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Biomedicine & Pharmacotherapy =... Oct 2021MicroRNAs play an important role in health and disease. TGF-β signaling, upregulated by HIV Tat, and in chronic airway diseases and smokers upregulates miR-145-5p to...
BACKGROUND
MicroRNAs play an important role in health and disease. TGF-β signaling, upregulated by HIV Tat, and in chronic airway diseases and smokers upregulates miR-145-5p to suppress cystic fibrosis transmembrane conductance regulator (CFTR). CFTR suppression in chronic airway diseases like Cystic Fibrosis, COPD and smokers has been associated with suppressed MCC and recurrent lung infections and inflammation. This can explain the emergence of recurrent lung infections and inflammation in people living with HIV.
METHODS
Tat-induced aberrant microRNAome was identified by miRNA expression analysis. microRNA mimics and antagomirs were used to validate the identified miRNAs involved in Tat mediated CFTR mRNA suppression. CRISPR-based editing of the miRNA target sites in CFTR 3'UTR was used to determine rescue of CFTR mRNA and function in airway epithelial cell lines and in primary human bronchial epithelial cells exposed to TGF-β and Tat.
FINDINGS
HIV Tat upregulates miR-145-5p and miR-509-3p. The two miRNAs demonstrate co-operative effects in suppressing CFTR. CRISPR-based editing of the miRNA target site preserves CFTR mRNA and function in airway epithelial cells INTERPRETATION: Given the important roles of TGF-β signaling and the multitude of genes regulated by miRNAs, we demonstrate that CRISPR-based gene-specific microRNA antagonism approach can preserve CFTR mRNA and function in the context of HIV Tat and TGF-β signaling without suppressing expression of other genes regulated by miR-145-5p.
Topics: 3' Untranslated Regions; Bronchi; CRISPR-Cas Systems; Cell Line; Cells, Cultured; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Gene Editing; Humans; MicroRNAs; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Up-Regulation; tat Gene Products, Human Immunodeficiency Virus
PubMed: 34463266
DOI: 10.1016/j.biopha.2021.112090 -
Microbiological Reviews Jun 1991Human immunodeficiency virus (HIV) has a complex life cycle in which both cellular and virus-encoded factors participate to determine the level of virus production. Two... (Review)
Review
Human immunodeficiency virus (HIV) has a complex life cycle in which both cellular and virus-encoded factors participate to determine the level of virus production. Two of the viral genes, tat and rev, are essential for virus replication and encode novel trans-activators that interact specifically with their cognate RNA target elements. Elucidation of their mechanisms of action is likely to expand our knowledge of gene regulation at transcriptional and posttranscriptional levels in the eukaryotic cell. Several viral genes (vif, vpu, and vpr) facilitate virus infection and/or release and may play a role in target cell tropism and infection in vivo. The functions of yet other viral genes (nef, vpt) remain unclear. Recent data also suggest that the tat gene product may have a role in HIV pathogenesis that goes beyond trans-activating virus expression. It can potentially impact on uninfected cells as a diffusible molecule and alter the growth of different cell types.
Topics: Antiviral Agents; Gene Expression Regulation, Viral; Gene Products, rev; Gene Products, tat; Genes, Viral; HIV; HIV Long Terminal Repeat; Herpesviridae; Humans; Opportunistic Infections; Regulatory Sequences, Nucleic Acid; Transcriptional Activation; Virus Replication; rev Gene Products, Human Immunodeficiency Virus; tat Gene Products, Human Immunodeficiency Virus
PubMed: 1886517
DOI: 10.1128/mr.55.2.193-205.1991 -
The Journal of Biological Chemistry Oct 2002Human immunodeficiency virus, type 1-encoded transactivator protein Tat is known to be a substrate of and to interact with several nuclear histone acetyltransferases...
Human immunodeficiency virus, type 1-encoded transactivator protein Tat is known to be a substrate of and to interact with several nuclear histone acetyltransferases (HATs). Here we show that Tat is a general inhibitor of histone acetylation by cellular HATs and that for at least one of them, the CREB-binding protein (CBP), it induces a substrate selectivity. Indeed, in the presence of Tat, the acetylation of histones by CBP was severely inhibited, while that of p53 and MyoD remained unaffected. The C-terminal domain of Tat, dispensable for the activation of viral transcription, was found to be necessary and sufficient to interfere with histone acetylation. These results demonstrate that Tat is able to selectively modulate cellular protein acetylation by nuclear HATs and therefore to take over this specific signaling system in cells.
