Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tat activates transcription from the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) by increasing the processivity of RNA polymerase II. Recently, it has been demonstrated that the cellular kinase CDK9 and its binding partner cyclin T1 are involved in regulating transcriptional elongation and tat-activation. Cyclin T1, CDK9 and Tat bind as a complex to elements in TAR RNA that are required for tat-activation. Here, we used cyclin T1 mutants to define domains in this protein that bind to both CDK9 and Tat and are involved in stimulating tat-activation. The region of cyclin T1 extending from amino acid residues 1 to 263 is necessary for complex formation with Tat bound to TAR RNA and for stimulation of tat-activation in murine cells that are normally poorly responsive to the actions of Tat. In contrast, a smaller region of cyclin T1 was required to bind to CDK9 and stimulate its kinase activity. Recombinant cyclin T1 and CDK9 stimulated both basal and tat-induced in vitro transcriptional elongation from the HIV-1 LTR. The effects of Tat on transcriptional elongation may be mediated by its ability to increase CDK9 phosphorylation of the RNA polymerase II C-terminal domain. These results demonstrate that cyclin T1 interactions with Tat and TAR RNA are critical for activation of HIV-1 gene expression.
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PMID:Cyclin T1 domains involved in complex formation with Tat and TAR RNA are critical for tat-activation. 1032 25

Human immunodeficiency virus-1 Tat protein and human Cyclin T1 mediate transcriptional activation by enhancing the elongation efficiency of RNA polymerase II. Activation of transcription of the related equine infectious anemia virus (EIAV) requires a similar protein known as eTat, which does not function in human cells. Expression of equine Cyclin T1 in human cells rescues eTat function, suggesting a general mechanism of transcription activation among lentiviruses. Here we present the cloning of Cyclin T1 from canine D17 osteosarcoma cells, which support EIAV transactivation, and show that canine Cyclin T1 confers eTat transactivation to human cells. A two-amino-acid change, from 79-proline-glycine-80 to 79-histidine-arginine-80, confers on the human Cyclin T1 the ability to cooperate with eTat in transcriptional activation. These findings suggested that the regions of Cyclin T1 that interact with lentiviral Tat proteins and TAR RNA elements form an extended domain, which very likely has a conserved fold.
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PMID:Canine cyclin T1 rescues equine infectious anemia virus tat trans-activation in human cells. 1068 21

Cyclin T1 (CycT1) is a regulatory subunit of a general RNA polymerase II (RNAP II) elongation factor termed P-TEFb. The human immunodeficiency virus Tat protein directly associates with CycT1 to utilize CycT1/P-TEFb (also called TAK) for activation of RNAP II elongation of the integrated proviral genome. CycT1 mRNA and protein levels are induced in activated human peripheral blood lymphocytes and CycT1 protein levels are induced by a post-transcriptional mechanism when human U937 promonocytic cells are stimulated to differentiate into macrophage-like cells. To investigate mechanisms that regulate CycT1 RNA expression, we isolated the CycT1 promoter. Multiple transcription start sites were identified within 330 nucleotides upstream of the ATG initiation codon at +1. The CycT1 promoter lacks a TATA element and possesses high constitutive activity in plasmid transfection assays. Two distinct regions of the promoter were identified upstream of +1 that contain critical regulatory elements for CycT1 promoter function.
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PMID:Isolation and characterization of the human cyclin T1 promoter. 1090 36

Cyclin T1 was recently identified, together with cdk9 (previously named PITALRE), as part of the TAK multiprotein complex, a co-factor targeted by the human immunodeficiency virus Type 1 (HIV-1) protein named Tat, suggesting a role for this complex in transcription elongation. Although studies on mRNA and protein expression have shown that cyclin T1 is ubiquitous in adult human tissues, no data have yet been reported regarding the expression of this protein in different cell lineages. Using a polyclonal antiserum raised against cyclin T1, we investigated the pattern of expression of this protein in adult human tissues by immunohistochemistry. Cyclin T1 was expressed ubiquitously, although different levels of expression were found in various organs. Some specialized tissues, such as blood, lymphoid tissues, and cells of connective tissue origin, showed high cyclin T1 expression. These specific expression patterns are only partially justified by some well-known specialized functions of cyclin T1 in certain cell types, such as its involvement in peripheral blood lymphocytes and monocyte differentiation. The high expression level found in other tissues suggests new possible roles for cyclin T1 in cell types other than those of lymphoid tissue.
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PMID:Pattern of expression of cyclin T1 in human tissues. 1137 15

