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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Tat trans-activator protein from HIV-1 inhibits the function of the class II trans-activator protein (CIITA), resulting in reduced MHC class II gene transcription in human cells. Tat does so by competing with CIITA for binding to cyclin T1, a component of the transcriptional elongation complex PTEFb. Since Tat does not functionally interact with mouse cyclin T1, we decided to examine the ability of Tat to inhibit CIITA in mouse cells. We found that Tat inhibited CIITA activity in mouse cells though this inhibition was independent of cyclin T1. The inhibition required the transcriptional activation domain of CIITA, but did not involve alterations in MHC class II promoter occupancy. Although Tat blocked the interaction between CIITA protein and human cyclin T1, it had no effect on the binding between CIITA and mouse cyclin T1. Therefore, Tat can inhibit the ability of CIITA to activate transcription of MHC class II genes in mouse cells by a mechanism that appears to be distinct from that proposed for human cells.
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PMID:Inhibition of class II trans-activator function by HIV-1 tat in mouse cells is independent of competition for binding to cyclin T1. 1175 Jun 55

The human immunodeficiency virus type 1 (HIV-1) Tat protein activates transcription elongation by stimulating the Tat-activated kinase (TAK/p-TEFb), a protein kinase composed of CDK9 and its cyclin partner, cyclin T1. CDK9 is able to hyperphosphorylate the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase during elongation. In addition to TAK, the transcription elongation factor Spt5 is required for the efficient activation of transcriptional elongation by Tat. To study the role of Spt5 in HIV transcription in more detail, we have developed a three-stage Tat-dependent transcription assay that permits the isolation of active preinitiation complexes, early-stage elongation complexes, and Tat-activated elongation complexes. Spt5 is recruited in the transcription complex shortly after initiation. After recruitment of Tat during elongation through the transactivation response element RNA, CDK9 is activated and induces hyperphosphorylation of Spt5 in parallel to the hyperphosphorylation of the CTD of RNA polymerase II. However, immunodepletion experiments demonstrate that Spt5 is not required for Tat-dependent activation of the kinase. Chase experiments using the Spt5-depleted extracts demonstrate that Spt5 is not required for early elongation. However, Spt5 plays an important role in late elongation by preventing the premature dissociation of RNA from the transcription complex at terminator sequences and reducing the amount of polymerase pausing at arrest sites, including bent DNA sequences. This novel biochemical function of Spt5 is analogous to the function of NusG, an elongation factor found in Escherichia coli that enhances RNA polymerase stability on templates and shows sequence similarity to Spt5.
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PMID:Spt5 cooperates with human immunodeficiency virus type 1 Tat by preventing premature RNA release at terminator sequences. 1180

Ubiquitous gene expression has a variety of applications in transgenesis that include, for example cell lineage analyses in chimeras and gain-of-function related to xenotransplantations. Although several promoters have already been used to these aims, they often do not reliably or reproducibly target gene expression in mice. We have recently reported the site-independent expression of a bacterial artificial chromosome (BAC)-derived goat alpha-lactalbumin transgene in the mammary gland of mice and the subsequent localisation within the insert of this BAC of the cyclin T1 locus. This ubiquitously expressed gene encodes for a protein that acts as a co-factor for the HIV nuclear transcriptional activator. In the present paper, we report that the goat BAC transgene, which encompasses around 30 kb of the cyclin T1 promoter, also confers ubiquitous expression of this gene in the six transgenic mouse lines analysed. These results suggest that the cyclin T1 promoter could be a useful alternative to target ubiquitous gene expression in transgenics.
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PMID:Ubiquitous expression of goat cyclin T1 in transgenic mice. 1187 4

