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

The human immunodeficiency virus type-1 (HIV-1) Tat protein regulates transcription by stimulating RNA polymerase processivity. Using immobilised templates, we have been able to study the effects of Tat on protein kinase activity during the pre-initiation and elongation stages of HIV-1 transcription. In pre-initiation complexes formed at the HIV-1 LTR, the C-terminal domain (CTD) of RNA polymerase II is rapidly phosphorylated by transcription factor IIH (TFIIH). Addition of Tat does not affect either the rate or the extent of CTD phosphorylation in the pre-initiation complexes. By contrast, Tat is able to stimulate additional CTD phosphorylation in elongation complexes. This reaction creates a novel form of the RNA polymerase that we have called RNA polymerase IIo*. Formation of the RNA polymerase IIo* occurs only after transcription of templates carrying a functional TAR RNA element and is strongly inhibited by low concentrations of 5,6-dichloro-1-beta- D -ribofuranosyl benzimidazole (DRB), a potent inhibitor of CDK9, the protein kinase subunit of the Tat-associated kinase (TAK). Immunoblotting experiments have shown that CDK9 and its associated cyclin, cyclin T1, are present at equivalent levels in both the pre-initiation and elongation complexes. We conclude that activation of the CDK9 kinase, leading to CTD phosphorylation, occurs only in elongation complexes that have transcribed through the Tat-recognition element, TAR RNA.
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PMID:Direct evidence that HIV-1 Tat stimulates RNA polymerase II carboxyl-terminal domain hyperphosphorylation during transcriptional elongation. 1043 93

The intrinsic processivity of RNA polymerase II complexes arises from a complex interplay between the recently identified positive transcription elongation factor b (P-TEFb) and negative transcription elongation factors, DSIF (5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole [DRB]-sensitivity-inducing factor) and the negative elongation factor complex (NELF). Elements in nascent HIV-1 RNA function in concert with these factors and the HIV-1 Tat protein to ensure that viral transcription is induced strongly in activated T cells. Studies in the past year have elucidated key aspects of the Tat trans-activation mechanism that help to define this important paradigm for RNA-mediated control of transcription elongation.
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PMID:HIV-1 Tat: coping with negative elongation factors. 1044 48

HIV-1 gene expression relies upon a complex machinery that is primarily controlled by two viral regulatory proteins, Tat and Rev. Rev is involved in regulating post-transcriptional events of HIV-1 gene expression. The Tat protein transactivates transcription from the HIV-1 5' long terminal repeat (LTR) and acts in synergy with specific cellular factors. Recently, it has been shown that one set of these cellular factors is a protein kinase activity termed TAK (Tat-associated kinase), which activates transcription by hyperphosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II. TAK also enhances transcription of HIV-2, together with the retroviral transactivator, Tat-2. The TAK activity appears to be related to the CTD kinase P-TEFb, which stabilizes transcription elongation of many genes and was originally isolated from Drosophila extracts. Both TAK and P-TEFb contain at least two subunits: the cyclin-dependent kinase, CDK9 (PITALRE), the catalytic subunit, and the regulatory subunit, cyclin T1. CDK9 and cyclin T1 are ubiquitous factors that affects many cellular processes, including cell differentiation and apoptosis. The involvement of TAK in HIV-1 and HIV-2 gene expression is an important aspect in the biology of these two retroviruses, and may lead to the development of novel antiretroviral drugs and/or gene therapy approaches for the treatment of patients with AIDS.
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PMID:Regulatory functions of Cdk9 and of cyclin T1 in HIV tat transactivation pathway gene expression. 1053 59

