Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “TARS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMed1980

Lung function and symptoms of cigarette smokers related to tar yield and number of cigarettes smoked.

In a survey of over 18 000 male civil-servants, tar yield and number of cigarettes smoked daily were related to lung function and respiratory symptoms. Both phlegm production and airflow obstruction among smokers increased with daily cigarette consumption. Tar yield influenced phlegm production but not the degree of airflow obstruction. However, those smoking more than twenty cigarettes per day lost most of the advantage of smoking low-tar cigarettes since their phlegm production was the same as that of high-tar cigarette smokers. Ex-smokers had better lung function than current smokers with comparable total cigarette consumption; the difference between ex-smokers and current smokers was not related to the length of time that ex-smokers had abstained from smoking. Despite a reduction in phlegm production a change to low-tar cigarettes, may only be associated with an improvement in lung function if dialy cigarette consumption is also reduced. After stopping smoking there may be an initial improvement in lung function but ex-smokers never fully restore their lung function, no matter how long they have abstained from smoking. Although lower tar yield may reduce phlegm production and the risk of cancer, the development of airways obstruction may not be related to the tar content of cigarettes. Rather, the gaseous phase of tobacco smoke may contain the irritant agents leading to airways obstruction.

Adult↗
PubMed1998

Occupationally related tumors in tar refinery workers.

BACKGROUND: The study comprised 606 workers with tar-induced dermatosis employed in a German tar refinery. During the period from 1946 to 1996 they were recognized as having an occupational disease. OBJECTIVE: The aim of this study was to characterize the histologic findings and the localization of the occupational dermatosis and to determine the latency period of the carcinomas from the beginning of exposure in the tar refinery to the first occurrence of malignant skin tumors. Furthermore, the study aimed to check whether other skin changes were frequently diagnosed in addition to known tar-induced tumors. METHODS: The data were collected retrospectively from the documents of the Employer's Liability Insurance Association. RESULTS: Surgical removal of 4754 skin tumors was documented up to the end of 1996 in the study. In 90% of cases the histologic diagnosis was confirmed. Among other conditions, this yielded 2490 precancerous stages, 380 squamous cell carcinomas, 218 basal cell carcinomas, and 182 keratoacanthomas. The skin tumors were found mainly in the facial area, as well as on the forearms and hands. Latency from the first exposure in the tar refinery until manifestation of tar-induced dermatosis covered a period of 57 years. CONCLUSION: In comparison to the general population, the ratio of squamous cell to basal cell carcinomas was shifted toward the squamous cell carcinomas (1.7:1). Sunlight is known to be a cofactor in the pathogenesis of keratosis, squamous cell carcinomas, and basal cell carcinomas. However, the difference in location of these tumors shows that the role sunlight plays in the pathogenesis of precancerous lesions and squamous cell carcinomas may be overvalued. The latency period from the beginning of exposure to the manifestation of squamous cell carcinomas could not be evaluated because of an intervention bias as a result of preventive excisions of precancerous lesions. The frequent occurrence of keratoacanthomas (in 18.7% of the workers) and the early age at which this disease became manifest relative to the general population (median, 55 years) indicate that employment in a tar refinery can primarily or secondarily cause keratoacanthomas.

Adolescent↗
PubMed2004

Does increased cigarette consumption nullify any reduction in lung cancer risk associated with low-tar filter cigarettes?

