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PubMed1997

[Mutagenic effects of coal tar used in the treatment of psoriasis].

BACKGROUND: Pharmaceutic tar used in the treatment of psoriasis has a high contents of polycyclic aromatic carbohydrates which are considered to be carcinogenic. AIM: The study is aimed at the estimation of the genotoxic risk arising from the treatment of psoriatic patients by pharmaceutic tar. The estimation is performed by biomonitoring. METHODS: The used methods included: bacterial test on TA 98 strain of Salmonella typhimurium aimed at the assessment of mutagenity of urine and cytogenetic test aimed at the assessment of chromosomal aberrations in peripheral lymphocytes. RESULTS: The exposition of psoriatic patients to pharmaceutic tar significantly increased the index of mutagenity as an index of the presence of mutagen in urine, as well as the occurrence of chromosomal aberrations in peripheral lymphocytes. CONCLUSIONS: The results of monitoring have indicated that psoriatic patients treated by pharmaceutic tar are endangered by an increased genotoxic risk. (Tab. 2, Ref. 17.)

Adult↗
PubMed1988

Purification of the human immunodeficiency virus type 1 enhancer and TAR binding proteins EBP-1 and UBP-1.

Transcription of the human immunodeficiency virus type 1 (HIV-1) is regulated by viral proteins and cellular factors that bind to the viral long terminal repeat (LTR). At least five regions of the HIV LTR serve as binding sites for HeLa cellular proteins. One region containing two copies of the sequence GGGACTTTCC functions as an enhancer element for HIV transcriptional regulation. Another region between -17 and +44 known as the TAR region contains two copies of the sequence CTCTCTGG and is also important in tat-induced activation of the HIV LTR. HeLa cell extracts were used to purify cellular proteins binding to portions of the enhancer region (EBP-1) and the TAR region (UBP-1) by a combination of conventional and DNA affinity chromatography. Several species of proteins of between 55 and 60 kd were found to bind to specific sequences in the enhancer region and these proteins also bound to a portion of the NF-kappa B binding site in the immunoglobulin kappa enhancer. Two proteins of between 61 and 63 kd were the major species found to bind to specific sequences in the TAR region and fractions containing these proteins also bind to the TATA region. Both UBP-1 and EBP-1 exhibited specific binding as demonstrated by both UV cross-linking and DNase I footprinting. Mutations of either the enhancer or TAR regulatory regions prevented binding of these purified factors. These results demonstrate the binding of highly purified cellular proteins to important transcriptional regulatory regions in the HIV LTR.

Base Sequence↗
PubMed1992

TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation.

The Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for productive infection and is a potential target for antiviral therapy. Tat, a potent activator of HIV-1 gene expression, serves to greatly increase the rate of transcription directed by the viral promoter. This induction, which seems to be an important component in the progression of acquired immune deficiency syndrome (AIDS), may be due to increased transcriptional initiation, increased transcriptional elongation, or a combination of these processes. Much attention has been focused on the interaction of Tat with a specific RNA target termed TAR (transactivation responsive) which is present in the leader sequence of all HIV-1 mRNAs. This interaction is believed to be an important component of the mechanism of transactivation. In this report we demonstrate that in certain CNS-derived cells Tat is capable of activating HIV-1 through a TAR-independent pathway. A Tat-responsive element is found upstream within the viral promoter that in glial-derived cell lines allows transactivation in the absence of TAR. Deletion mapping and hybrid promoter constructs demonstrate that the newly identified Tat-responsive element corresponds to a sequence within the viral long terminal repeat (LTR) previously identified as the HIV-1 enhancer, or NF-kappa B domain. DNA band-shift analysis reveals NF-kappa B binding activity in glial cells that differs from that present in T lymphoid cells. Further, we observe that TAR-deleted mutants of HIV-1 demonstrate normal late gene expression in glial cells as evidenced by syncytia formation and production of viral p24 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Antenatal thrombocytopenia in three patients with TAR (thrombocytopenia with absent radii) syndrome.

Three fetuses with TAR (thrombocytopenia with absent radii) or TAR variant syndrome were found to be thrombocytopenic during the third trimester of the pregnancy. These findings indicate that fetal blood sampling, besides ultrasonography, skeletal radiographs, or even fetoscopy, may indeed contribute to the prenatal diagnosis of TAR syndrome, and thus may help in differentiating TAR syndrome from other syndromes with malformations of the upper limbs.

Abnormalities, Multiple↗
PubMed2002

Pyrolysis-gas chromatography/mass spectrometry of fractions separated from a low-temperature coal tar: an attempt to develop a general method for characterising structures and compositions of heavy hydrocarbon liquids.

