Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcriptional induction of genes is an essential part of the cellular response to interferons. To isolate yet unidentified IFN-regulated genes we have performed a differential screening on a cDNA library prepared from human lymphoblastoid Daudi cells treated for 16 h with human alpha/beta interferon (Hu-alpha/beta IFN). In the course of these studies we have isolated a human cDNA which codes for a protein sharing homology with the mouse Rpt-1 gene; it will be referred as Staf-50 for Stimulated Trans-Acting Factor of 50 kDa. Amino acid sequence analysis revealed that Staf-50 is a member of the Ring finger family and contains all the features of a transcriptional regulator able to initiate a second cascade of gene induction (secondary response). Staf-50 is induced by both type I and type II IFN in various cell lines and down-regulates the transcription directed by the long terminal repeat promoter region of human immunodeficiency virus type 1 in transfected cells. These data are consistent with a role of Staf-50 in the mechanism of transduction of the IFN antiviral action.
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PMID:Molecular cloning of a new interferon-induced factor that represses human immunodeficiency virus type 1 long terminal repeat expression. 779 67

The rev protein (Rev) of the human immunodeficiency virus type 1 (HIV-1) is known as a post-transcriptional regulator of viral gene expression. It is located in the cell nucleolus. Transiently expressed Rev caused nucleolar ballooning and deformity with aberrant accumulation of rRNAs, and de novo synthesis of rRNAs decreased dramatically in these cells. However, similarly expressed rex protein (Rex) of the human T-cell leukemia virus type I, which is a functional homologue to Rev, did not affect nucleolar structure and function. Rev expression resulted in cell death with nucleolar destruction in an inducible cell line. Analysis of Rev mutants revealed that both the nucleolar targeting signal of Rev and the multimerization domain are prerequisites to the nucleolar disintegration by Rev. Human T-cells acutely infected with HIV-1 contained nucleoli which were deformed and filled with Rev, but chronically infected cells had intact nucleoli. Involvement of Rev in cytopathic effects in HIV-1 infection is discussed.
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PMID:Cytotoxic activity of rev protein of human immunodeficiency virus type 1 by nucleolar dysfunction. 822 12

The 86 amino acid trans-activator (Tat) protein of human immunodeficiency virus type 1 (HIV-1) is an RNA-binding transcriptional regulator. HIV-1 Tat proteins (wild type and Thr40Lys mutant) and the HIV-1 Tat peptide fragments Tat(32-48) and Tat(32-72) were chemically synthesized. One- and two-dimensional nuclear magnetic resonance spectroscopy experiments were performed to elucidate the structural features of these proteins. In fluorescence quenching studies of the full-length Tat protein (Thr40Lys), Trp11 was found to be only partially protected against solvent accessibility. Circular dichroism melting studies monitored a slight cooperative change in the conformation of the Tat with increasing temperature. Backbone NH protons of amino acids located in the main core element of the protein are partially protected against exchange.
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PMID:Spectroscopic investigations of HIV-1 trans-activator and related peptides in aqueous solutions. 910 85

The main transcriptional regulator of the human immunodeficiency virus, the Tat protein, recognizes and binds to a small structured RNA element at the 5' end of every viral mRNA, termed TAR. On the basis of published structural data of the molecular interactions between TAR and Tat-related peptides, we defined requirements for potential low-molecular weight inhibitors of TAR recognition by the Tat protein. In accordance with the resulting concept, a series of compounds was synthesized. In vitro evaluation of their potential to directly interfere with Tat-TAR interaction was used to define a new chemical class of potent Tat antagonistic substances. The most active compound competed with Tat-TAR complexation with a competition dose CD50 of 22 nM in vitro and blocked HIV expression in a cellular Tat transactivation system with an IC50 of 1.2 microM. The close relation between structural features of the interaction between TAR and a new type of inhibitory agent, "In-PRiNts" (for inhibitor of protein-ribonucleotide sequences), such as CGP 40336A and those of the Tat-TAR complex was confirmed by RNase A footprinting and by two-dimensional NMR. Structural implications for the complex between this class of compounds and TAR RNA will be presented.
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PMID:A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition. 954 39