Epidemiological data suggest that smoking filter and lower tar cigarettes is associated with less lung cancer risk than is smoking plain and higher tar cigarettes. A recent National Cancer Institute monograph claimed these apparent benefits of lower delivery products may be illusory if relative risks are adjusted for daily consumption, and switching leads to "compensation" for reduced nicotine intake by increasing numbers of cigarettes smoked. To investigate this, we compared relative risks unadjusted and adjusted for daily cigarette consumption. Overall estimates of the filter/plain relative risk, using random-effects meta-analysis, were 0.61 (95%confidence interval 0.54 to 0.70) for unadjusted data and 0.66 (0.58 to 0.76) for adjusted data. The lower tar/higher tar relative risk was estimated as 0.60 (0.45 to 0.81) for unadjusted data and 0.73 (0.64 to 0.83) for adjusted data. The risk reductions were clearly seen regardless of gender, study location, period, or design, and when only studies providing both unadjusted and adjusted estimates were considered. Whether or not relative risk estimates are adjusted for cigarette consumption is not crucial to the conclusion of a clear advantage to filter cigarettes and tar reduction. Data on "compensation" for amount smoked were reviewed and any increase following switching to reduced-tar-yield cigarettes was shown to be quite small. Other biases in the epidemiology are also discussed, and we conclude that the apparent advantage to reduced-tar-delivery products is real and likely to be a marked underestimate of the reduction in lung cancer risk from lifetime smoking of low-tar cigarettes.

Age Factors↗
PubMed2004

What do Marlboro Lights smokers know about low-tar cigarettes?

The present study examined the extent to which Marlboro Lights smokers perceive lower health risks associated with using a low-tar cigarette and the extent to which they are aware of filter vents in their cigarettes. The data for this study came from a nationally representative random-digit-dialed telephone survey of 1,046 adult current cigarette smokers (aged 18 years or older) conducted between May and September 2001. Respondents were asked about the brand and type of cigarettes smoked, beliefs about the health benefits associated with low-tar and filtered cigarettes, and awareness of ventilation holes in the filters of their cigarettes. Marlboro Lights was the most popular brand, smoked by 19% of survey respondents. Only 32% of Marlboro Lights smokers reported that the filters on their cigarettes were ventilated. Many Marlboro Lights smokers believed incorrectly that lower tar, light, and ultra-light cigarettes were less harmful compared with higher tar, full-flavored cigarettes. For example, only 11% of Marlboro Lights smokers knew that the tar delivery of a light cigarette was about the same as that of a full-flavored cigarette. The responses of Marlboro Lights smokers to questions about the hazards of low-tar cigarettes were similar to those expressed by smokers of other cigarette brands. The data presented in this paper reveal that smokers of the leading light cigarette brand sold in the United States today, Marlboro Lights, are for the most part unaware of filter vents in the cigarettes they smoke and are misinformed about the health risk of using low-tar and filtered cigarettes.

Adult↗
PubMed2003

Cigarette tar yield and risk of upper digestive tract cancers: case-control studies from Italy and Switzerland.

BACKGROUND: Tobacco smoking is one of the main risk factors for oral, pharyngeal and oesophageal cancers in developed countries. Information on the role of the tar yield of cigarettes in upper digestive tract carcinogenesis is sparse and needs to be updated because the tar yield of cigarettes has steadily decreased over the last few decades. PATIENTS AND METHODS: We analysed two case-control studies, from Italy and Switzerland, conducted between 1992 and 1999, involving 749 cases of oral and pharyngeal cancer and 1770 controls, and 395 cases of squamous-cell oesophageal carcinoma and 1066 matched controls. Odds ratios (ORs) were estimated by unconditional multiple logistic regression models, including terms for age, sex, study centre, education and alcohol consumption. RESULTS: Based on the brand of cigarettes smoked for the longest time, the multivariate ORs for current smokers compared with never smokers were 6.1 for <20 mg and 9.8 for >or=20 mg tar for oral and pharyngeal neoplasms, and 4.8 and 5.4 for oesophageal cancer, respectively. For the cigarette brand smoked in the previous six months, the ORs for >or=10 mg compared with <10 mg were 1.9 for cancer of the oral cavity and pharynx and 1.8 for oesophageal cancer, after allowance for number of cigarettes and duration of smoking. CONCLUSIONS: The present study confirms the direct relationship between the tar yield of cigarettes and upper digestive tract neoplasms, and provides innovative information on lower tar cigarettes, which imply reduced risks compared with higher tar ones. However, significant excess risks were observed even in the lower tar category, thus giving unequivocal indications for stopping smoking as a priority for prevention of upper digestive tract neoplasms.