Activation of cellular genes typically involves control of transcription initiation by DNA-binding regulatory proteins. The human immunodeficiency virus transactivator protein, Tat, provides the first example of the regulation of viral gene expression through control of elongation by RNA polymerase II. In the absence of Tat, initiation from the long terminal repeat is efficient, but transcription is impaired because the promoter engages poorly processive polymerases that disengage from the DNA template prematurely. Activation of transcriptional elongation occurs following the recruitment of Tat to the transcription machinery via a specific interaction with an RNA regulatory element called TAR, a 59-residue RNA leader sequence that folds into a specific stem-loop structure. After binding to TAR RNA, Tat stimulates a specific protein kinase called TAK (Tat-associated kinase). This results in hyperphosphorylation of the large subunit of the RNA polymerase II carboxyl- terminal domain. The kinase subunit of TAK, CDK9, is analogous to a component of a positive acting elongation factor isolated from Drosophila called pTEFb. Direct evidence for the role of TAK in transcriptional regulation of the HIV long terminal repeat comes from experiments using inactive mutants of the CDK9 kinase expressed in trans to inhibit transcription. A critical role for TAK in HIV transcription is also demonstrated by selective inhibition of Tat activity by low molecular mass kinase inhibitors. A second link between TAK and transactivation is the observation that the cyclin component of TAK, cyclin T1, also participates in TAR RNA recognition. It has been known for several years that mutations in the apical loop region of TAR RNA abolish Tat activity, yet this region of TAR is not required for binding by recombinant Tat protein in vitro, suggesting that the loop region acts as a binding site for essential cellular co-factors. Tat is able to form a ternary complex with TAR RNA and cyclin T1 only when a functional loop sequence is present on TAR.
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PMID:Tackling Tat. 1055 Feb 6

Human immunodeficiency virus type-1 (HIV-1) is a highly pathogenic lentivirus that requires transcription of its provirus genome for completion of the viral life cycle and the production of progeny virions. Since the first genetic analysis of HIV-1 in 1985, much has been learned about the transcriptional regulation of the HIV-1 genome in infected cells. It has been demonstrated that HIV-1 transcription depends on a varied and complex interaction of host cell transcription factors with the viral long terminal repeat (LTR) promoter. The regulatory elements within the LTR interact with constitutive and inducible transcription factors to direct the assembly of a stable transcription complex that stimulates multiple rounds of transcription by RNA polymerase II (RNAPII). However, the majority of these transcripts terminate prematurely in the absence of the virally encoded trans-activator protein Tat, which stimulates HIV-1 transcription elongation by interacting with a stem-loop RNA element (TAR) formed at the extreme 5' end of all viral transcripts. The Tat-TAR interaction recruits a cellular kinase into the initiation-elongation complex that alters the elongation properties of RNAPII during its transit through TAR. This review summarizes our current knowledge and understanding of the regulation of HIV-1 transcription in infected cells and highlights the important contributions human lentivirus gene regulation has made to our general understanding of the transcription process.
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PMID:Regulation of HIV-1 transcription. 1055 96

Tat activation of HIV-1 transcription is mediated by human transcription elongation factor P-TEFb, which interacts with Tat and phosphorylates the C-terminal domain of RNA polymerase II. The catalytic subunit of the P-TEFb complex, Cdk9, has been shown to interact with cyclin T and several other proteins of unknown identity. Consequently, the exact subunit composition of active P-TEFb has not been determined. Here we report the affinity purification and identification of the Cdk9-associated proteins. In addition to forming a heterodimer with cyclin T1, Cdk9 interacted with the molecular chaperone Hsp70 or a kinase-specific chaperone complex, Hsp90/Cdc37, to form two separate chaperone-Cdk9 complexes. Although the Cdk9/cyclin T1 dimer was exceptionally stable and produced slowly in the cell, free and unprotected Cdk9 appeared to be degraded rapidly. Several lines of evidence indicate the heterodimer of Cdk9/cyclin T1 to be the mature, active form of P-TEFb responsible for phosphorylation of the C-terminal domain of RNA polymerase II interaction with the Tat activation domain, and mediation of Tat activation of HIV-1 transcription. Pharmacological inactivation of Hsp90/Cdc37 function by geldanamycin revealed an essential role for the chaperone-Cdk9 complexes in generation of Cdk9/cyclin T1. Our data suggest a previously unrecognized chaperone-dependent pathway involving the sequential actions of Hsp70 and Hsp90/Cdc37 in the stabilization/folding of Cdk9 as well as the assembly of an active Cdk9/cyclin T1 complex responsible for P-TEFb-mediated Tat transactivation.
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PMID:Requirement for a kinase-specific chaperone pathway in the production of a Cdk9/cyclin T1 heterodimer responsible for P-TEFb-mediated tat stimulation of HIV-1 transcription. 1061 16