Topics: Acetylation; Acetyltransferases; Animals; Binding Sites; CREB-Binding Protein; Cell Cycle Proteins; DNA Primers; Gene Products, tat; Genes, Reporter; HIV-1; HeLa Cells; Histone Acetyltransferases; Humans; Jurkat Cells; Luciferases; Nuclear Proteins; Polymerase Chain Reaction; Saccharomyces cerevisiae Proteins; Trans-Activators; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Tumor Suppressor Protein p53; p300-CBP Transcription Factors; tat Gene Products, Human Immunodeficiency Virus
PubMed: 12154097
DOI: 10.1074/jbc.M206694200 -
Acta Endocrinologica (Bucharest,... 2022Interventions that suppress hepatic gluconeogenesis from amino acids may be useful for improving glycemic control in diabetic patients.
CONTEXT
Interventions that suppress hepatic gluconeogenesis from amino acids may be useful for improving glycemic control in diabetic patients.
OBJECTIVES
It was shown that administration of glucocorticoid receptor antagonist Mifepristone (MIF) leads to variously pronounced changes in the alanine-, aspartate-, tyrosine- aminotransferases (ALT, AST, TAT) activity in the liver of experimental animals. It has been suggested that this selective effect of MIF may be related to differences in the expression of the corresponding genes. The aim of the study was to investigate the gene expression and activity of ALT, AST and TAT in the liver of rats with streptozotocin-related diabetes (StD) under the long-term oral MIF administration.
METHODS
Male Wistar rats (n=48) with StD under the 10-days oral MIF administration were used. It was measured the activity of ALT, AST, TAT enzymes and relative expression of this genes in the liver of experimental animals.
RESULTS
In rats with StD the gene expression of all three studied aminotransferases in the liver was statistically significantly increased and their activity was increased as well. MIF administration did not change the studied genes expression and enzymes activity to healthy rats and caused a decrease in expression of ALT and AST genes and activity of these enzymes to rats with StD. However, the expression of the TAT gene and the activity of this enzyme in the liver of rats with StD increased upon MIF administration in comparison with animals with StD.
CONCLUSIONS
The introduction of MIF against the background of StD reduces the expression of genes and the activity of ALT and AST in the liver, what determine the transamination of amino acids to include them in gluconeogenesis, but increases the expression of genes and the activity of TAT, what determine the inclusion of tyrosine in the biogenic amines synthesis. The mechanisms of such selectivity require further study.
PubMed: 36212251
DOI: 10.4183/aeb.2022.145 -
Disease Models & Mechanisms Oct 2020Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with...
Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with HIVAN all over the world. Furthermore, once HIVAN is established in children, it is difficult to revert its long-term progression, and we need better animal models of childhood HIVAN to test new treatments. To define whether the HIV-1 trans-activator () gene precipitates HIVAN in young mice, and to develop an inducible mouse model of childhood HIVAN, an HIV-Tat gene cloned from a child with HIVAN was used to generate recombinant adenoviral vectors (rAd-). rAd- and control vectors (2×10) were expressed in the kidney of newborn wild-type and HIV-transgenic (Tg) FVB/N mice without significant proteinuria (=5; 8 per group). Mice were sacrificed 7 and 35 days later to assess their renal outcome, the expression of HIV-genes and growth factors, and markers of cell growth and differentiation by RT-qPCR, immunohistochemistry and/or western blots. HIV-Tat induced the expression of HIV-1 genes and heparin-binding growth factors in the kidney of HIV-Tg mice, and precipitated HIVAN in the first month of life. No significant renal changes were detected in wild-type mice infected with rAd- vectors, suggesting that HIV-Tat alone does not induce renal disease. This new mouse model of childhood HIVAN highlights the critical role that HIV-Tat plays in the pathogenesis of HIVAN, and could be used to study the pathogenesis and treatment of HIVAN in children and adolescents.
