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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Guanine ribonucleosides substituted at the 8 position of the guanine ring are a unique class of immunomodulators, the lead compound of which is 7-allyl-8-oxoguanosine (loxoribine). We conducted a double-blind randomized phase I study to evaluate the safety, pharmacokinetics, and immunologic effects of single ascending doses of loxoribine in patients with advanced cancer. Twenty-four patients were treated in three dose tiers of 8 patients each, utilizing a unique statistical design, so that within each group, patients were randomized in blocks of 4 to receive loxoribine initially and then placebo 4 weeks later--a sequence that was reversed in the remaining 4 patients. In 23 courses of loxoribine and 20 courses of placebo, toxicity was mild and infrequent at all dose tiers (1 mg/kg, 5 mg/kg and 10 mg/kg. Both antibody-dependent cellular cytotoxicity and lymphokine-activated killer cytotoxicity were transiently depressed following loxoribine administration at all doses. Loxoribine is safe at doses up to 10 mg/kg in patients with advanced cancer, and produces modest immunologic effects. Further testing, particularly in conjunction with other immunologic agents, is warranted.
Cytokines Cell Mol Ther 2000 Dec
PMID:Phase 1, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer. 1156 55

We show using PCR that psbC, atpA and petB genes are present in the plastid DNA minicircles from the dinoflagellate Amphidinium operculatum, extending the set of plastid genes identified from this organism. Unusually, the petBand atpA genes are located on the same minicircle. PCR using primers based on the "core" region found on all coding minicircles revealed the existence of a number of DNA minicircles with no apparent coding function. Northern analysis of total RNA from A. operculatum showed that the petB and atpA genes are represented on separate transcripts, despite being encoded in close proximity on the same minicircle. The possibility of transcript editing was investigated by RT-PCR, but psaA, psbA, psbB and atpB transcripts showed no evidence of editing, indicating that GUA can be used as an initiation codon in A. operculatum.
Mol Genet Genomics 2001 Dec
PMID:Organisation and expression of the plastid genome of the dinoflagellate Amphidinium operculatum. 1181 Feb 35

Crosslinking of mRNA analog, dodecaribonucleotide pUUAGUAUUUAUU derivative carrying a perfluoroarylazido group at the guanine N7, was studied in model complexes with 80S ribosomes involving tRNA and in binary complex (i.e., in the absence of tRNA). It was shown that, irrespectively of complex formation conditions (13 mM Mg2+, or 4 mM Mg2+ in the presence of polyamines), the mRNA analog in binary complex with 80S ribosomes was crosslinked with sequence 1840-1849 of 18S rRNA, but in the complexes formed with participation of Phe-TPHKPhe (where the G residue carrying the arylazido group occupied position-3 to the first nucleotide of the UUU codon at the P site) the analog was crosslinked with nucleotide 1207. The presence and the nature of tRNA at the E site had no effect on the environment of position-3 of the mRNA analog. Efficient crosslinking of the mRNA analog with tRNA was observed in all studied types of complex. Modified codon GUA, when located at the E site, underwent crosslinking with both cognate valine tRNA and noncognate aspartate tRNA for which the extent of binding at the E site of 80S ribosomes was almost the same and depended little on Mg2+ concentration and the presence of polyamines.
Mol Biol (Mosk)
PMID:[Crosslinking of mRNA analog, pUUAGUAUUUAUU derivative with a photoactivated group at the guanosine residue, with human 80S ribosomes]. 1186 1

