Disease relevance of Tat

• To study the underlying regulatory mechanisms, the TAT structural gene was isolated from a lambda bacteriophage rat DNA library [1].
• During development, this demethylation occurs before birth, at a stage where the Tat gene is not yet inducible, and it could thus prepare the enhancer for subsequent stimulation by hypoglycemia at birth [2].
• Exposure of cultured neurons to the neurotoxic HIV proteins gp120 and Tat resulted in increased cellular levels of sphingomyelin, ceramide, and HNE [3].
• The ceramide precursor palmitoyl-CoA sensitized neurons to Tat and gp120 toxicity, whereas an inhibitor of ceramide production reduced Tat and gp120-induced increases of ceramide and HNE and protected the neurons from Tat and gp120-induced death [3].
• PTPmu wedge Tat peptide had no effect on PC12 cells but blocked the PTPmu-dependent phenotype of neurite outgrowth of retinal ganglion neurons on a PTPmu substrate, whereas LAR wedge peptide had no effect [4].

Psychiatry related information on Tat

• To determine the role of the Tat protein of the human immunodeficiency virus type 1 (HIV-1) in the pathogenesis of HIV-1 associated dementia, recombinant Tat was injected intraventricularly as a single or repeated dose into male Sprague-Dawley rats [5].
• A deficiency of hepatic tyrosine aminotransferase in humans is responsible for a syndrome of keratitis, palmar and plantar erosions and hyperkeratosis and mental retardation [6].

High impact information on Tat

• Using this property we have identified in vivo HNF5 bound to its sites within two glucocorticoid-responsive units of the rat tyrosine aminotransferase (TAT) gene [7].
• All the identified protein contacts to DNA are found exclusively in the TAT-expressing hepatoma cells [8].
• Surprisingly, all DNA-binding activities are present in nuclei of TAT-expressing and nonexpressing cells, indicating that the mere presence of factors is not sufficient for their interaction with a binding site in vivo [8].
• Genomic sequencing reveals methylation of CpG dinucleotides in the regions analyzed in nonexpressing cells, whereas no methylation is found in TAT-expressing cells [8].
• These cells induce tyrosine aminotransferase and MMTV in response to the synthetic glucocorticoid, dexamethasone [9].

Chemical compound and disease context of Tat

• Methamphetamine and human immunodeficiency virus protein Tat synergize to destroy dopaminergic terminals in the rat striatum [10].
• Cytotoxic effects of exposure to the human immunodeficiency virus type 1 protein Tat in the hippocampus are enhanced by prior ethanol treatment [11].
• Reexamination of the effects of actinomycin D (AMD) on the intracellular level and rate of synthesis of tyrosine aminotransferase (TAT) in hepatoma tissue culture (HTC) cells reveals that much apparent controversy can be resolved with acknowledgment of the multi-faceted nature of this inhibitor's action [12].
• TAT specific activity was determined weekly in host liver and hepatoma, in the presence and absence of cofactor, before and after the administration of hydrocortisone [13].
• TAT activity of hepatomas was two times greater than that of host liver, and lack of dietary pyridoxine was without effect [13].

Biological context of Tat

• 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 [1].
• The primary structure of tyrosine aminotransferase, as deduced from the nucleotide sequence of complementary DNA, was confirmed by fast atom bombardment mass spectrometry of tryptic peptides derived from the purified protein [14].
• Like the isoenzymes of aspartate aminotransferase, tyrosine aminotransferase may contain two domains, with a central, catalytic core, and a small domain made up of both amino- and carboxyl-terminal components [14].
• The primary structure of rat tyrosine aminotransferase (L-tyrosine:2-oxoglutarate aminotransferase; EC 2.6.1.5), a liver-specific enzyme involved in gluconeogenesis, has been deduced from the nucleotide sequence of a cloned full-length cDNA [15].
• The catalytic relevance of the putative rat TAT active site residues Asn54 and Arg57, which are strictly conserved in TATs (Asn17 and Arg20 in T. cruzi TAT) but differ in ASATs and ARATs, was also explored [16].

Anatomical context of Tat

• Spliced and unspliced viral transcripts were expressed in lymph nodes, thymus, liver, kidney, and spleen, suggesting that Tat and Rev are functional [17].
• Several peptides, including penetratin and Tat, are known to translocate across the plasma membrane [18].
• CEP1347 also enhanced survival of both rat and human neurons and inhibited the activation of human monocytes after exposure to Tat and gp120 [19].
• 7. Effects of Tat were studied by using a stable Tat expressing RAW264.7 cell line or by addition of recombinant Tat protein to co-cultures [20].
• Defining the pathway for Tat-mediated delivery of beta-glucuronidase in cultured cells and MPS VII mice [21].

