Disease relevance of Tat

• Whereas in wild-type animals the TAT promoter becomes DNase I hypersensitive at birth, such hypersensitivity fails to develop in lethal albino deletion homozygotes [1].
• Chromosomal assignment and trans regulation of the tyrosine aminotransferase structural gene in hepatoma hybrid cells [2].
• Inhibition of human immunodeficiency virus type 1 replication in vitro in acutely and persistently infected human CD4+ mononuclear cells expressing murine and humanized anti-human immunodeficiency virus type 1 Tat single-chain variable fragment intrabodies [3].
• The 6-aminoquinolone derivatives were not only inhibitory to the Tat-mediated transactivation of the HIV-1 LTR promoter, but were also found to interfere in a cell-dependent way with the transactivation process mediated from the human CMV immediate early and the human EF-1alpha promoter [4].
• Lipopolysaccharide (LPS) and the neurotoxic HIV Tat protein, which cause dopamine neuronal toxicity after direct infusion into brain, cause activation of cultured mouse microglial cells as evidenced by increased expression of intracellular cyclooxygenase-2 and elevated secretion of tumor necrosis factor-alpha [5].

Psychiatry related information on Tat

• Alcohol abuse is a risk factor of HIV infection and we hypothesize that alcohol and Tat may interact in an additive or synergistic fashion to influence molecular processes which can contribute to their toxic effects [6].
• This would allow excess Tat to remain outside the cell and interact with synaptosomal membranes, leading to oxidative stress and neurotoxicity, which could contribute to dementia associated with HIV [7].
• The recombination TAT-choline acetyltransferase fusion protein injected intravenously improves the memory and cognitive dysfunction in Alzheimer's disease model mice induced by amyloid-beta peptide [8].

High impact information on Tat

• We also provide evidence that human Tse-1 resides on the homologous chromosome (human chromosome 17), and that hybrids retaining active Tse-1 loci lack TAT-specific mRNA [9].
• Furthermore, removal of fibroblast chromosome 11 from the populations by back-selection resulted in reexpression of TAT activity to full parental levels [9].
• Hepatoma clones retaining only fibroblast chromosome 11 were specifically extinguished for liver-specific tyrosine aminotransferase (TAT) expression, while expression of four other hepatic traits and of numerous constitutive markers was unaffected [9].
• Here we report that the tat gene product (Tat) is released from both HIV-1-acutely infected H9 cells and tat-transfected COS-1 cells [10].
• Expression of cyclins A, B, D1, E, and cdc2, of c-fos and tyrosine aminotransferase is deregulated [11].

Chemical compound and disease context of Tat

• Pro-inflammatory and pro-oxidant properties of the HIV protein Tat in a microglial cell line: attenuation by 17 beta-estradiol [12].
• MK-801, a non-competitive NMDA receptor antagonist that is known to protect against methamphetamine neurotoxicity, prevents microglial activation by LPS and HIV Tat [5].
• Finally, we demonstrated that TAT-fusion proteins did not affect the insulin secretion capability of islets, as determined by glucose static incubation and by reversion of hyperglycemia in diabetic immunodeficient mice [13].
• METHODS: We compared the inducible 2-component expression system (C3-human immunodeficiency virus/transactivator of transcription [C3-Tat/HIV]) with the constitutive cytomegalovirus (CMV) promoter in the polyarticular collagen-induced arthritis (CIA) model in mice [14].
• This short peptide contains two runs of four arginine residues, suggesting that the VP13/14 nuclear localization signal may behave in a manner similar to that of the arginine-rich nuclear localization signals of the retrovirus transactivator proteins Tat, Rev, and Rex [15].

Biological context of Tat

• Deletions near the albino locus on chromosome 7 of the mouse affect the level of tyrosine aminotransferase mRNA [16].
• Thus, the TAT structural genes of both parental cell types were coordinately regulated in the intertypic hybrids, and the TAT phenotype of the cells was determined by the presence or absence of fibroblast Tse-1 [2].
• The DNA sequence at the 5' end of the gene was determined and compared with the corresponding sequence of the rat tyrosine aminotransferase gene [17].
• The tyrosine aminotransferase (TAT) gene is expressed in a tissue and developmental-specific manner [17].
• The mouse tyrosine aminotransferase gene has been mapped distal to the serum esterase-1 locus on mouse chromosome 8, using a restriction fragment length polymorphism between two mouse species [17].