A large number of cytoplasmic tRNAs are imported into the kinetoplast-mitochondrion of Leishmania by a receptor-mediated process. To identify the sequences recognized by import receptors, mitochondria were incubated with a combinatorial RNA library. Repeated cycles of amplification of the imported sequences (SELEX) resulted in rapid selection of several import aptamers containing sequence motifs present in the anticodon arm, the D arm, the V-T region, and acceptor stem of known tRNAs, confirming or suggesting the presence of import signals in these domains. As predicted, truncated derivatives of tRNA(Ile)(UAU) containing the D arm or the V-T region were imported in vitro. Four aptamers were studied in detail. All were imported in vitro as well as in transiently transfected cells, using the same pathway as tRNA, but their individual import efficiencies were different. Two types of aptamers were discernible: the A arm and D arm homologues (type I), which were efficiently transferred across the inner mitochondrial membrane, and the V-T homologues (type II), which were not. Remarkably, subnanomolar concentrations of type I RNAs stimulated the entry of type II RNAs into the matrix, whereas type II RNAs inhibited inner membrane transfer of type I RNAs. Moreover, tRNA(Tyr)(GUA) and tRNA(Ile)(UAU) interacted with one another as type I and type II, respectively. Such cooperative and antagonistic interactions may allow the use of a limited number of receptors to recognize a large number of tRNAs of variable affinity and enable the maintenance of a properly balanced tRNA pool for mitochondrial translation.
Mol Cell Biol 2002 Jun
PMID:Mitochondrial RNA import in Leishmania tropica: aptamers homologous to multiple tRNA domains that interact cooperatively or antagonistically at the inner membrane. 1202 47

GTPases of the Ras subfamily regulate a diverse array of cellular-signaling pathways, coupling extracellular signals to the intracellular response machinery. Guanine nucleotide exchange factors (GEFs) are primarily responsible for linking cell-surface receptors to Ras protein activation. They do this by catalyzing the dissociation of GDP from the inactive Ras proteins. GTP can then bind and induce a conformational change that permits interaction with downstream effectors. Over the past 5 years, approximately 20 novel Ras-family GEFs have been identified and characterized. These data indicate that a variety of different signaling mechanisms can be induced to activate Ras, enabling tyrosine kinases, G-protein-coupled receptors, adhesion molecules, second messengers, and various protein-interaction modules to relocate and/or activate GEFs and elevate intracellular Ras-GTP levels. This review discusses the structure and function of the catalytic or CDC25 homology domain common to almost all Ras-family GEFs. It also details our current knowledge about the regulation and function of this rapidly growing family of enzymes that include Sos1 and 2, GRF1 and 2, CalDAG-GEF/GRP1-4, C3G, cAMP-GEF/Epac 1 and 2, PDZ-GEFs, MR-GEF, RalGDS family members, RalGPS, BCAR3, Smg GDS, and phospholipase C(epsilon).
Prog Nucleic Acid Res Mol Biol 2002
PMID:A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases. 1210 58