Aged↗
PubMed1994

Comparison of DNA adduct formation in mice fed coal tar or benzo[a]pyrene.

Coal tar is a complex mixture containing hundreds of compounds, including the carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene. In order to compare the metabolic activation of a single carcinogen versus a complex mixture containing the carcinogen, we determined the DNA adduct profiles in B6C3F1 mice fed doses of coal tar or benzo[a]pyrene at concentrations corresponding to the amount of benzo[a]pyrene found in the respective coal tar treatments. DNA adduct formation was quantified in liver, lungs and forestomach by 32P-postlabeling and was found to increase as a function of dose in each tissue with both coal tar and benzo[a]pyrene. In mice fed benzo[a]pyrene, a major adduct was detected with the same elution characteristics by TLC and HPLC as the major adduct, 10 beta-(deoxyguanosin-N2-yl)-7 beta, 8 alpha, 9 alpha-trihydroxy-7,8,9,10- tetrahydrobenzo[a]-pyrene (dG-N2-BPDE), obtained from reacting (+/-)-antibenzo[a]pyrene-7,8- dihydrodiol-9,10-epoxide (BPDE) with DNA. DNA binding was in the order forestomach > or = liver > lung, except at the highest dose group where the order was liver > forestomach > lung. In mice fed coal tar, a diagonal zone of radioactivity with a number of discrete adducts was observed. One area of radioactivity contained the major BPDE adduct, dG-N2-BPDE, based on co-elution by TLC and HPLC with the synthesized adduct. Total DNA binding was greater in the coal tar-fed mice than in the mice fed benzo[a]pyrene, and the adduct levels were in the order lung > liver > forestomach. These results indicate that there are tissue-specific differences in the activation of coal tar components when compared to a representative carcinogen contained within the mixture.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1998

A comparison of the tumors induced by coal tar and benzo[a]pyrene in a 2-year bioassay.

The tumorigenicity of two coal tar mixtures was compared to that of benzo[a]pyrene after 2 years of feeding. Mixture 1, a composite of coal tar from seven coal gasification plant waste sites, was fed to female B6C3F1 mice (48 mice per group) for 2 years at doses of 0.0, 0.01, 0.03, 0.1, 0.3, 0.6 and 1.0%. Mixture 2, which was composed of coal tar from two of the seven waste sites and another site having a high benzo[a]pyrene content, was fed at doses of 0.0, 0.03, 0.1 and 0.3%. Additional groups of mice were fed 0, 5, 25 and 100 ppm benzo[a]pyrene. The coal tar diets induced a dose-related increase in hepatocellular adenomas and carcinomas, alveolar/bronchiolar adenomas and carcinomas, forestomach squamous epithelial papillomas and carcinomas, small intestine adenocarcinomas, histiocytic sarcomas, hemangiosarcomas in multiple organs and sarcomas. Benzo[a]pyrene treatment resulted in an increased incidence of papillomas and/or carcinomas of the forestomach, esophagus and tongue. A comparison of the results indicated that the benzo[a]pyrene in the coal tar diets could be responsible for the forestomach tumors. In contrast, the lung and liver tumors appeared to be due to other genotoxic components contained within the coal tar mixture, while the small intestine tumors resulted from chemically-induced cell proliferation that occurred at high doses of coal tar.

Adenoma↗
PubMed2000

Cancer risk estimation for mixtures of coal tars and benzo(a)pyrene.

