.5INK4B, an N-terminally extended and fully active form of p15INK4B, is initiated from an upstream GUG codon. 1076 30

RGS proteins comprise a family of proteins named for their ability to negatively regulate heterotrimeric G protein signaling. Biochemical studies suggest that members of this protein family act as GTPase-activating proteins for certain Galpha subunits, thereby accelerating the turn-off mechanism of Galpha and terminating signaling by both Galpha and Gbetagamma subunits. In the present study, we used confocal microscopy to examine the intracellular distribution of several RGS proteins in COS-7 cells expressing RGS-green fluorescent protein (GFP) fusion proteins and in cells expressing RGS proteins endogenously. RGS2 and RGS10 accumulated in the nucleus of COS-7 cells transfected with GFP constructs of these proteins. In contrast, RGS4 and RGS16 accumulated in the cytoplasm of COS-7 transfectants. As observed in COS-7 cells, RGS4 exhibited cytoplasmic localization in mouse neuroblastoma cells, and RGS10 exhibited nuclear localization in human glioma cells. Deletion or alanine substitution of an N-terminal leucine repeat motif present in both RGS4 and RGS16, a domain identified as a nuclear export sequence in HIV Rev and other proteins, promoted nuclear localization of these proteins in COS-7 cells. In agreement with this observation, treatment of mouse neuroblastoma cells with leptomycin B to inhibit nuclear protein export by exportin1 resulted in accumulation of RGS4 in the nucleus of these cells. GFP fusions of RGS domains of RGS proteins localized in the nucleus, suggesting that nuclear localization of RGS proteins results from nuclear targeting via RGS domain sequences. RGSZ, which shares with RGS-GAIP a cysteine-rich string in its N-terminal region, localized to the Golgi complex in COS-7 cells. Deletion of the N-terminal domain of RGSZ that includes the cysteine motif promoted nuclear localization of RGSZ. None of the RGS proteins examined were localized at the plasma membrane. These results demonstrate that RGS proteins localize in the nucleus, the cytoplasm, or shuttle between the nucleus and cytoplasm as nucleo-cytoplasmic shuttle proteins. RGS proteins localize differentially within cells as a result of structural differences among these proteins that do not appear to be important determinants for their G protein-regulating activities. These findings suggest involvement of RGS proteins in more complex cellular functions than currently envisioned.
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PMID:Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs. 1079 63

It is well established that, like glycine and D-alanine, D-serine potentiates glutamate neurotransmission via the N-methyl-D-aspartate (NMDA) receptor by selective stimulation of its strychnine-insensitive glycine site and acts as a co-agonist of the glutamate receptor. D-Serine has been found to modify behavioral changes associated with higher brain functions such as memory, convulsion, anxiety, psychotomimetic-induced abnormal behavior and cerebellar ataxia. Interestingly, a substantial amount of free D-serine has been demonstrated in mammalian brains, although it has long been presumed that D-amino acids are uncommon in mammals. Free D-serine is predominantly concentrated in the brain with a persistent high content throughout life. The patterns of the regional variations and the postnatal changes in brain D-serine are closely correlated with those of the R2B subunit of the N-methyl-D-aspartate (NMDA) type excitatory amino acid receptor. Moreover, D-serine is released to the extracellular space and taken up into the brain homogenates, C6 glioma cells and primary culture of astrocytes of the rat cerebral cortex. Recently, the conversion of L-serine to its D-form by serine racemase has been suggested by in vivo and in vitro experiments. These data are consistent with the view that D-serine might be an intrinsic positive modulator of the brain NMDA receptor containing the R2B subunit and play a pivotal role in controlling behavioral expression in mammals.
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PMID:[Endogenous D-serine in mammalian brains]. 1089 22