Cyclin T1 (CycT1), a component of positive-transcription-elongation factor-b (P-TEFb), is an essential cofactor for transcriptional activation by lentivirus Tat proteins. It is thought that low CycT1 expression levels restrict human immunodeficiency virus type 1 (HIV-1) expression levels and replication in resting CD4+ lymphocytes. In this study, we undertook a functional analysis of the cycT1 promoter to determine which, if any, promoter elements might be responsible for cellular activation state-dependent CycT1 expression. The cycT1 gene contains a complex promoter that exhibits an extreme degree of functional redundancy: five nonoverlapping fragments were found to exhibit significant promoter activity in immortalized cell lines, and these elements could interact in a synergistic or redundant manner to mediate cycT1 transcription. Reporter gene expression, mediated by the cycT1 promoter, was detectable in unstimulated transfected primary lymphocytes and multiple sites within the promoter could serve to initiate transcription. While utilization of these start sites was significantly altered by the application of exogenous stimuli to primary lymphocytes and two distinct promoter elements exhibited enhanced activity in the presence of phorbol ester, overall cycT1 transcription was only modestly enhanced in response to cell activation. These observations prompted a reexamination of CycT1 protein expression in primary lymphocytes. In fact, steady-state CycT1 expression is only slightly lower in unstimulated lymphocytes compared to phorbol ester-treated cells or a panel of immortalized cell lines. Importantly, CycT1 is expressed at sufficient levels in unstimulated primary cells to support robust Tat activity. These results strongly suggest that CycT1 expression levels in unstimulated primary lymphocytes do not profoundly limit HIV-1 gene expression or provide an adequate mechanistic explanation for proviral latency in vivo.
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PMID:Cyclin T1 expression is mediated by a complex and constitutively active promoter and does not limit human immunodeficiency virus type 1 Tat function in unstimulated primary lymphocytes. 1173 86

Cyclin T1, together with the kinase CDK9, is a component of the transcription elongation factor P-TEFb which binds the human immunodeficiency virus type 1 (HIV-1) transactivator Tat. P-TEFb facilitates transcription by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II. Cyclin T1 is an exceptionally large cyclin and is therefore a candidate for interactions with regulatory proteins. We identified granulin as a cyclin T1-interacting protein that represses expression from the HIV-1 promoter in transfected cells. The granulins, mitogenic growth factors containing repeats of a cysteine-rich motif, were reported previously to interact with Tat. We show that granulin formed stable complexes in vivo and in vitro with cyclin T1 and Tat. Granulin bound to the histidine-rich domain of cyclin T1, which was recently found to bind to the CTD, but not to cyclin T2. Binding of granulin to P-TEFb inhibited the phosphorylation of a CTD peptide. Granulin expression inhibited Tat transactivation, and tethering experiments showed that this effect was due, at least in part, to a direct action on cyclin T1 in the absence of Tat. In addition, granulin was a substrate for CDK9 but not for the other transcription-related kinases CDK7 and CDK8. Thus, granulin is a cellular protein that interacts with cyclin T1 to inhibit transcription.
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PMID:The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription. 1258 88

Human cyclin T1, the cyclin partner of Cdk9 kinase in the positive transcription elongation factor b (P-TEFb), is an essential cellular cofactor that is recruited by the human immunodeficiency virus type 1 (HIV-1) Tat transactivator to promote transcriptional elongation from the HIV-1 long terminal repeat (LTR). Here we exploit fluorescence resonance energy transfer (FRET) to demonstrate that cyclin T1 physically interacts in vivo with the promyelocytic leukaemia (PML) protein within specific subnuclear compartments that are coincident with PML nuclear bodies. Deletion mutants at the C-terminal region of cyclin T1 are negative for FRET with PML and fail to localize to nuclear bodies. Cyclin T1 and PML are also found associated outside of nuclear bodies, and both proteins are present at the chromatinized HIV-1 LTR promoter upon Tat transactivation. Taken together these results suggest that PML proteins regulate Tat- mediated transcriptional activation by modulating the availability of cyclin T1 and other essential cofactors to the transcription machinery.
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PMID:Recruitment of human cyclin T1 to nuclear bodies through direct interaction with the PML protein. 1272 82