Two-year chronic bioassays were conducted by using B6C3F1 female mice fed several concentrations of two different mixtures of coal tars from manufactured gas waste sites or benzo(a)pyrene (BaP). The purpose of the study was to obtain estimates of cancer potency of coal tar mixtures, by using conventional regulatory methods, for use in manufactured gas waste site remediation. A secondary purpose was to investigate the validity of using the concentration of a single potent carcinogen, in this case benzo(a)pyrene, to estimate the relative risk for a coal tar mixture. The study has shown that BaP dominates the cancer risk when its concentration is greater than 6,300 ppm in the coal tar mixture. In this case the most sensitive tissue site is the forestomach. Using low-dose linear extrapolation, the lifetime cancer risk for humans is estimated to be: Risk < 1.03 x 10(-4) (ppm coal tar in total diet) + 240 x 10(-4) (ppm BaP in total diet), based on forestomach tumors. If the BaP concentration in the coal tar mixture is less than 6,300 ppm, the more likely case, then lung tumors provide the largest estimated upper limit of risk, Risk < 2.55 x 10(-4) (ppm coal tar in total diet), with no contribution of BaP to lung tumors. The upper limit of the cancer potency (slope factor) for lifetime oral exposure to benzo(a)pyrene is 1.2 x 10(-3) per microgram per kg body weight per day from this Good Laboratory Practice (GLP) study compared with the current value of 7.3 x 10(-3) per microgram per kg body weight per day listed in the U.S. EPA Integrated Risk Information System.

Animals↗
PubMed1997

The influence of cigarette consumption and smoking machine yields of tar and nicotine on the nicotine uptake and oral mucosal lesions in smokers.

The purpose of this investigation, which has been performed as two studies, was to evaluate the association between the daily exposure to nicotine (measured as cigarette smoking machine yields) and the actual uptake of nicotine by cigarette smokers, as well as the association between oral mucosal changes and the exposure to cigarette smoke. In Study 1, consumption data, soft tissue changes and nicotine intake were measured in 47 habitual smokers using cigarettes with tar and nicotine yields within the ranges 9.3-12.2 and 0.72-1.16 mg per cigarette, respectively. The subjects were divided into three groups based on daily cigarette consumption; group averages (standard deviation) were 10.8 (2.2), 17.9 (1.9) and 28.4 (6.1) cigarettes per day. The group averages of tar deliveries from their usual brands of cigarettes were 11.1, 11.0 and 10.5 mg per cigarette, and group averages of nicotine deliveries were 1.05, 1.05 and 1.06 mg per cigarette, respectively. In Study 2, the same data were measured in a group of 77 habitual smokers with an average individual consumption of 11-21 cigarettes per day. The participants in Study 2 were divided into three groups according to tar delivery from their usual brands to cigarettes, with group averages of tar being 6.4 (1.2), 11.0 (1.2) and 16.0 (1.1) mg per cigarette, and of nicotine being 0.70 (0.12), 1.05 (0.12) and 1.34 (0.08) mg per cigarette, respectively. The average consumption of all three groups was within the range 17.1 to 17.9 cigarettes per day. The daily exposures to nicotine and tar were measured as the smoking machine yields multiplied by the number of cigarettes smoked per day. Nicotine uptake was determined by monitoring nicotine and its seven main metabolites in 24-h urine samples. In Study 1 there were significant differences between the three groups in the total amount of nicotine and metabolites excreted in the 24-h urine. The average nicotine uptake was 14.9, 24.4 and 35.4 mg per day, respectively. In Study 2, the 24-h excretion of nicotine and metabolites was about the same in all three groups and averaged 24.5 mg per day. The nicotine uptake was significantly correlated to the number of cigarettes smoked per day but not to the smoking machine yields of tar and nicotine per cigarette. The average prevalences for each of the different oral mucosal lesions (leukoedema, smoker's palate and hairy tongue) were found to increase with increasing consumption and nicotine uptake (Study 1); they were also independent of tar and nicotine yields from the cigarettes smoked (Study 2). These results indicate that the actual uptake of nicotine by smokers could not be estimated from the smoking machine yields. Reduction in exposure to smoke components may best be accomplished if smokers are encouraged to smoke fewer lower-yield cigarettes and to avoid smoking more of each cigarette.

Adult↗
PubMedDate not supplied

Relationship between cigarette yields, puffing patterns, and smoke intake: evidence for tar compensation?