1) In the rat pituitary, angiotensin type 1B receptors (AT1B) are located in lactotrophs and corticotrophs. 2) Activation of AT1B receptors are coupled to Gq/11 (Guanine protein coupled receptor, or GPCR); they increase phospholipase beta C (PLC) activity resulting in inositol 1,4,5 triphosphate (InsP3) and diacylglycerol (DAG) formation. A biphasic increase in [Ca2+]i triggered by InsP3 and DAG ensues. 3) As many GPCRs, AT1B pituitary receptors rapidly desensitize. 4) This was observed in the generation of InsP3, the mobilization of intracellular Ca(2+), and in prolactin release. Both homologous and heterologous desensitization was evidenced. 5) Desensitization of the angiotensin II type 1 (AT1) receptor in the pituitary shares similarities and differences with endogenously expressed or transfected AT1 receptors in different cell types. 6) In the pituitary hyperplasia generated by chronic estrogen treatment there was desensitization or alteration in angiotensin II (Ang II) evoked intracellular Ca2+ increase, InsP3 generation, and prolactin release. This correlates with a downregulation of AT1 receptors. 7) In particular, in hyperplastic cells Ang II failed to evoke a transient acute peak in [Ca2+]i, which was replaced by a persistent plateau phase of [Ca2+]i increase. 8) Different calcium channels participate in Ang II induced [Ca2+]i increase in control and hyperplastic cells. While spike phase in control cells is dependent on intracellular stores sensitive to thapsigargin, in hyperplastic cells plateau increase is dependent on extracellular calcium influx. 9) Signal transduction of the AT1 pituitary receptor is greatly modified by hyperplasia, and it may be an important mechanism in the control of the hyperplastic process. 10) In the hypothalamus and brain stem there is a predominant expression of AT1A and AT2 mRNA. 11) Ang II acts at specific receptors located on neurons in the hypothalamus and brain stem to elicit alterations in blood pressure, fluid intake, and hormone secretion. 12) Calcium channels play important roles in the Ang II induced behavioral and endocrine responses. 13) Ang II, in physiological concentrations, can activate AT1 receptors to stimulate both Ca2+ release from intracellular stores and Ca2+ influx from the extracellular space to increase [Ca2+]i in polygonal and stellate astroglia of the hypothalamus and brain stem. 14) In primary cell culture of neurons from newborn rat hypothalamus and brain stem, it has also been determined that Ang II elicits an AT1 receptor mediated inhibition of delayed rectifier K(+) current and a stimulation of Ca2+ current. 15) In primary cell cultures derived from the subfornical organ or the organum vasculosum laminae terminalis of newborn rat pups, Ang II produced a pronounced desensitization of the [Ca2+]i response. 16) Hypothalamic and pituitary Ang II systems are involved in different functions, some of which are related. At both levels Ang II signals through [Ca2+]i in a characteristic way.
Cell Mol Neurobiol 2002 Jun
PMID:Angiotensin and calcium signaling in the pituitary and hypothalamus. 1246 73

Nucleobase transporters play an important role in the physiology of protozoan parasites, because these organisms are purine auxotrophs and rely entirely on salvage of these vital compounds. Purine transporters have also been shown to mediate the uptake of important antiparasitic drugs. In the current study, we investigated the uptake of [(3)H]adenine, [(3)H]hypoxanthine, and [(3)H]allopurinol, an antileishmanial hypoxanthine analog, by Leishmania major. These compounds were all taken up by a single high-affinity transporter, LmNBT1, with K(m) values of 4.6 +/- 0.9, 0.71 +/- 0.07, and 54 +/- 3 microM, respectively. Guanine and xanthine fully inhibited [(3)H]adenine transport, with K(i) values of 2.8 +/- 0.7 and 23 +/- 8 microM. Using purine analogs, an inhibitor profile for LmNBT1 was obtained, which allowed the construction of a quantitative model for the interactions between the transporter binding site and the permeant. The model predicts that hypoxanthine was bound through hydrogen bonds to N(1)H, N3, N7, and N(9)H of the purine ring, with a total Gibbs free energy of -39.5 kJ/mol. The interactions with adenine were similar, except for a weak hydrogen bond to N1 (unprotonated in adenine). The predicted mode of substrate binding for LmNBT1 was almost identical to that for the Trypanosoma brucei H2 (TbH2) transporter. It is proposed that the architecture of their respective binding sites is very similar and that LmNBT1 can be named a functional homolog of TbH2.
Mol Pharmacol 2003 Apr
PMID:A Leishmania major nucleobase transporter responsible for allopurinol uptake is a functional homolog of the Trypanosoma brucei H2 transporter. 1264 82