Anatomical context of Tat

• In agreement with in vivo studies, hepatocyte lines derived from mice homozygous for the deletion expressed reduced mRNA levels of a number of liver genes including TAT, PEPCK, X1, X2, and X7 in comparison with heterozygous and wild-type cell lines [18].
• TAT-specific mRNA was detected in normal but not in mutant hepatocyte lines [19].
• The cytokines and possibly chemokines that are induced by Tat modify the action of astrocytes such that the survival of neurons is compromised [20].
• Pathogenetic alteration induced by Tat involves a series of interactions between circulating monocyte/macrophages, endothelial cells, and astrocytes [20].
• In addition, T cell responses to regulatory proteins Rev, Nef, and Tat were induced [21].

Associations of Tat with chemical compounds

• Lastly, pre-treatment of microglial cells with physiological concentrations of 17 beta-estradiol suppressed Tat-mediated microglial activation by interfering with Tat-induced MAPK activation [12].
• We hypothesize that abusive drugs, such as methamphetamine (METH), can directly influence specific molecular processes that can further contribute to toxic effects of Tat [22].
• Moreover, treatment with NS-398 significantly attenuated Tat-induced activation of microglial cells [23].
• Tyrosine aminotransferase (TyrATase; L-tyrosine: 2-oxoglutarate aminotransferase, EC 2.6.1.5) from rat liver is subject to glucocorticoid and cAMP as well as developmental control [24].
• This sequence is very similar to the insulin response sequence found in the regulatory region of other genes negatively regulated by insulin such as those encoding phosphoenolpyruvate carboxykinase, tyrosine aminotransferase, and insulin-like growth factor-binding protein 1 [25].

Regulatory relationships of Tat

• TNFalpha suppressed expression of mature liver-specific genes such as tyrosine aminotransferase and apolipoproteins [26].
• In conclusion, the data show that the 5'-flanking region of the rat TAT gene contains elements specifying regulated expression and establish that the 5'-flanking region of the TAT gene is responsive to the enzyme deficiency characteristic of the albino lethal mice [27].
• Since Kaposi spindle cells, which are the proliferative component of the sarcoma, differentiate from an endothelial precursor, it is noteworthy that spindle cells derived from Kaposi-like lesions of the Tat transgenic mice downregulate EDF-1 when compared to microvascular endothelial cells isolated from the same tissue [28].
• Interestingly, P15-Tat induced apoptosis as evidenced by rapid caspase activation and cellular cytotoxicity in a variety of tumor cell lines [29].
• Efficient retroviral gene transfer of a Tat-regulated herpes simplex virus thymidine kinase gene for HIV gene therapy [30].

Other interactions of Tat

• This assignment demonstrated that the Tat-1 structural gene was not syntenic with Tse-1, a chromosome 11-linked locus that negatively regulates TAT expression in trans (A. M. Killary and R. E. K. Fournier, Cell 38:523-534, 1984) [2].
• By contrast, the deletions do not affect the appearance of three DNase I-hypersensitive sites upstream of the TAT promoter in the liver, nor do they affect two hypersensitive sites upstream of the expressed alpha-fetoprotein gene [1].
• Moreover, synergistic effects of Tat plus METH on the tumor necrosis factor-alpha and interleukin-1beta mRNA levels were observed in the striatal region [22].
• These results indicate that the hsdr-1 locus is dispensable for the glucocorticoid induced transcription of these genes but not of TAT [31].
• The mechanism of destruction of the CNS by Tat appears to involve autocrine and paracrine pathways that depend not only on Tat, but cytokine and chemokine signaling pathways that are altered by viral infection [20].

Analytical, diagnostic and therapeutic context of Tat

• Specifically, normal differentiation of the TAT promoter chromatin appears to depend directly or indirectly on the action and product of a gene mapping within the deleted region [1].
• The structural gene encoding liver-specific tyrosine aminotransferase (TAT; EC 2.6.1.5) was assigned to mouse chromosome 8 by screening a series of hybrid cell lines for retention of murine Tat-1 gene sequences by genomic Southern blotting [2].
• Circular dichroism and NMR studies of Tat deletion mutants localize the KIX-binding domain of Tat to the N-terminal 24 residues of Tat [32].
• Pronounced acute immunosuppression in vivo mediated by HIV Tat challenge [33].
• Tat-induced XCL1 expression was further confirmed by XCL1-specific RT-PCR and ELISA [34].

References