The relationship between cigarette yields (of nicotine, tar, and carbon monoxide), puffing patterns, and smoke intake was studied by determining puffing patterns and measuring blood concentrations of nicotine and carboxy-haemoglobin (COHb) in a sample of 55 smokers smoking their usual brand of cigarette. Regression analyses showed that the total volume of smoke puffed from a cigarette was a more important determinant of peak blood nicotine concentration than the nicotine or tar yield of the cigarette, its length, or the reported number of cigarettes smoked on the test day. There was evidence of compensation for a lower tar yield over and above any compensation for nicotine. When nicotine yield was controlled for, smokers of lower-tar cigarettes not only puffed more smoke from their cigarettes than smokers of higher-tar cigarettes but they also had higher plasma nicotine concentrations, suggesting that they were compensating for the reduced delivery of tar by puffing and inhaling a greater volume of smoke. The results based on the COHb concentrations were consistent with this interpretation. If an adequate intake of tar proves to be one of the main motives for smoking, then developing a cigarette that is acceptable to smokers and also less harmful to their health will be much more difficult.

Carboxyhemoglobin↗
PubMed1980

The effects of coal tar and ultraviolet radiation upon the incorporation of thymidine into DNA by Ehrlich ascites carcinoma cells in vitro.

The effects of coal tar with and without radiation from three types of sources upon the incorporation of thymidine into DNA by Ehrlich ascites carcinoma cells were investigated. It was found that addition of varying concentrations of coal tar inhibited the thymidine incorporation by progressively greater amounts. Irradiation by mercury vapor lamp or fluorescent tubes, both emitting predominantly UVA (320-400 nm) and visible radiations, inhibited the DNA synthesis to a small extent. However irradiation with either of these sources in the presence of tar gave a synergistic effect on the DNA synthesis. Irradiation with a predominantly UVB (260--320nm) source inhibited the DNA synthesis to a large extent. Irradiation with this source in the presence of coal tar did not give a synergistic effect but gave a summation effect. These findings have relevance in helping to choose the approporate radiation source for tar phototherapy of psoriasis. This in vitro system could also be used for other applications such as determining potencies of various tars or tar fractions.

Animals↗
PubMed1978

Human skin aryl hydrocarbon hydroxylase. Induction by coal tar.

Coal tar products, which are widely used in treating dermatologic disease, contain numerous polycyclic aromatic hydrocarbons, including 3,4-benzo[a]pyrene (BP). BP is among the most potent environmental chemical carcinogens and is known to evoke tumors in the skin of experimental animals and perhaps also of man. In this study the effect of cutaneous application of coal tar solution (U. S. Pharmacopeia) on aryl hydrocarbon hydroxylase (AHH) activity in the skin of patients usually treated with this drug was investigated. AHH, a cytochrome P-450 dependent carcinogen-metabolizing enzyme appears to play an important role in the activation of polycyclic hydrocarbons into reactive moieties that can bind to DNA and that may directly induce cancer. Application of coal tar solution to human skin caused a two to five-fold induction of cutaneous AHH in nine subjects. In further studies, the incubation of human skin with coal tar solution in vitro also caused variable induction of cutaneous AHH. Maximum responses in both systems occurred after 24 h and enzyme activity in vitro was time- and tissue- and substrate-concentration dependent. Studies in experimental animals showed that topical application of coal tar solution caused induction of AHH in skin and, after percutaneous absorption, in liver as well. Assay of several defined constituents of coal tar for AHH induction showed that BP was the most potent inducer of AHH tested. These studies indicate that topical application of coal tar solution in doses ordinarily used in treating dermatologic disease causes induction of AHH in human skin and suggest that such induced enzymatic activity could relate to carcinogenic responses to this agent in skin or, after percutaneous absorption, in other tissues as well.

Animals↗
PubMed1996

The tar fraction of cigarette smoke does not promote arteriosclerotic plaque development.

