Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.1.108 (TAT)
2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disease of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in hepatic tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5), a 454-amino acid protein encoded by a gene with 12 exons. To identify the causative mutations in five TAT alleles cloned from three RHS patients, chimeric genes constructed from normal and mutant TAT alleles were tested in directing TAT activity in a transient expression assay. DNA sequence analysis of the regions identified as nonfunctional revealed six different point mutations. Three RHS alleles have nonsense mutations at codons 57, 223, and 417, respectively. One "complex" RHS allele carries a GT----GG splice donor mutation in intron 8 together with a Gly----Val substitution at amino acid 362. A new splice acceptor site in intron 2 of the fifth RHS allele leads to a shift in reading frame.
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PMID:Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. 135 62

In transient gene expression assays we observed an increase in expression of the bacterial chloramphenicol acetyl-transferase (CAT) gene, under the transcriptional control of the HIV-1 LTR (pLTR-CAT), when this plasmid was cotransfected into Vero or MRC-5 cells with a plasmid containing either the HCMV immediate early 1 and 2 (E1, IE2) genes (pRL43a) or just the IE2 gene (pMP18). When the HCMV IE1 gene (pMP12) was cotransfected with pLTR-CAT into Vero cells the level of measurable CAT gene activity was below the level observed when pLTR-CAT was cotransfected with a nonspecific carrier plasmid (pGEM3). The negative influence of the HCMV IE1 gene product on the HIV-1 LTR in Vero cells was also observed when the HIV-1 tat gene (pLTR-TAT) was contransfected into Vero cells with pLTR-CAT and pMP12. However, when the HCMV IE1 gene was cotransfected into rhabdomyosarcoma (RD) cells with proviral HIV-1 DNA, an increase in viral production, as monitored by measurement of HIV-1 reverse transcriptase activity, was observed. In electrophoretic mobility shift assays, nuclear extracts obtained 15 hr post-HCMV infection (hpi) were found to contain a lower level of interaction with an oligonucleotide which corresponded to the HIV-1 LTR Sp-1 binding motif. Nuclear extracts obtained 40 hpi of MRC-5 cells had a greater level of interaction with, and changed the mobility of, the Sp-1 oligonucleotide relative to the uninfected nuclear extracts. HCMV-infected MRC-5 cell nuclear extracts also contain a factor(s) which interacted with the HIV-1 LTR between nucleotide positions -15 to -2 relative to the HIV-1 mRNA start site.
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PMID:Characterization of multiple molecular interactions between human cytomegalovirus (HCMV) and human immunodeficiency virus type 1 (HIV-1). 215

Overlapping chromosomal deletions at the albino locus on chromosome 7 of the mouse affect the expression of several liver enzymes, including tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5). With cloned TAT DNA the integrity of the TAT structural gene and its expression and inducibility by glucocorticoids and cAMP were examined in deletion homozygous mice. No difference in the structure of the gene between normal and mutant mice was detected by Southern blotting. Severely reduced amounts of TAT mRNA were detected in homozygous mutants. The residual mRNA levels could not be modulated by glucocorticoids or cAMP. We conclude that a trans-acting control function required for expression and inducibility of mouse TAT can be assigned to the chromosomal region near the albino locus.
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PMID:Deletions near the albino locus on chromosome 7 of the mouse affect the level of tyrosine aminotransferase mRNA. 285 94

Studies of the genomic structure of human T-lymphotropic virus type III (HTLV-III) and related viruses, implicated as the causal agent of acquired immune deficiency syndrome (AIDS), have identified a sixth open reading frame in addition to the five previously known within the genome (gag, pol, sor, env and 3'orf). This gene, called tat-III, lies between the sor and env genes and is able to mediate activation, in a trans configuration, of the genes linked to HTLV-III long terminal repeat (LTR) sequences. We now present evidence that the product of tat-III is an absolute requirement for virus expression. We show that derivatives of a biologically competent molecular clone of HTLV-III, in which the tat-III gene is deleted or the normal splicing abrogated, failed to produce or expressed unusually low levels of virus, respectively, when transfected into T-cell cultures. The capacity of these tat-III-defective genomes was transiently restored by co-transfection of a plasmid clone containing a functional tat-III gene or by introducing the TAT-III protein itself. As HTLV-III and related viruses are the presumed causal agents of AIDS and associated conditions, the observation that tat-III is critical for HTLV-III replication has important clinical implications, and suggests that specific inhibition of the activity of tat-III could be a novel and effective therapeutic approach to the treatment of AIDS.
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PMID:The trans-activator gene of HTLV-III is essential for virus replication. 300 95