Guanine-uracil (G.U) wobble base-pairs are a detrimental lesion in DNA. Previous investigations have shown that such wobble base-pairs are more prone to base-opening than the normal G.C base-pairs. To investigate the sequence-dependence of base-pair opening we have performed 5ns molecular dynamics simulations on G.U wobble base-pairs in two different sequence contexts, TGT/AUA and CGC/GUG. Furthermore, we have investigated the effect of replacing the guanine base in each sequence with a fluorescent guanine analogue, 6-methylisoxanthopterin (6MI). Our results indicate that each sequence opens spontaneously towards the major groove in the course of the simulations. The TGT/AUA sequence has a greater proportion of structures in the open state than the CGC/GUG sequence. Incorporation of 6MI yields wobble base-pairs that open more readily than their guanine counterparts. In order of increasing open population, the sequences are ordered as CGC<TGT<CMC<TMT, where M represents 6MI. Both members of the base-pair open towards the major groove in a symmetrically coupled motion. Opening results in breakage of the H3(U)-O6(G/6MI) hydrogen bond, and distortion of the H1(G/6MI)-O2(U) hydrogen bond. Structural consequences of the opening include the formation of the H21(G/6MI)-O2(U) hydrogen bond and a change in local solvation in the grooves and particularly near N3-H3 of uracil. Additionally, DNA flexibility is reduced in the open state for bending towards the major groove generating two nearly discrete states: closed unbent and open bent. The observed differences in the local structural and dynamical properties of the G.U base-pair may play an important role in the activity of DNA repair enzymes that initiate base excision by distorting the DNA and flipping the target base from inside the DNA helix.
J Mol Biol 2003 Jul 18
PMID:Contribution of opening and bending dynamics to specific recognition of DNA damage. 1285 Jan 40

SGEF (SH3-containing Guanine Nucleotide Exchange Factor) is a RhoGEF of unknown function. We found the SGEF protein to be expressed in many established cell lines and highly expressed in human liver tissue. SGEF stimulated the formation of large interconnected membrane ruffles across dorsal surfaces when expressed in fibroblasts. SGEF required its proline-rich amino-terminus to generate dorsal, but not lateral, membrane ruffles and a functional SH3 domain to colocalize with filamentous actin at sites of membrane protrusion. Full-length SGEF activated RhoG, but not Rac, when expressed in fibroblasts. Further, recombinant SGEF DH/PH protein exchanged nucleotide on RhoG, but not on Rac1 or Rac3, in vitro. Scanning electron microscopy of fibroblasts demonstrated that SGEF induced dorsal ruffles that were morphologically similar to those generated by constitutively active RhoG, but not constitutively active Rac1. Transient expression of SGEF stimulated fibroblast uptake of 10-kDa dextran, a marker of macropinocytosis. This required the full-length protein and a catalytically active DH domain. Finally, activated RhoG was found to be more effective than activated Rac, and comparable to SGEF, in its ability to trigger dextran uptake. Together, this work establishes SGEF as a RhoG exchange factor and provides evidence that both SGEF and RhoG regulate membrane dynamics in promotion of macropinocytosis.
Mol Biol Cell 2004 Jul
PMID:SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis. 1513 29

RNA polymerase II (Pol II) termination is triggered by sequences present in the nascent transcript. Termination of pre-mRNA transcription is coupled to recognition of cis-acting sequences that direct cleavage and polyadenylation of the pre-mRNA. Termination of nonpolyadenylated [non-poly(A)] Pol II transcripts in Saccharomyces cerevisiae requires the RNA-binding proteins Nrd1 and Nab3. We have used a mutational strategy to characterize non-poly(A) termination elements downstream of the SNR13 and SNR47 snoRNA genes. This approach detected two common RNA sequence motifs, GUA[AG] and UCUU. The first motif corresponds to the known Nrd1-binding site, which we have verified here by gel mobility shift assays. We also show that Nab3 protein binds specifically to RNA containing the UCUU motif. Taken together, our data suggest that Nrd1 and Nab3 binding sites play a significant role in defining non-poly(A) terminators. As is the case with poly(A) terminators, there is no strong consensus for non-poly(A) terminators, and the arrangement of Nrd1p and Nab3p binding sites varies considerably. In addition, the organization of these sequences is not strongly conserved among even closely related yeasts. This indicates a large degree of genetic variability. Despite this variability, we were able to use a computational model to show that the binding sites for Nrd1 and Nab3 can identify genes for which transcription termination is mediated by these proteins.
Mol Cell Biol 2004 Jul
PMID:Identification of cis elements directing termination of yeast nonpolyadenylated snoRNA transcripts. 1522 27


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