In addition to being the single greatest known environmental cause of cancer, cigarette smoke (CS) is also a major contributor to heart disease. We reported previously that 1) inhalation of either mainstream or sidestream CS promotes aortic arteriosclerotic plaque development; 2) 1,3 butadiene, a vapor-phase component of CS, promotes plaque development at 20 ppm, which at the time was only 2 times higher than the threshold limit value; and 3) individual tar fraction carcinogens in CS, including polynuclear aromatic hydrocarbons (PAHs) and nitrosamines, either do not promote plaque development or do so only at high concentrations. These results suggested that the tar fraction is not the primary source of plaque-promoting agents in CS. We asked whether repeated exposure to the tar fraction of CS, collected in a cold trap (TAR), promotes plaque development in an avian model of arteriosclerosis. Acetone extracts of mainstream CS tar from burning, unfiltered reference cigarettes were solubilized in dimethyl sulfoxide (DMSO) and injected weekly into cockerels for 16 weeks (25 mg/kg/week). Positive controls were injected weekly with the synthetic PAH carcinogen, 7,12 dimethylbenz(a)anthracene (DMBA) dissolved in DMSO and negative controls were injected with DMSO. Plaque location and prevalence did not differ from group to group. Morphometric analysis of plaque cross-sectional areas showed that plaque sizes, which are log-normally distributed, were significantly larger in the DMBA cockerels compared to both the TAR and DMSO groups. There were no significant differences in plaque size between DMSO and TAR cockerels. The results reported here, combined with other recent findings, support the conclusion that the primary arteriosclerotic plaque-promoting components of CS are in the vapor phase.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Examination of TAR-independent Trans activation by human immunodeficiency virus type 1 Tat in human glial cells.

Astrocytic glial cells derived from central nervous system (CNS) can support human immunodeficiency virus type 1 (HIV-1) replication in cell culture, may be infected in tissue culture, and are thought to be a large HIV-1 reservoir in vivo. The Tat protein of HIV-1 interacts with a cis-acting target sequence referred to as TAR. However, Tat can also stimulate gene expression directed from some heterologous promoters and, in certain circumstances, an HIV-1 long terminal repeat (LTR) that lacks the TAR element. Therefore, we attempted to investigate Tat trans activation of HIV-1 LTR in the astrocytic glial cells. Using transfection of LTR-reporter gene constructs and HIV-1 proviral constructs, we demonstrate TAR-dependent replication in astrocytic cells. We also examined the expression of HIV-1 env gene from an LTR that lacks TAR element. In a previous study (Kim and Panganiban: J Virol 67:3739-3747, 1993), we observed that env expression is trans activated only by the full-length Tat protein through a TAR-independent manner in HeLa cells. However, in astrocytic glial cells, the trans activation of env expression from the LTR-lacking TAR element was mediated by the first exon peptide of Tat as well as the full-length Tat peptide through a post-transcriptional mechanism rather than a transcriptional one. This result suggests that cell type-specific factor(s) is involved in the TAR-independent Tat responsiveness.

Astrocytoma↗
PubMed1990

HIV-1 tat protein stimulates transcription by binding to a U-rich bulge in the stem of the TAR RNA structure.

The HIV-1 trans-activator protein, tat, is an RNA binding protein with a high affinity for a U-rich bulge near the tip of the stem in the RNA stem-loop structure encoded by the trans-activation responsive region (TAR). A Scatchard analysis of tat binding has shown that the purified protein forms a one-to-one complex with HIV-1 TAR RNA with a dissociation constant of Kd = 12 nM. Deletion of the uridine residues in the bulge or substitution with guanine residues produced RNAs with a 6- to 8-fold lower affinity than wild-type TAR. Introduction of a point mutation expected to destabilize base pairing in nearby residues of the TAR stem-loop structure reduced tat binding 10-fold. In contrast, mutations that alter the sequence of the six nucleotide long loop at the tip of TAR RNA structure, and mutations which alter the sequence of the stem whilst preserving Watson-Crick base pairing, do not affect tat binding significantly. There is a direct correlation between the ability of tat to bind to TAR RNA and to activate HIV transcription. Viral LTRs carrying TAR sequences encoding any of the mutations known to produce transcripts which bind tat weakly, are not stimulated efficiently by tat in vivo.