A low-temperature coal tar has been fractionated by column chromatography into acetonitrile, pyridine and 1-methyl-2-pyrrolidinone- (NMP) solubles. The tar and its fractions have been examined by pyrolysis-gas chromatography/mass spectrometry (GC/MS). Fractionation by planar chromatography was also carried out for purposes of comparison. Molecular masses of the fractions were estimated by size-exclusion chromatography (SEC), and bulk structural characterisation was carried out by (13)C-NMR and UV-fluorescence spectrometry. SEC showed that the fractions shifted to progressively shorter elution times (higher apparent masses) with diminishing solubility, i.e. from acetonitrile to NMP solubles. UV-fluorescence spectra showed parallel shifts to longer wavelengths and lower fluorescence quantum yields, indicating increasing sizes of aromatic ring systems and increasingly complex molecules. GC/MS analysis of the tar showed alkanes from C10 to C32 and extensive series of alkylated aromatics, phenols, indenes, naphthalenes, phenanthrenes and fluoranthenes. Pyrolysis-GC/MS results for the acetonitrile solubles closely resembled the data for the tar sample, with extensive series of alkylated benzenes, phenols and naphthalenes as well as alkanes from C16 to C28. The pyridine-soluble fraction showed no significant aromatic pyrolysis products and only relatively weak signals for alkanes between C16 and C27. The NMP-soluble fraction showed even less overall signal, with no significant aromatic components and weak signals for alkanes between C21 and C25, even though (13)C-NMR analyses showed that approximately half of the carbon detected was aromatic. The aliphatics are assumed to provide bridging structures between polycyclic aromatic (PCA) ring systems.

Journal Article↗
PubMed1994

Requirement of the human immunodeficiency virus type 1 env gene sequence for TAR-independent trans activation by Tat from the major immediate-early promoter of murine cytomegalovirus.

Previously it has been demonstrated that the human immunodeficiency virus type 1 (HIV-1) Tat protein mediates induction of the HIV-1 env expression through a TAR-independent manner in heterologous and homologous promoter systems (Kim and Risser, 1993, J. Virol. 67, 239; Kim and Panganiban, 1993, J. Virol. 67, 3739). To further explore the transactivation of HIV-1 env gene, I examined expression of the env, the bacterial CAT, and the firefly luciferase genes from a heterologous promoter, the major immediate-early promoter (MIEP) of murine cytomegalovirus (MCMV). Here we show that Tat augments gene expression from the MCMV MIEP only when linked to the env gene. Surprisingly, in contrast to the expression from an HIV-1 LTR lacking the TAR element, TAR-independent transactivation of env gene expression from MCMV MIEP did not require the full length Tat protein. In addition, deletion of the previously identified cis-acting Tat-responsive element in env did not affect Tat transactivation of the env gene expression. Thus, there are multiple distinct elements that mediate Tat responsiveness in the absence TAR.

Bacterial Proteins↗
PubMed2002

HIV-1 nucleocapsid protein activates transient melting of least stable parts of the secondary structure of TAR and its complementary sequence.

The nucleocapsid protein NCp7 of HIV-1 possesses a nucleic acid chaperone activity that is critical in minus and plus strand transfer during reverse transcription. The minus strand transfer notably relies on the ability of NCp7 to destabilize the stable stem with five contiguous, double-stranded segments of both the TAR sequence at the 3' end of the viral genome and the complementary sequence, cTAR, in minus strong-stop DNA. In order to examine the nature and the extent of NCp7 destabilizing activity, we investigated, by absorbance and fluorescence spectroscopy, the interaction of TAR and cTAR with a (12-55)NCp7 peptide containing the zinc-finger motifs but lacking the ability to aggregate the oligonucleotides. The absorbance changes in the UV band of cTAR show that seven to eight base-pairs, on average, are melted per oligonucleotide at a ratio of one peptide to 7.5 nucleotides. In contrast, the melting of TAR does not exceed an average of one base-pair per oligonucleotide. This may be linked to the greater stability of TAR, since a strong correlation between NCp7 destabilizing effect and oligonucleotide stability was observed. The effect of (12-55)NCp7 on the stem terminus was investigated by using a cTAR molecule doubly labeled at the 3' and 5' ends by a donor/acceptor couple. In the absence of the peptide, about 80 % of the oligonucleotides are in a dark non-fluorescent state, having a close proximity of the two dyes. The remaining 20 % are distributed between three fluorescent species, having either the terminal segment, the two terminal segments or all segments of the stem melted. This is in line with a fraying mechanism wherein the stem terminus fluctuates rapidly between open and closed states. Addition of (12-55)NCp7 shifts the equilibrium toward the open species, suggesting that NC enhances fraying of the stem terminus. Taken together, our data suggest that NCp7 activates the transient opening of base-pairs in the least stable parts of the stem. Also, this activity of NCp7 was found to be dependent on the zinc-finger motifs, since no melting was observed with a fingerless NCp7 peptide.