For a few of retroviruses, the level of synthesis of viral proteins is greatly increased in the presence of a transactivator gene which is encoded by the virus. For instance, for HIV, TAT acts on target sequences present in the viral long terminal repeat (LTR). HIV-1 recombinant retrovirus (RRV), where the gag, pol and part of env genes have been exchanged for the reporter nlsLacZ gene, expresses the reporter gene only in presence of TAT. When the RRV is tat defective, this activity can be complemented by tat present on a second molecule. The expression of nlsLacZ can then be detected by a simple histochemical staining. If this complementation can also be provided by a wild type virus, then their detection and titration would be greatly simplified.
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PMID:[Toward an unpublished method of detecting human retroviruses: activation of HIV-1 LacZ recombinant provirus by the tat gene product]. 314 19

Tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5) from rat liver is subject to glucocorticoid, cAMP, and developmental control. To study the underlying regulatory mechanisms, the TAT structural gene was isolated from a lambda bacteriophage rat DNA library. Heteroduplex analysis revealed that the 2.4-kilobase-long TAT mRNA is encoded by a gene that extends over 11 kilobases and is interrupted by 11 introns. To characterize the presumptive control region, the DNA sequence around the 5' end of the gene was determined and the start site of transcription was identified by nuclease S1 protection experiments. A short sequence homology in an equivalent position relative to the cap site was detected between TAT and tryptophan oxygenase, another glucocorticoid-controlled gene from rat liver. This sequence is related to the sequence 5' T-G-T-T-C-T 3' found in regions of the long terminal repeat of mouse mammary tumor virus, which has been shown to interact with the glucocorticoid receptor [Scheidereit, C., Geisse, J., Westphal, H. M. & Beato, M. (1983) Nature (London) 304, 749-752].
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PMID:Isolation and characterization of the rat tyrosine aminotransferase gene. 614 18

Tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5) gene activity is stimulated by glucocorticoids and glucagon and is repressed by insulin. Expression and responsiveness to the different signal transduction pathways are restricted to the liver, in which the gene is activated shortly after birth. Here we provide a model for the basis of this tissue specificity of the hormonal control. In the two enhancers mediating hormone induction of TAT gene activity we find the hormone response elements in combination with binding sites for constitutive liver-enriched transcription factors: proteins of the hepatocyte nuclear factor 3 family bind in the vicinity of the glucocorticoid response element located 2.5 kb upstream of the transcription start site, while hepatocyte nuclear factor 4 interacts with an essential element in the cAMP-responsive enhancer at -3.6 kb. By juxtaposing the liver-specific element and the target sequence of the signal transduction pathway the regulatory properties of either enhancer can be reconstituted. Thus, the interdependence of the respective enhancer motifs restricts the hormonal activation of the TAT gene to the liver. The coincidence of the onset of TAT gene expression around birth with the perinatal changes in the concentrations of glucocorticoids, glucagon, and insulin suggests cooperation of signal transduction pathways and cell type-specific transcription factors in the developmental activation of the TAT gene.
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PMID:Activation of the tyrosine aminotransferase gene is dependent on synergy between liver-specific and hormone-responsive elements. 810 67

Human immunodeficiency virus 1 (HIV1) infection is associated with severe psoriasis, B cell lymphoma, and Kaposi's sarcoma. A deregulated production of interleukin 6 (IL-6) has been implicated in the pathogenesis of these diseases. The molecular mechanisms underlying the abnormal IL-6 secretion of HIV1-infected cells may include transactivation of the IL-6 gene by HIV1. To test this hypothesis, we used the pIL6Pr-chloramphenicol acetyltransferase (CAT) plasmid, an IL-6 promoter-CAT construct, as a target of the transactivating function of the HIV1 TAT protein. By cotransfecting the pIL6Pr-CAT and the tat-expressing pSVT8 plasmid in MC3 B-lymphoblastoid or in HeLa epithelial cells, we observed that TAT transactivates the human IL-6 promoter. These results were confirmed when pIL6Pr-CAT was transfected in MC3 or HeLa cells that constitutively expressed the tat gene in a sense (pSVT8 cells) or antisense (pSVT10 cells) orientation. 5' deletion plasmids of pIL6Pr-CAT, in which regions at -658, -287, and -172 were inserted 5' to the cat gene, were transiently transfected in pSVT10 and pSVT8 cells and showed that TAT-induced activation of the IL-6 promoter required a minimal region located between -287 and -54 bp. Moreover, experiments with plasmids carrying the -658, -287, and -172 bp regions of the IL-6 promoter inserted downstream to a TAR-deleted HIV1-LTR identified the sequence of -172 to -54 as the minimal region of the IL-6 promoter required for TAT to transactivate the TAR-deleted HIV1-LTR. By DNA-protein binding experiments, tat-transfected cells expressed a consistent increase in kappa B and nuclear factor (NF)-IL-6 binding activity. Accordingly, the pDRCAT and IL-1REK9CAT, carrying tandem repeats of NF-kappa B or NF-IL6 binding motifs, respectively, were activated in TAT-expressing cells. The biological relevance of the TAT-induced IL-6 secretion was addressed by generating 7TD1 cells, an IL-6-dependent mouse cell line, stably expressing the tat gene. These tat-positive cells expressed the endogenous IL-6 gene, secreted high amounts of murine IL-6, and grew efficiently in the absence of exogenous IL-6. Moreover, the tat-positive 7TD1 cells sustained the growth of parental 7TD1 cells and showed a dramatic increase in their tumorigenic potency. These results suggest that TAT protein may play a role in the pathogenesis of some HIV1-associated diseases by modulating the expression of host cellular genes.
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PMID:The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein. 811 88