Topics: AIDS-Associated Nephropathy; Albuminuria; Amino Acid Sequence; Animals; Animals, Newborn; Apoptosis; Cell Dedifferentiation; Cell Proliferation; Child; Disease Models, Animal; Fibroblast Growth Factor 2; HIV-1; Humans; Kidney; Mice, Transgenic; Podocytes; RNA, Messenger; Vascular Endothelial Growth Factor A; beta-Galactosidase; env Gene Products, Human Immunodeficiency Virus; tat Gene Products, Human Immunodeficiency Virus
PubMed: 32917744
DOI: 10.1242/dmm.045641 -
Metabolites Apr 2022Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane...
Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane integrin αvβ3 of tumor cells. Via a specific hormone receptor on the integrin, tetrac-based therapeutic agents modulate expression of genes relevant to cancer cell proliferation, survival and energy metabolism. P-bi-TAT, a novel bivalent tetrac-containing synthetic compound has anticancer activity in vitro and in vivo against glioblastoma multiforme (GBM) and other types of human cancers. In the current study, microarray analysis was carried out on a primary culture of human GBM cells exposed to P-bi-TAT (10 tetrac equivalent) for 24 h. P-bi-TAT significantly affected expression of a large panel of genes implicated in cancer cell stemness, growth, survival and angiogenesis. Recent interest elsewhere in ATP synthase as a target in GBM cells caused us to focus attention on expression of genes involved in energy metabolism. Significantly downregulated transcripts included multiple energy-metabolism-related genes: electron transport chain genes ATP5A1 (ATP synthase 1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase (ubiquinone) FA8), NDUFV2I and other NDUF genes. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Qualitatively similar actions of P-bi-TAT on expression of subsets of energy-metabolism-linked genes were also detected in established human GBM and pancreatic cancer cell lines. In conclusion, acting at αvβ3 integrin, P-bi-TAT caused downregulation in human cancer cells of expression of a large number of genes involved in electron transport and oxidative phosphorylation. These observations suggest that cell surface thyroid hormone receptors on αvβ3 regulate expression of genes relevant to tumor cell stemness and energy metabolism.
PubMed: 35448512
DOI: 10.3390/metabo12040325 -
Aging Nov 2023We investigated the effects of heat shock protein 10 (HSP10) protein on memory function, hippocampal neurogenesis, and other related genes/proteins in adult and aged...
We investigated the effects of heat shock protein 10 (HSP10) protein on memory function, hippocampal neurogenesis, and other related genes/proteins in adult and aged mice. To translocate the HSP10 protein into the hippocampus, the Tat-HSP10 fusion protein was synthesized, and Tat-HSP10, not HSP10, was successfully delivered into the hippocampus based on immunohistochemistry and western blotting. Tat-HSP10 (0.5 or 2.0 mg/kg) or HSP10 (control protein, 2.0 mg/kg) was administered daily to 3- and 21-month-old mice for 3 months, and observed the senescence maker P16 was significantly increased in aged mice and the treatment with Tat-HSP10 significantly decreased P16 expression in the hippocampus of aged mice. In novel object recognition and Morris water maze tests, aged mice demonstrated decreases in exploratory preferences, exploration time, distance moved, number of object contacts, and escape latency compared to adult mice. Treatment with Tat-HSP10 significantly improved exploratory preferences, the number of object contacts, and the time spent swimming in the target quadrant in aged mice but not adults. Administration of Tat-HSP10 increased the number of proliferating cells and differentiated neuroblasts in the dentate gyrus of adult and aged mice compared to controls, as determined by immunohistochemical staining for Ki67 and doublecortin, respectively. Additionally, Tat-HSP10 treatment significantly mitigated the reduction in sirtuin 1 mRNA level, -methyl-D-aspartate receptor 1, and postsynaptic density 95 protein levels in the hippocampus of aged mice. In contrast, Tat-HSP10 treatment significantly increased sirtuin 3 protein levels in both adult and aged mouse hippocampus. These suggest that Tat-HSP10 can potentially reduce hippocampus-related aging phenotypes.
Topics: Animals; Mice; Cell Differentiation; Chaperonin 10; Hippocampus; Neurogenesis; Neuronal Plasticity; Tyrosine Transaminase
PubMed: 38011257
DOI: 10.18632/aging.205182 -
Frontiers in Cellular Neuroscience 2022Methamphetamine (Meth) abuse is a common HIV co-morbidity that is linked to aggravated Central Nervous System (CNS) inflammation, which accentuates HIV- associated...
Methamphetamine signals transcription of IL1β and TNFα in a reactive oxygen species-dependent manner and interacts with HIV-1 Tat to decrease antioxidant defense mechanisms.