FBI-1 is a cellular POZ-domain-containing protein that binds to the HIV-1 LTR and associates with the HIV-1 transactivator protein Tat. Here we show that elevated levels of FBI-1 specifically stimulate Tat activity and that this effect is dependent on the same domain of FBI-1 that mediates Tat-FBI-1 association in vivo. FBI-1 also partially colocalizes with Tat and Tat's cellular cofactor, P-TEFb (Cdk9 and cyclin T1), at the splicing-factor-rich nuclear speckle domain. Further, a less-soluble population of FBI-1 distributes in a novel peripheral-speckle pattern of localization as well as in other nuclear regions. This distribution pattern is dependent on the FBI-1 DNA binding domain, on the presence of cellular DNA, and on active transcription. Taken together, these results suggest that FBI-1 is a cellular factor that preferentially associates with active chromatin and that can specifically stimulate Tat-activated HIV-1 transcription.
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PMID:FBI-1 can stimulate HIV-1 Tat activity and is targeted to a novel subnuclear domain that includes the Tat-P-TEFb-containing nuclear speckles. 1190 72

Replication of human immunodeficiency virus requires Tat protein which activates elongation of RNA polymerase II transcription at the HIV-1 promoter through interaction with the cyclin T1 (CycT1) subunit of the positive transcription elongation factor complex (P-TEFb). Tat binds directly through its transactivation domain to the CycT1 subunit of the P-TEFb and induces loop sequence specific binding of the P-TEFb onto nascent HIV-1 TAR RNA. By using a gel electrophoresis method and a comprehensive set of TAR loop mutants, we have identified the sequence and structural determinants for high-affinity CycT1-Tat-TAR ternary complex formation. Our results show that CycT1 and Tat binding to TAR RNA is highly cooperative, and a capacity of 85%, a Hill coefficient of 2.7, and a dissociation constant (K(D)) of 2.45 nM were observed. These results indicate that there are three binding sites on TAR RNA. CycT1 does not bind TAR RNA in the absence of Tat, and Tat binding to TAR, while detectable, is very inefficient in the absence of CycT1. It is conceivable that the CycT1-Tat heterodimer directly binds to TAR RNA in the U-rich RNA bulge region and this binding facilitates the interactions of the CycT1-Tat heterodimer at the other two sites in the RNA loop region. On the basis of our results, we suggest a model where CycT1 interacts with Tat protein and positions the protein complex to make contacts with the G34 region of the loop sequence; G34 is critical for CycT1-Tat binding and forms a C30.G34 base pair. Two functional groups, O6 and N7, at nucleotide positions 32 and 34 in the TAR loop are essential for CycT1-Tat interactions with TAR RNA. The identity of two nucleotides, U31 and G33, is not critical, but they contribute to the stabilization of the RNA-protein complex. The presence of a single-nucleotide bulge of A35 or C35 is essential for distortion of the backbone RNA structure as well as the accessibility of functional groups in the major groove of the double-helical region. CycT1-Tat interaction with TAR RNA represents another example of the flexibility and complexity of RNA structure involved in protein recognition.
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PMID:Specific HIV-1 TAR RNA loop sequence and functional groups are required for human cyclin T1-Tat-TAR ternary complex formation. 1200 1

Replication of HIV requires the Tat protein, which activates elongation of RNA polymerase II transcription at the HIV-1 promoter by interacting with the cyclin T1 (CycT1) subunit of the positive transcription elongation factor complex b (P-TEFb). The transactivation domain of Tat binds directly to the CycT1 subunit of P-TEFb and induces loop sequence-specific binding of P-TEFb onto nascent HIV-1 trans-activation responsive region (TAR) RNA. We used systematic RNA-protein photocross-linking, Western blot analysis, and protein footprinting to show that residues 252-260 of CycT1 interact with one side of the TAR RNA loop and enhance interaction of Tat residue K50 to the other side of the loop. Our results show that TAR RNA provides a scaffold for two protein partners to bind and assemble a regulatory switch in HIV replication. RNA-mediated assembly of RNA-protein complexes could be a general mechanism for stable ribonucleoprotein complex formation and a key step in regulating other cellular processes and viral replication.
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PMID:TAR RNA loop: a scaffold for the assembly of a regulatory switch in HIV replication. 1204 47