Base Pairing↗
PubMed1995

A Simple and Rapid TAR-Dependent in vitro Transcription Assay Using T Cell Nuclear Extracts and Synthetic tat1-86 Protein.

A 'G-less' cassette was cloned downstream of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) to facilitate rapid identification of authentic LTR-directed transcription in T cell nuclear extracts. Despite a high constitutive level of transcription, addition of chemically synthesized full-length HIV-1(bru) tat (amino acids 1-86) stimulated transcription 3-fold but only if the template included the TAR region of the LTR. Suppression of basal transcription in T cell nuclear extracts by sodium citrate increased the relative level of tat stimulation, but neither potassium chloride nor histone H1 had an effect. A mutant synthetic tat polypeptide, lacking residues 22-32 in the cysteine-rich domain, was inactive in uptake assays and failed to stimulate transcription. Short basic peptides that competed full-length tat from complexes with TAR RNA also inhibited tat stimulation of transcription, whereas short basic peptide unable to bind TAR or compete tat from complexes were also unable to inhibit tat stimulation of transcription. These data confirm that active HIV-1 tat must first interact with TAR RNA via basic amino acid residues in order to stimulate transcription of downstream sequences. Copyright 1995 S. Karger AG, Basel

Journal Article↗
PubMed2004

Carcinogenic potential of tobacco tar-resistant Staphylococcus aureus in buccal cavity.

PURPOSE: The effects of cigarette smoking on the association between inflammation and cancer were studied, since some bacteria induce the production of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine and endogenous tumor promoter, in cells. METHODS: Bacteria from a gargled solution from the buccal cavity of 20 individuals were cultured in the presence of 4 mg/ml cigarette-smoke condensates. Although cigarette-smoke condensates inhibited growth of Staphylococcus aureus strongly and that of Staphylococcus warneri weakly, tobacco tar-resistant S. aureus and S. warneri were obtained. RESULTS: One tobacco tar-resistant S. aureus strain (Sa-TA10) induced expression of the TNF-alpha gene in both Bhas 42 cells (v-Ha-ras transfected BALB/3T3 cells) and human lung cancer cell line H226B, while one tobacco tar-resistant S. warneri (Sw-TA75) did not induce it significantly. Moreover, Sa-TA10 induced formation of transformed foci and soft-agar colony in Bhas 42 cells in cooperation with the v-Ha-ras gene. The results suggested that Sa-TA10 has carcinogenic potential, whereas Sw-TA75 does not. CONCLUSION: These data suggest that tobacco tar-resistant S. aureus, with carcinogenic potential, is present in the buccal cavity of some individuals, and that cigarette smoking simultaneously inhibits growth of most of the bacteria and selects carcinogenic bacteria.

3T3 Cells↗
PubMed1993

Modeling and solution structure probing of the HIV-1 TAR stem-loop.

We present a model for the three-dimensional structure of the HIV TAR stem-loop, based on a modeling algorithm which makes use of the known X-ray coordinates of tRNAs to generate a model structure, which has then been tested experimentally in solution by enzymatic and chemical structure probing of ribo-oligonucleotides encompassing the TAR sequence. The modeling suggested that the structure of TAR was similar to that of the anti-codon loop of tRNA(Asp), having a loop of just three single-stranded residues with a mismatched adenine excluded from the helical stem on the 3' side of the loop. The structural probing is consistent with such a structure for the loop, and reveals an unusual structure around the 5' uridine-rich bulge, which is the binding target for the transactivator protein Tat. These data may be useful in understanding the interaction of TAR with the Tat protein and may aid in the design of anti-AIDS drugs. The coordinates of the model are available on request.

Base Sequence↗
PubMed2004

Synthesis and biological evaluation of novel beta-carboline derivatives as Tat-TAR interaction inhibitors.

Four new beta-carboline derivatives were synthesized bearing guanidinium group or amino group-terminated side chain targeting the TAR element. Compounds 5 and 6 with terminal guanidinium group showed inhibitory activities on Tat-TAR interaction as well as to HIV-1 in MT4 cells. Furthermore, capillary electrophoresis assay implied that compound 6 could not only bind to TAR but also hinder the Tat-TAR interaction.