Base Sequence↗
PubMed1993

Lupus autoantigen Ku protein binds HIV-1 TAR RNA in vitro.

The control of HIV-1 gene expression depends upon interaction of Tat with the trans-activation responsive (TAR) element present at the 5' end of all HIV-1 transcripts. The TAR sequence forms a stable hair-pin structure that binds Tat and several cellular factors in vitro. In the absence of Tat, TAR acts as a transcription terminator. Tat in conjunction with a cellular factor(s) acts to increase the elongation capacity of the transcription complex. Here we report that Ku protein, the autoantigen in patients with systemic lupus erythematosus, binds TAR RNA in vitro with high affinity and specificity forming a single protein-RNA complex. Ku, a heterodimer of Ku72 and Ku86 that non-specifically binds the ends of DNA fragments, appears to recognize the terminal loop of TAR RNA. UV-crosslinking showed that both subunits of Ku are in proximity to the RNA. Further, Ku shows a 5-fold higher affinity for TAR RNA than for the ends of dsDNA. As Ku is involved in the stimulation of the elongation property of the RNA polymerase II and activation of several transcription factors, the specific interaction of Ku with TAR raises intriguing possibilities for its function in HIV-1 gene expression.

Antigens, Nuclear↗
PubMed1993

TAR-independent activation of HIV-1 requires the activation domain but not the RNA-binding domain of Tat.

The Tat protein of HIV-1 is a potent activator of transcription directed by the viral long terminal repeat. In most cell types this activation requires a specific interaction between Tat and an RNA target termed TAR in the 5'-leader sequence of HIV-1 mRNAs. We have previously reported that in astrocytic cells Tat is capable of activating transcription in a TAR-independent manner through an alternative Tat-responsive element in the LTR (J. P. Taylor et al., EMBO J. 11(9), 3395-3403, 1992). In this report we demonstrate that TAR-independent activation by Tat can effectively bypass competition by decoy TAR RNA molecules. Studies with site-directed mutants demonstrate that the RNA-binding domain of Tat is dispensable for TAR-independent activation of HIV-1. In contrast, the requirement for specific components of the Tat activation domain suggests that common targets exist for this viral trans-activator to exert its activity in TAR-independent and TAR-dependent transactivation pathways of HIV-1 transcriptional activation.

Amino Acid Sequence↗
PubMed1994

HIV-1 TAR RNA has an intrinsic ability to activate interferon-inducible enzymes.

The TAR sequence at the 5'-termini of all HIV-1 mRNA species forms a stable structure that is responsible for both transcriptional and translational regulation of HIV-1. Previously we and others reported that purified TAR RNA synthesized by in vitro transcription could activate two interferon-induced enzymes, the protein kinase (PKR) and 2-5A-synthetase. Because the PKR- and 2-5A-systems block protein synthesis initiation and induce RNA decay, respectively, these findings suggested mechanisms for the control of HIV-1 replication by the interferon system. To determine if contaminating dsRNA from in vitro transcription reactions was responsible for this effect, as suggested by Gunnery et al. 1990, (Proc., Natl. Acad. Sci. USA 87, 8687), we have reexamined these findings using chemically synthesized TAR (nucleotides +1 to +57). TAR RNA is shown here to have an intrinsic ability to activate PKR and 2-5A-synthetase. In contrast, a mutant form of TAR designed to have a disrupted secondary structure did not stimulate either enzyme. Chemically synthesized TAR mimicked other dsRNA species in its ability to activate and inhibit PKR at low and high RNA concentrations, respectively. HIV-1 TAT protein inhibited activation of PKR by HIV-1 TAR RNA suggesting an escape mechanism for the virus.

2',5'-Oligoadenylate Synthetase↗