Agonist affinity changes dramatically as a result of serine to alanine mutations (S193A, S194A, and S197A) within the fifth transmembrane region of D2 dopamine receptors and other receptors for monoamine neurotransmitters. However, agonist 2D-structure does not predict which drugs will be sensitive to which point mutations. Modeling drug-receptor interactions at the 3D level offers considerably more promise in this regard. In particular, a comparison of the same test set of agonists across receptors differing minimally (point mutations) offers promise to enhance the understanding of the structural bases for drug-receptor interactions. We have previously shown that comparative molecular field analysis (CoMFA) can be applied to comparisons of affinity at recombinant D1 and D2 dopamine receptors for the same set of agonists, a differential QSAR. Here, we predicted agonist K(L) for the same set of agonists at wild type D2 vs S193A, S194A, and S197A receptors using CoMFA. Each model used bromocriptine as the template. ln(1/K(L)) values for the low-affinity agonist binding conformation at recombinant wild type and mutant D2 dopamine receptors stably expressed in C6 glioma cells were used as the target property for the CoMFA of the 16 aligned agonist structures. The resulting CoMFA models yielded cross-validated R(2) (q(2)) values ranging from 0.835 to 0.864 and simple R(2) values ranging from 0.999 to 1.000. Predictions of test compound affinities at WT and each mutant receptor were close to measured affinity values. This finding confirmed the predictive ability of the models and their differences from one another. The results strongly support the idea that CoMFA models of the same training set of compounds applied to WT vs mutant receptors can accurately predict differences in drug affinity at each. Furthermore, in a "proof of principle", two different templates were used to derive the CoMFA model for the WT and S193A mutant receptors. Pergolide was chosen as an alternate template because it showed a significant increase in affinity as a result of the S193A mutation. In this instance both the bromocriptine- and pergolide-based CoMFA models were similar to one another but different from those for the WT receptor using bromocriptine- or pergolide- as templates. The pergolide-based S193A model was more strikingly different from that of the WT receptor than was the bromocriptine-based S193A model. This suggests that a "dual-template" approach to differential CoMFA may have special value in elucidating key differences across related receptor types and in determining important elements of the drug-receptor interaction.
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PMID:CoMFA-based prediction of agonist affinities at recombinant wild type versus serine to alanine point mutated D2 dopamine receptors. 1095 9

Apoptosis of NG108-15 neuroblastoma x glioma hybrid cells (NG108-15 cells) is induced by a morphine alkaloid derivative, buprenorphine hydrochloride (Bph). In a previous report, we used various apoptosis inhibitors to identify the "death pathway," and found that caspase inhibitors Ac-YVAD-CHO (Ac-Tyr-Val-Ala-Asp-CHO) and Ac-DEVD-CHO (Ac-Asp-Glu-Val-Asp-CHO) did not inhibit this particular apoptosis. Here, we tested Z-VAD-FMK (Z-Val-Ala-Asp[OMe]-CH2F) and Z-DEVD-FMK (Z-Asp[OMe]-Glu-[OMe]Val-Asp[OMe]-CH2F) for their ability to inhibit Bph-induced NG108-15 apoptosis. These tri- or tetra-peptide caspase inhibitors have a fluoromethyl ketone in their C-terminus instead of an aldehyde, and thus are more permeable than Ac-YVAD-CHO and AC-DEVD-CHO. Our observations of DNA ladder formation, cell morphology changes, and caspase-3 activities all indicated that these cell membrane-permeable caspase inhibitors completely inhibited the apoptosis, providing strong evidence that this apoptosis occurs through the caspase cascade "death pathway." Our previous report also showed that pretreatment of NG108-15 cells with TPCK (N-tosyl-L-phenylalanyl chloromethyl ketone) prevented DNA fragmentation and decreased the cell viability in Bph-induced apoptosis. The comparison of caspase-3 activities in Bph-induced samples with or without TPCK pretreatment revealed that caspase-3 was activated in both samples. Taken together, these results indicate that the Bph-induced apoptosis of NG108-15 cells occurs via the conventional caspase-dependent death pathway and that TPCK pretreatment results in a DNA ladder-deficient apoptosis.
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PMID:Apoptosis of NG108-15 cells induced by buprenorphine hydrochloride occurs via the caspase-3 pathway. 1096 98


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