Human immunodeficiency virus type 1 (HIV-1)-infected subjects show a high incidence of Epstein-Barr virus (EBV) infection. This suggests that EBV may function as a cofactor that affects HIV-1 activation and may play a major role in the progression of AIDS. To test this hypothesis, we generated two EBV-negative human B-cell lines that stably express the EBNA2 gene of EBV. These EBNA2-positive cell lines were transiently transfected with plasmids that carry either the wild type or deletion mutants of the HIV-1 long terminal repeat (LTR) fused to the chloramphenicol acetyltransferase (CAT) gene. There was a consistently higher HIV-1 LTR activation in EBNA2-expressing cells than in control cells, which suggested that EBNA2 proteins could activate the HIV-1 promoter, possibly by inducing nuclear factors binding to HIV-1 cis-regulatory sequences. To test this possibility, we used CAT-based plasmids carrying deletions of the NF-kappa B (pNFA-CAT), Sp1 (pSpA-CAT), or TAR (pTAR-CAT) region of the HIV-1 LTR and retardation assays in which nuclear proteins from EBNA2-expressing cells were challenged with oligonucleotides encompassing the NF-kappa B or Sp1 region of the HIV-1 LTR. We found that both the NF-kappa B and the Sp1 sites of the HIV-1 LTR are necessary for EBNA2 transactivation and that increased expression resulted from the induction of NF-kappa B-like factors. Moreover, experiments with the TAR-deleted pTAR-CAT and with the tat-expressing pAR-TAT plasmids indicated that endogenous Tat-like proteins could participate in EBNA2-mediated activation of the HIV-1 LTR and that EBNA2 proteins can synergize with the viral tat transactivator. Transfection experiments with plasmids expressing the EBNA1, EBNA3, and EBNALP genes did not cause a significant HIV-1 LTR activation. Thus, it appears that among the latent EBV genes tested, EBNA2 was the only EBV gene active on the HIV-1 LTR. The transactivation function of EBNA2 was also observed in the HeLa epithelial cell line, which suggests that EBV and HIV-1 infection of non-B cells may result in HIV-1 promoter activation. Therefore, a specific gene product of EBV, EBNA2, can transactivate HIV-1 and possibly contribute to the clinical progression of AIDS.
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PMID:Epstein-Barr virus nuclear antigen 2 transactivates the long terminal repeat of human immunodeficiency virus type 1. 838 79

Transfer of "anti-HIV-1 genes" into hematopoietic stem cells of human immunodeficiency virus-1 (HIV-1)-infected individuals may be a potent therapeutic approach to render mature cells arising from transduced stem cells resistant to the destructive events associated with HIV-1 infection. To determine the feasibility of gene therapy for acquired immunodeficiency syndrome in individuals already infected with HIV-1, granulocyte colony-stimulating factor mobilized peripheral blood CD34+ cells were isolated from HIV-1-infected individuals and transduced with retroviral vectors containing three different anti-HIV-1-genes: the Rev binding domain of the Rev Responsive Element (RRE decoy) (L-RRE-neo), a double hammerhead ribozyme vector targeted to cleave the tat and rev transcripts (L-TR/TAT-neo), and the trans-dominant mutant of rev (M10) (L-M10-SN). As a control, a vector mediating only neomycin resistance (LN) was used. After 3 days of transduction on allogeneic stroma in the presence of stem cell factor, interleukin-6 (IL-6), and IL-3, the cultures were G418-selected, and then challenged with HIV-1(JR-FL) and a primary HIV-1 isolate. Compared with the control cultures, the L-RRE-neo-, L-TR/TAT-neo-, and L-M10-SN-transduced cultures displayed up to 1,000-fold inhibition of HIV-1 replication after challenge with HIV-1(JR-FL) and the primary HIV-1 isolate. Growth of the hematopoietic cells in long-term bone marrow culture was not perturbed by the presence of any of the anti-HIV-1 genes. This study shows that anti-HIV-1 genes can be introduced into CD34+ cells from individuals already infected with HIV-1, and strongly inhibit HIV-1 replication in primary monocytes derived from the CD34+ progenitors.
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PMID:Inhibition of human immunodeficiency virus-1 (HIV-1) replication after transduction of granulocyte colony-stimulating factor-mobilized CD34+ cells from HIV-1-infected donors using retroviral vectors containing anti-HIV-1 genes. 911 67


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