The human immunodeficiency virus type 1 transcriptional regulator Tat increases the efficiency of elongation, and complexes containing the cellular kinase CDK9 have been implicated in this process. CDK9 is part of the Tat-associated kinase TAK and of the elongation factor P-TEFb (positive transcription elongation factor-b), which consists minimally of CDK9 and cyclin T. TAK and P-TEFb are both able to phosphorylate the carboxy-terminal domain (CTD) of RNA polymerase II, but their relationships to one another and to the stimulation of elongation by Tat are not well characterized. Here we demonstrate that human cyclin T1 (but not cyclin T2) interacts with the activation domain of Tat and is a component of TAK as well as of P-TEFb. Rodent (mouse and Chinese hamster) cyclin T1 is defective in Tat binding and transactivation, but hamster CDK9 interacts with human cyclin T1 to give active TAK in hybrid cells containing human chromosome 12. Although TAK is phosphorylated on both serine and threonine residues, it specifically phosphorylates serine 5 in the CTD heptamer. TAK is found in the nuclear and cytoplasmic fractions of human cells as a large complex (approximately 950 kDa). Magnesium or zinc ions are required for the association of Tat with the kinase. We suggest a model in which Tat first interacts with P-TEFb to form the TAK complex that engages with TAR RNA and the elongating transcription complex, resulting in hyperphosphorylation of the CTD on serine 5 residues.
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PMID:Human and rodent transcription elongation factor P-TEFb: interactions with human immunodeficiency virus type 1 tat and carboxy-terminal domain substrate. 1036 92

We have previously identified a cDNA encoding a cellular protein, Tip60 (Tat interactive protein, 60 kDa), that specifically interacts with the Tat (transactivating transcriptional regulator) protein of the human immunodeficiency virus-1 (HIV-1). In this report, we have characterized cellular Tip and find that it is a 60 kDa nuclear protein expressed in a wide variety of differentiated cell lines from insects to man. To identify cellular functions of Tip, we have assayed the effects of Tip on cellular pathways that Tat has been reported to affect. Overexpression of Tip results in an almost complete block in activation of a Gal4-CREB (cAMP response element binding protein) fusion protein by cyclic AMP dependent protein kinase A (PKA). This inhibition appears to be mediated through direct interaction of Tip and CREB, since Tip directly binds to CREB protein in vitro. We show that amino acid substitutions of two conserved amino acids found in the putative acetyl coenzyme A binding motif of Tip completely abolishes the histone acetyltransferase (HAT) activity of recombinant Tip. Inhibition of CREB activation by Tip is not diminished in a HAT negative Tip mutant, indicating that Tip can negatively regulate gene expression independent of HAT activity. Recently, Tip has also been shown to be a transcriptional coactivator of nuclear hormone receptors; therefore, Tip can both activate transcription factors of one signaling pathway (nuclear hormone receptors) and bind to a different transcription factor (CREB) and inhibit activation of another signaling pathway.
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PMID:Tip60 inhibits activation of CREB protein by protein kinase A. 1072 Apr 89

The main transcriptional regulator of the human immunodeficiency virus is the Tat protein, which recognises and binds to a fragment RNA at the 5' end of viral mRNA, named transactivation response element (TAR) RNA. Extensive mutagenesis studies have shown that a region of TAR RNA important for Tat binding involves a set of nucleotides surrounding a characteristic UCU nucleotide bulge. The specific Tat-TAR complex formation enhances the rate of transcription elongation but inhibition of that interaction prevents the human immunodeficiency virus type 1 (HIV-1) replication. If so, a possibility of virus inactivation would be a site specific degradation of the TAR RNA element. To break down and inactivate TAR RNA, we designated the anti-hammerhead (HH) ribozyme to cleave nucleosides within the bulge. We showed for the first time the new type of the AUC hammerhead ribozyme, which hydrolyses specifically the TAR RNA element at C8 nucleotide in the bulge (C24 in the standard TAR RNA numbering). The cleavage reaction has broad magnesium requirements. Mn and particularly Ca are less efficient. Argininamide interferes with the cleavage of TAR RNA induced by the ribozyme. These results have two implications; (i) structural, where the HIV-1 TAR RNA element in solution occurs in equilibrium of only two forms, one of which, a double stranded RNA, meets structural requirements for ribozyme pairing and cleavage, and (ii) functional, the HH ribozyme can be explored for an inactivation of HIV-1 through the TAR RNA element deintegration.
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PMID:The specific hydrolysis of HIV-1 TAR RNA element with the anti-TAR hammerhead ribozyme: structural and functional implications. 1132 24