Associations of Tat with chemical compounds

• Tyrosine aminotransferase belongs to a superfamily of enzymes which includes aspartate aminotransferase and can be aligned so that many invariant, functional residues coincide [14].
• Aggregation of neurons was inhibited by the addition of monoclonal antibodies directed against the RGD and basic domains of Tat, but not against the proline-rich domain [22].
• Furthermore, kainate-induced neuronal loss in hippocampal CA1 and CA3 subregions was prevented by intracerebroventricular injection of Tat-Glur6 - 9c [23].
• By contrast treatment of slice cultures with Tat in the absence of RAW264.7 cells was not neurotoxic [20].
• Furthermore, cytogenetic data exhibited less chromosomal damage in Tat-producing cells after recovery from cisplatin treatment, corroborating electrophoretic data [24].

Physical interactions of Tat

• A cystine-dependent inactivator of tyrosine aminotransferase co-purifies with gamma-cystathionase (cystine desulfurase) [25].
• It is concluded from these studies that lysosomotrophic reagents enhance tyrosine aminotransferase induction by glucocorticoids and stabilize unbound glucocorticoid receptor both in vivo and in vitro without any effect on in vitro transformation of the steroid-receptor complex [26].
• Induction of tyrosine aminotransferase and amino acid transport in rat hepatoma cells by insulin and the insulin-like growth factor, multiplication-stimulating activity. Mediation by insulin and multiplication-stimulating activity receptors [27].

Regulatory relationships of Tat

• However, transduction of exogenous RACK1 expressed as a Tat-fusion protein was able to rescue c-fos mRNA expression after chronic ethanol exposure [28].
• In this system the enzyme tyrosine aminotransferase is induced by glucagon, (10(-6) to 10(-8) M) hydrocortisone (10(-5) to 10(-8) M), and cyclic adenosine 3':5'-monophosphate (cAMP) (10(-4) to 10(-5) M) [29].
• The nuclear proteins which act synergistically with the glucocorticoid receptor to induce transcription of the tyrosine aminotransferase gene include factors recognizing the CACCC element [30].
• It induced tyrosine aminotransferase in the liver and repressed thymidine kinase in the thymus very effectively [31].
• In this work we found that the induction of tyrosine aminotransferase by glucocorticoid in rat hepatocytes was suppressed concentration-dependently by TGF-beta and H-7, an inhibitor of protein kinase C, but not by other polypeptide growth factors tested or by H-8, an inhibitor of cyclic nucleotide dependent protein kinases [32].

Other interactions of Tat

• The carboxyl terminus of tyrosine aminotransferase contains features that typify proteins with short half-lives; it includes two negatively charged, hydrophilic segments that are enriched for glutamyl residues and are similar to a PEST region in ornithine decarboxylase (Rogers, S., Wells, R., and Rechsteiner, M. (1986) Science 234, 364-368) [14].
• First, transduction of full-length RACK1 (Tat-RACK1) resulted in the induction of c-fos expression and enhancement of ethanol activities [33].
• Fusion of the Tat-translocating domain to the N-terminus of the enzyme produced a cell permeable, functional enzyme, as evidenced by immunocytochemistry and by the cleavage of cytosolic SNAP25 in intact PC12 cells [34].
• Thus, Tat-catalase should be a useful tool to dissect H(2)O(2)-dependent events in signaling pathways [35].
• Ethanol in the presence of disulfiram (N,N,N',N'-tetraethylthiuram disulfide, an inhibitor of aldehyde dehydrogenase) inhibited liver beta-alanine-oxoglutarate aminotransferase (beta-AlaAT I) activity yet activated tyrosine aminotransferase (TAT) in weanling rats in vivo [36].

Analytical, diagnostic and therapeutic context of Tat

• Membrane permeation peptides, such as Tat basic domain, have emerged as useful membrane transduction agents with potential utility in therapeutic delivery and diagnostic imaging [37].
• Using a gel-shift assay and affinity chromatography on an L-arginine column we found that these compounds bind specifically to the transactivation responsive element RNA in vitro with Kd values in the range of 20-400 nM, which is comparable to the Kd of native Tat bound to the transactivation responsive element (10-12 nM) [38].
• To explore the possibility that Tat can affect primary brain cells, we examined the effect of recombinant Tat protein on rat cortical brain cell cultures [39].
• In this study we examined temporal progression of histopathological changes induced by a single microinjection of Tat 1-72 into the rat striatum [40].
• Thus, the diminishing TAT effect on PPI at day 90 in a longitudinal study design was attributed to repeated testing, rather than 'recovery of function'. Collectively, the data suggested that hippocampal Tat injections in neonatal rats produced alterations in the pre-attentive process of sensorimotor gating, as indexed by PPI [41].

References