Methamphetamine (Meth) abuse is a common HIV co-morbidity that is linked to aggravated Central Nervous System (CNS) inflammation, which accentuates HIV- associated neurological disorders, triggered both directly or indirectly by the drug. We used the well-established human innate immune macrophage cell line system (THP1) to demonstrate that Reactive Oxygen Species (ROS) immediately induced by Meth play a role in the increased transcription of inflammatory genes, in interaction with HIV-1 Tat peptide. Meth and Tat, alone and together, affect early events of transcriptional activity, as indicated by changes in RNA polymerase (RNAPol) recruitment patterns throughout the genome, via ROS-dependent and -independent mechanisms. IL1β (IL1β) and TNF α (TNFα), two genes with defining roles in the inflammatory response, were both activated in a ROS-dependent manner. We found that this effect occurred via the activation of the activator protein 1 (AP-1) comprising cFOS and cJUN transcription factors and regulated by the SRC kinase. HIV-1 Tat, which was also able to induce the production of ROS, did not further impact the effects of ROS in the context of Meth, but promoted gene activity independently from ROS, via additional transcription factors. For instance, HIV-1 Tat increased NFkB activation and activated gene clusters regulated by Tata box binding peptide, ING4 and IRF2. Importantly, HIV-1 Tat decreased the expression of anti-oxidant genes, where its suppression of the detoxifying machinery may contribute to the aggravation of oxidative stress induced by ROS in the context of Meth. Our results provide evidence of effects of Meth via ROS and interactions with HIV Tat that promote the transcription of inflammatory genes such as IL1β and TNFα.
PubMed: 36060276
DOI: 10.3389/fncel.2022.911060 -
Poultry Science May 2023In a previous study, the laying pattern of Muscovy duck was explored by macro-fitting the laying curve of Muscovy duck, and transcriptome sequencing technique of the...
In a previous study, the laying pattern of Muscovy duck was explored by macro-fitting the laying curve of Muscovy duck, and transcriptome sequencing technique of the ovarian tissues was used to screen the egg-related gene "TAT." Moreover, recent results have shown that TAT is expressed in organs such as oviduct, ovary, and testis. The objective of this study is to examine the effect of TAT gene on egg production traits of Muscovy ducks. First, the expression levels of TAT gene in highest producing (HP) and lowest producing (LP) in 3 tissues related to reproduction were examined, and the results indicated that the expression of TAT gene in hypothalamus was significantly different between HP and LP groups. Then, 6 SNP loci (g. 120G>T, g, 122G>A, g, 254G> A, g. 270C >T, g, 312G>A, and g. 341C>A) were detected in TAT gene. Further, association analysis between the six SNP loci of TAT gene and egg production traits of 652 individual Muscovy ducks was done. The results showed that g. 254G>A and g. 270C>T were significantly correlated (P < 0.05 or 0.001) with the egg production traits of Muscovy ducks. This study elucidated the molecular mechanism that TAT gene might be regulating the egg production traits of Muscovy ducks.
Topics: Female; Male; Animals; Ducks; Genes, tat; Chickens; Polymorphism, Genetic; Phenotype
PubMed: 36972669
DOI: 10.1016/j.psj.2023.102551 -
Oncotarget Apr 2017The human immunodeficiency virus type I (HIV-1) has developed several strategies to condition the host environment to promote viral replication and spread. Viral... (Review)
Review
The human immunodeficiency virus type I (HIV-1) has developed several strategies to condition the host environment to promote viral replication and spread. Viral proteins have evolved to perform multiple functions, aiding in the replication of the viral genome and modulating the cellular response to the infection. Tat is a small, versatile, viral protein that controls transcription of the HIV genome, regulates cellular gene expression and generates a permissive environment for viral replication by altering the immune response and facilitating viral spread to multiple tissues. Studies carried out utilizing biochemical, cellular, and genomic approaches show that the expression and activity of hundreds of genes and multiple molecular networks are modulated by Tat via multiple mechanisms.
Topics: Animals; Apoptosis; Disease Susceptibility; Gene Expression Regulation; Gene Expression Regulation, Viral; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Immunomodulation; MicroRNAs; Protein Transport; Transcriptional Activation; tat Gene Products, Human Immunodeficiency Virus
PubMed: 28187438
DOI: 10.18632/oncotarget.15174