Human herpesvirus-8 (HHV-8) is a lymphotropic virus associated with several AIDS-related neoplasms. Two ORFs play a critical role in the regulation of virus replication: ORF50, encoding an immediate-early transcriptional activator, and ORF57, encoding a post-transcriptional regulator. We analysed their effects on the activation of the human immunodeficiency virus type 1 (HIV-1) LTR. ORF50 interacted synergically with tat, inducing a 10-fold enhancement of HIV-1 LTR transactivation. This effect occurred both in BCBL-1 cells, latently infected with HHV-8, and in HL3T1 cells, an epithelial cell line non-permissive to HHV-8 infection. Also, ORF57 enhanced tat-induced transactivation of HIV-1 LTR, but only in BCBL-1 cells, suggesting that its action was likely mediated by the induction of other viral functions. Finally, when both ORFs were expressed, the enhancement of transactivation induced by ORF50 was partially inhibited. The findings suggest that ORF57 can modulate ORF50 activity and that ORF50 may render biologically active small amounts of tat.
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PMID:Human herpesvirus-8 (Kaposi's sarcoma-associated herpesvirus) ORF50 interacts synergistically with the tat gene product in transactivating the human immunodeficiency virus type 1 LTR. 1145 4

Chemokines are important mediators of inflammation. It has been demonstrated that there is an increase in chemokine expression in both the sera and brain of individuals infected with human immunodeficiency virus type 1 (HIV-1). The HIV-1 viral protein, Tat, a transcriptional regulator, has been detected in the central nervous system (CNS) of infected individuals, and has been demonstrated to induce chemokines from various cells within the brain. The authors now show that the interaction of human microglia, the resident phagocytes of the brain, with Tat leads to dramatic increases in the secretion of the chemokines CCL2, CXCL8, CXCL10, CCL3, CCL4, and CCL5. Treatment of microglia with Tat plus specific inhibitors of signal transduction pathways demonstrated that the induction of each chemokine is regulated differently. Tat-induced expression of CCL2 and CCL4 was mediated by the activation of the extracellular regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K) pathway, whereas the induction of CXCL8 and CCL3 was mediated only by the p38 MAPK pathway. Tat-induced CXCL10 expression was mediated, to some extent, by activation of the ERK1/2 MAPK pathway, phosphatidylinositol 3-kinase pathway, and the p38 MAPK pathway, whereas CCL5 expression was not mediated by any pathway tested. Western blot analysis demonstrated phosphorylation of ERK 1/2 and Akt upon stimulation of microglia with Tat. These data suggest that a soluble HIV-1 viral protein can alter the chemokine balance in the brain, which can then lead to an influx of inflammatory cells and contribute to the neuropathogenesis of HIV-1 infection.
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PMID:Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. 1520 27

First identified as peptides derived from the human immunodeficiency virus (HIV) transcriptional regulator Tat and the Drosophila transcription factor Antennapedia, transduction (or cell-penetrating) peptide sequences enable soluble proteins to cross biological membranes and interact with cytosolic and nuclear targets. Proteins containing such sequences have been found to function as transcription factors, to inhibit apoptosis, to play roles in axon guidance, or to transport viral mRNA between cells. The recent demonstration that dynorphins are able to act as transduction peptides suggests that these neuropeptides may have roles independent of opiate receptor activation.
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PMID:Transduction peptides within naturally occurring proteins. 1633 16


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