The c-Myc protein is up-regulated in many different types of cancer, suggesting that a detailed understanding of Myc function is an important goal. Our previous studies have focused on determining the mechanism by which Myc activates transcription using the target gene cad as an experimental model. Previously, we found that Myc activates cad transcription at a post-RNA polymerase II recruitment step and that the Myc transactivation domain interacts with a number of cdk-cyclin complexes. We now extend these studies to determine the role of these cyclin-cdk complexes in Myc-mediated transactivation. We have found that cyclin T1 binding to Myc localizes to the highly conserved Myc Box I, whereas cdk8 binding localizes to the amino-terminal 41 amino acids of the Myc transactivation domain. We showed that recruitment of cdk8 is sufficient for activation of a synthetic promoter construct. In contrast, the ability of Myc to activate transcription of the cad promoter correlates with binding of cyclin T1. Furthermore, recruitment of cyclin T1 to the cad promoter via a Gal4 fusion protein or through protein-protein interaction with the HIV-1 Tat protein can also activate cad transcription. These results suggest that Myc activates transcription by stimulating elongation and that P-TEFb is a key mediator of this process.
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PMID:Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter. 1217 5

The human immunodeficiency virus type 1 (HIV-1) Tat protein is essential for viral replication and stimulates transcription of the integrated provirus by recruiting the kinase complex TAK/P-TEFb, composed of cyclin T1 (CycT1) and Cdk9, to the viral TAR RNA element. TAK/P-TEFb phosphorylates the RNA polymerase II complex and stimulates transcriptional elongation. In this report, we investigated the regulation of TAK/P-TEFb in primary human macrophages, a major target cell of HIV infection. While Cdk9 levels remained constant, CycT1 protein expression in freshly isolated monocytes was very low, increased early during macrophage differentiation, and, unexpectedly, decreased to very low levels after about 1 week in culture. The kinase activity of TAK/P-TEFb paralleled the changes in CycT1 protein expression. RNA analysis indicated that the transient induction of CycT1 protein expression involves a posttranscriptional mechanism. In transient transfection assays, the ability of Tat to transactivate the HIV long terminal repeat (LTR) in the late differentiated macrophages was greatly diminished relative to its ability to transactivate the HIV LTR in early differentiated cells, strongly suggesting that CycT1 is limiting for Tat function in late differentiated macrophages. Interestingly, lipopolysaccharide, a component of the cell wall of gram-negative bacteria, reinduced CycT1 expression late in macrophage differentiation. These results raise the possibility that regulation of CycT1 expression may be involved in establishing latent infection in macrophages and that opportunistic infection may reactivate the virus by inducing CycT1 expression.
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PMID:Transient induction of cyclin T1 during human macrophage differentiation regulates human immunodeficiency virus type 1 Tat transactivation function. 1236

Tat is a critical regulatory factor in HIV-1 gene expression. It mediates the transactivation of transcription from the HIV-1 LTR by binding to the transactivation response (TAR) element in a complex with cyclin T1. Because of its critical and early role in HIV gene expression, Tat and its interaction with the TAR element constitute important therapeutic targets for the treatment of HIV-1 infection. Based on the known nucleolar localization properties of Tat, we constructed a chimeric small nucleolar RNA-TAR decoy that localizes to the nucleoli of human cells and colocalizes in the nucleolus with a Tat-enhanced GFP fusion protein. When the chimeric RNA was stably expressed in human T lymphoblastoid CEM cells it potently inhibited HIV-1 replication. These results demonstrate that the nucleolar trafficking of Tat is critical for HIV-1 replication and suggests a role for the nucleolus in HIV-1 viral replication.
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PMID:A nucleolar TAR decoy inhibitor of HIV-1 replication. 1237 17

The cyclin T1 (Cyc T1) protein has been recently identified, associated with the cyclin-dependent kinase 9 (CDK 9), as to be involved in the transcriptional activation of the Human Immunodeficiency Virus type 1 (HIV-1) by the Tat protein. In this study, the sequence of the 7 kb goat Cyc T1 cDNA is reported as well as the exon/intron structure of the gene. Its observed ubiquitous expression is consistent with the promoter structure.
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PMID:Sequence of goat cyclin T1 cDNA, gene organisation and expression analysis. 1242 57


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