CC3 is a metastasis suppressor that inhibits metastasis of the variant small cell lung carcinoma (v-SCLC) by predisposing cells to apoptosis. The same protein was also reported as a cellular cofactor, TIP30, which stimulates HIV-1 Tat-activated transcription by interacting with both Tat and RNA polymerase II. We report here that TIP30/CC3 is a novel serine/threonine kinase. It phosphorylates the heptapeptide repeats of the C-terminal domain (CTD) of the largest RNA polymerase II subunit in a Tat-dependent manner. Amino acid substitutions in the putative ATP binding motif that abolish the TIP30 kinase activity also inhibit the ability of TIP30 to enhance Tat-activated transcription or to sensitize NIH 3T3 and v-SCLC cells to apoptosis. Furthermore, ectopic expression of TIP30/CC3 in v-SCLC cells induces expression of a number of genes that include the apoptosis-related genes Bad and Siva, as well as metastasis suppressor NM23-H2. These data demonstrate a molecular mechanism for TIP30/CC3 function and suggest a novel pathway for regulating apoptosis.
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PMID:TIP30 has an intrinsic kinase activity required for up-regulation of a subset of apoptotic genes. 1069 37

Transcription from the HIV-1 long terminal repeat (LTR) is regulated by the viral transactivator Tat, which increases RNA polymerase II (RNAP II) processivity. Previous reports have demonstrated that phosphorylation of the RNAP II carboxy-terminal domain by TFIIH and P-TEFb is important for Tat transactivation. Our present results demonstrate that phosphorylation of the RAP74 subunit of TFIIF is also an important step in Tat transactivation. Interestingly, while the general transcription factor TFIIF is required for both basal and Tat-activated transcription, phosphorylation of the RAP74 subunit occurs in the presence of Tat and correlates with a high level of transcription activity. Using a biotinylated DNA template transcription assay, we provide evidence that RAP74 is phosphorylated by TAF(II)250 during Tat-activated transcription. Depletion of RAP74 from the HeLa nuclear extract inhibited HIV-1 LTR-driven basal transcription and Tat transactivation. The addition of TFIIF, reconstituted from recombinant RAP30 and RAP74, to the depleted HeLa nuclear extract resulted in restoration of Tat transactivation. Of importance, the exogenous RAP74 was rapidly phosphorylated in the presence of Tat. These results suggest that RAP74 phosphorylation is one important step, of several, in the Tat transactivation cascade.
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PMID:Phosphorylation of the RAP74 subunit of TFIIF correlates with Tat-activated transcription of the HIV-1 long terminal repeat. 1070 53

SPT5 and its binding partner SPT4 regulate transcriptional elongation by RNA polymerase II. SPT4 and SPT5 are involved in both 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB)-mediated transcriptional inhibition and the activation of transcriptional elongation by the human immunodeficiency virus type 1 (HIV-1) Tat protein. Recent data suggest that P-TEFb, which is composed of CDK9 and cyclin T1, is also critical in regulating transcriptional elongation by SPT4 and SPT5. In this study, we analyze the domains of SPT5 that regulate transcriptional elongation in the presence of either DRB or the HIV-1 Tat protein. We demonstrate that SPT5 domains that bind SPT4 and RNA polymerase II, in addition to a region in the C terminus of SPT5 that contains multiple heptad repeats and is designated CTR1, are critical for in vitro transcriptional repression by DRB and activation by the Tat protein. Furthermore, the SPT5 CTR1 domain is a substrate for P-TEFb phosphorylation. These results suggest that C-terminal repeats in SPT5, like those in the RNA polymerase II C-terminal domain, are sites for P-TEFb phosphorylation and function in modulating its transcriptional elongation properties.
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PMID:Domains in the SPT5 protein that modulate its transcriptional regulatory properties. 1075 82

The activation of the HIV-1 long terminal repeat (LTR) by the viral transcriptional transactivator Tat is an essential step in the viral replication cycle. To increase the processivity of RNA polymerase II, Tat interacts with the positive transcription elongation factor b (P-TEFb) and cyclin-dependent kinase (CDK)-activating kinase (CAK). In this study, we demonstrate that a pseudo-substrate peptide for CDK7, mC2p, inhibits HIV-1 replication as well as Tat transactivation. Specifically, mC2p blocks only the activity of CAK and not that of P-TEFb. Moreover, mC2p inhibits Tat transactivation and HIV replication. Therefore, the activation of CDK7 by Tat is considered a critical step of Tat transactivation and mC2p and related compounds represent potential candidates for novel anti-HIV therapeutics.
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PMID:HIV-1 replication is inhibited by a pseudo-substrate peptide that blocks Tat transactivation. 1079 93


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