Cyclin T1 (CycT1) is a cellular transcription elongation factor that also participates in Tat-mediated activation of several lentiviral promoters. In human immunodeficiency virus (HIV), CycT1 is required for Tat to bind tightly to TAR and interacts in the ternary complex via its Tat-TAR recognition motif (TRM). In the related bovine immunodeficiency virus (BIV), Tat recognizes its cognate TAR element with high affinity and specificity in the absence of CycT1. At both promoters, CycT1 recruits the Cdk9 kinase, which phosphorylates RNA polymerase II to generate processive transcription complexes. To examine the physical properties of CycT1, we purified a functional domain corresponding to residues 1-272 and found that it possesses a stably folded core, as judged by partial proteolysis and circular dichroism experiments. Interestingly, the C-terminal 20 residues corresponding to the TRM appear conformationally flexible or disordered. The TRM of the bovine CycT1 (bCycT1) is similarly sensitive to proteolysis yet differs in sequence from the human protein. In particular, bCycT1 lacks a cysteine at residue 261 known to be critical for HIV but not BIV ternary complex formation, and mutagenesis data are consistent with a proposed role for this cysteine in metal binding. The apparent flexibility of the TRM suggests that conformational rearrangements may accompany formation of CycT1-Tat-TAR ternary complexes and may contribute to different TAR recognition strategies in different lentiviruses.
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PMID:Evidence for conformational flexibility in the Tat-TAR recognition motif of cyclin T1. 1497 56

The macrophage is an important cell type in the pathophysiology of human immunodeficiency virus type 1 (HIV-1) infection. Macrophages both support viral replication and are capable of attracting and activating lymphocytes, thus rendering CD4+ T lymphocytes highly permissive for infection. The viral Tat protein, whose function is mediated by the cellular cyclin T1 protein complexed with CDK9, is required for efficient transcription of the integrated HIV-1 provirus by RNA polymerase II. Cyclin T1 expression is highly regulated during macrophage differentiation, and this has important implications for HIV-1 replication. In monocytes isolated from healthy blood donors, cyclin T1 protein expression is low and is induced to high levels within the first few days of differentiation by a post-transcriptional mechanism. After 1-2 weeks of macrophage differentiation, however, cyclin T1 expression is shut off. Treatment of macrophages with lipopolysaccharide (LPS) can re-induce cyclin T1, indicating that the activation status of macrophages can regulate cyclin T1 expression. Recent results indicate that HIV-1 infection is able to induce cyclin T1 expression in macrophages. Future studies of cyclin T1 regulation in macrophages may suggest means of manipulating expression of this crucial cellular co-factor for therapeutic benefit in HIV-1 infected individuals.
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PMID:HIV-1 infection and regulation of Tat function in macrophages. 1518 43

The cellular positive transcription elongation factor b (P-TEFb), containing cyclin T1 and cyclin-dependent kinase 9 (CDK9), interacts with the human immunodeficiency virus, type 1 (HIV-1) regulatory protein Tat to enable viral transcription and replication. Cyclin T1 is an unusually long cyclin and is engaged by cellular regulatory proteins. Previous studies showed that the granulin/epithelin precursor (GEP) binds the histidine-rich region of cyclin T1 and inhibits P-TEFb function. GEP is composed of repeats that vary in sequence and properties. GEP also binds directly to Tat. Here we show that GEP and some of its constituent granulin repeats can inhibit HIV-1 transcription via Tat without directly binding to cyclin T1. The interactions of granulins with Tat and cyclin T1 differ with respect to their binding sites and divalent cation requirements, and we identified granulin repeats that bind differentially to Tat and cyclin T1. Granulins DE and E bind Tat but do not interact directly with cyclin T1. These granulins are present in complexes with Tat and P-TEFb in which Tat forms a bridge between the cellular proteins. Granulins DE and E repress transcription from the HIV-1 LTR and gene expression from the viral genome, raising the possibility of developing granulin-based inhibitors of viral infection.
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PMID:Granulin and granulin repeats interact with the Tat.P-TEFb complex and inhibit Tat transactivation. 1565 95


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