Anti-HIV Agents↗
PubMed2005

Identification of amino acids that promote specific and rigid TAR RNA-tat protein complex formation.

The Tat protein and the transactivation responsive (TAR) RNA form an essential complex in the HIV lifecycle, and mutations in the basic region of the Tat protein alter this RNA-protein molecular recognition. Here, EPR spectroscopy was used to identify amino acids, flanking an essential arginine of the Tat protein, which contribute to specific and rigid TAR-Tat complex formation by monitoring changes in the mobility of nitroxide spin-labeled TAR RNA nucleotides upon binding. Arginine to lysine N-terminal mutations did not affect TAR RNA interfacial dynamics. In contrast, C-terminal point mutations, R56 in particular, affected the mobility of nucleotides U23 and U38, which are involved in a base-triple interaction in the complex. This report highlights the role of dynamics in specific molecular complex formation and demonstrates the ability of EPR spectroscopy to study interfacial dynamics of macromolecular complexes.

Amino Acid Sequence↗
PubMed2004

Rational design of inhibitors of HIV-1 TAR RNA through the stabilisation of electrostatic "hot spots".

The targeting of RNA for the design of novel anti-viral compounds has until now proceeded largely without incorporating direct input from structure-based design methodology, partly because of lack of structural data, and complications arising from substrate flexibility. We propose a paradigm to explain the physical mechanism for ligand-induced refolding of trans-activation response element (TAR RNA) from human immunodeficiency virus 1 (HIV-1). Based upon Poisson-Boltzmann analysis of the TAR structure, as bound by a peptide derived from the transcriptional activator protein, Tat, our hypothesis shows that two specific electrostatic interactions are necessary to stabilise the conformation. This result contradicts the belief that a single argininamide residue is responsible for stabilising the TAR fold, as well as the conventional wisdom that electrostatic interactions with RNA are non-specific or dominated by phosphates. We test this hypothesis by using NMR and computational methods to model the interaction of a series of novel inhibitors of the in vitro RNA-binding activities for a peptide derived from Tat. A subset of inhibitors, including the bis-guanidine compound rbt203 and its analogues, induce a conformation in TAR similar to that brought about by the protein. Comparison of the interactions of two of these ligands with the RNA and structure-activity relationships observed within the compound series, confirm the importance of the two specific electrostatic interactions in the stabilisation of the Tat-bound RNA conformation. This work illustrates how the use of medicinal chemistry and structural analysis can provide a rational basis for prediction of ligand-induced conformational change, a necessary step towards the application of structure-based methods in the design of novel RNA or protein-binding drugs.

Anti-HIV Agents↗
PubMed2005

Specific interactions between HIV-1 nucleocapsid protein and the TAR element.

During retroviral reverse transcription, the minus-strand strong-stop DNA (ss-cDNA) is transferred to the 3' end of the genomic RNA and this requires the repeat (R) sequences present at both ends of the genome. In vitro, the human immunodeficiency virus type 1 (HIV-1) R sequence can promote DNA strand transfer when present in ectopic internal positions. Using HIV-1 model systems, the R sequences and nucleocapsid protein (NC) were found to be key determinants of ss-cDNA transfer. To gain insights into specific interactions between HIV-1 NC and RNA and the influence of NC on R folding, we investigated the secondary structures of R in two natural contexts, namely at the 5' or 3' end of RNAs representing the terminal regions of the genome, and in two ectopic internal positions that also support efficient minus-strand transfer. To investigate the roles of NC zinc fingers and flanking basic domains in the NC/RNA interactions, we used NC mutants. Analyses of the viral RNA/NC complexes by chemical and enzymatic probings, and gel retardation assays were performed under conditions allowing ss-cDNA transfer by reverse transcriptase. We report that NC binds the TAR apical loop specifically in the four genetic contexts without changing the folding of the TAR hairpin and R region significantly, and this requires the NC zinc fingers. In addition, we show that efficient annealing of cTAR DNA to the 3' R relies on sequence complementarities between TAR and cTAR terminal loops. These findings suggest that the TAR apical loop in the acceptor RNA is the initiation site for the annealing reaction that is chaperoned by NC during the minus-strand transfer.

Amino Acid Sequence↗
PubMed2005

A PNA-transportan conjugate targeted to the TAR region of the HIV-1 genome exhibits both antiviral and virucidal properties.

We have earlier reported that anti-TAR PNA conjugated with the membrane-transducing peptide transportan inhibits transactivation of the HIV-1 LTR resulting in decreased production of HIV-1 virions by chronically infected H9 cells (N., Kaushik, A., Basu, P., Palumbo, R.L., Myers, V.N., Pandey, 2002. Anti-TAR polyamide nucleotide analog conjugated with a membrane permeating peptide inhibits HIV-1 production. J. Virol. 76, 3881-3891). In this study, we have found that the PNA(TAR)-transportan conjugate is efficiently internalized by cells and kinetics analysis reveals a sigmoidal curve with a cooperativity index of 6, indicating very rapid cellular uptake. Additionally, analysis of uptake at varying temperatures or in the presence of phenylarsine oxide revealed that the mechanism of uptake is neither receptor-dependent nor occurs via endocytosis. We also found that the PNA(TAR)-transportan conjugate exhibits potent virucidal activity as HIV-1 virions pretreated with the conjugate were rendered noninfectious, suggesting that the conjugate may also permeate the virus envelope. The anti-HIV-1 virucidal activity of the conjugate may be useful either in topical formulations designed to block HIV-1 infection or as a prophylactic agent for inactivation of HIV-1 in the circulating plasma prior to attachment and entry.

Anti-HIV Agents↗
PubMed2003

EPR spectroscopic analysis of TAR RNA-metal ion interactions.

Metal ion-induced changes in HIV-1 TAR RNA internal dynamics were determined by the changes in EPR spectral width for TAR RNAs containing spin-labeled nucleotides (U23, U25, U38, and U40). This gave a dynamic signature for each of 10 metal ions studied, which fell into one of three distinct groups. While Li(+) and K(+) had little effect on TAR RNA internal dynamics, Na(+) unexpectedly had a dynamic signature that was similar to Ca(2+) and Sr(2+), with a decrease in mobility at U23 and U38, little or no change at U25, and an increase in mobility at U40. Mg(2+), Co(2+), Ni(2+), Zn(2+), and Ba(2+) had similar effects on U23, U38, and U40, but the mobility of U25 was markedly increased. Our results show that RNA dynamics change upon metal binding to the TAR RNA bulge, indicating that RNA structure adapts to accommodate metal ions of different size and coordination properties.

Base Sequence↗
PubMed2002

Tar ball frequency data and analytical results from a long-term beach monitoring program.

Following the spill of fuel oils from the New Carissa in February 1999, approximately 300 km of beaches on the Pacific coast of North America were surveyed. A long-term observation program focused on the documentation of stranded tar balls in the vicinity of the spill site. Systematic beach surveys which were conducted over the period March 1999 to April 2001 and semi-logarithmic scale, time-series plots proved the most useful format for identifying trends. Beach monitoring continued through to August 2001. by which time 212 tar balls had been analyzed by GC/MS for their chemical characteristics. The samples of tar balls collected between February 1999 and August 2001 were qualitatively compared with New Carissa source oils (NCSO) and 101 (48%) were not consistent with NSCO. The presence of tar balls that are not related to an incident can confound attempts to define cleanup or endpoint criteria and to assess possible injury to natural resources.

Accidents↗
PubMed1995

Requirement for HIV-1 TAR sequences for Tat activation in rodent cells.

HIV-1 gene expression is activated via an interaction between the virally encoded Tat protein and a target RNA, TAR. TAR is located at the immediate 5' end of all viral mRNAs and comprises a partially base-paired stem with a tripyrimidine bulge in the upper stem and a hexanucleotide loop. In vitro, Tat binds specifically to the bulge and upper stem region with no requirement for the loop. In contrast, when Tat activation is analyzed in primate cells, mutations in the loop abolish activation, suggesting a critical role for loop binding cellular factors. However, in rodent cells the reverse is true. Messages with a mutation in the TAR loop are activated whereas messages harboring a wild-type TAR sequence are not activated. By testing the effect of mutations in the bulge and stem in the context of mutation in the loop we now show that this loop-independent activation by Tat in rodent cells requires the critical bulge-stem sequences needed for Tat binding in vitro. These data suggest that in rodent cells, as in vitro, Tat does not require a loop binding cofactor. In rodent cells containing human chromosome 12 (CHO12), however, Tat activation is both bulge and loop dependent. It appears that rodent cells, but not CHO12 cells, are refractory to the normal Tat/TAR activation pathway not by virtue of lacking a loop binding cofactor, but rather by the presence of a loop binding inhibitor of either Tat binding or the activation process.

Animals↗