Original Literature | Model OverView |
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Publication
Title
HIV-1 infection and regulation of Tat function in macrophages.
Affiliation
Department of Molecular Virology and Microbiology, Baylor College of Medicine,One Baylor Plaza, Houston, TX 77030, USA.
Abstract
The macrophage is an important cell type in the pathophysiology of humanimmunodeficiency virus type 1 (HIV-1) infection. Macrophages both support viralreplication and are capable of attracting and activating lymphocytes, thusrendering CD4+ T lymphocytes highly permissive for infection. The viral Tatprotein, whose function is mediated by the cellular cyclin T1 protein complexedwith CDK9, is required for efficient transcription of the integrated HIV-1provirus by RNA polymerase II. Cyclin T1 expression is highly regulated duringmacrophage differentiation, and this has important implications for HIV-1replication. In monocytes isolated from healthy blood donors, cyclin T1 proteinexpression is low and is induced to high levels within the first few days ofdifferentiation by a post-transcriptional mechanism. After 1-2 weeks ofmacrophage differentiation, however, cyclin T1 expression is shut off. Treatmentof macrophages with lipopolysaccharide (LPS) can re-induce cyclin T1, indicatingthat the activation status of macrophages can regulate cyclin T1 expression.Recent results indicate that HIV-1 infection is able to induce cyclin T1expression in macrophages. Future studies of cyclin T1 regulation in macrophagesmay suggest means of manipulating expression of this crucial cellular co-factorfor therapeutic benefit in HIV-1 infected individuals. Copyright 2004 ElsevierB.V.
PMID
15183343
|
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--
--
csml-variable:Double
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0
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DSIF:NELF:RNA polymerase II{p}
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0
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RNA:cyclinT1:Cdk9:Tat
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0
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Tat:cyclinT1:cdk9
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m13
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0
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DSIF:NELF:RNA polymerase II
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cyclinT1:cdk9
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Tat
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NF-kappaB
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7SK SnRNA
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7SK SnRNA:Tat:cyclinT1:cdk9:MAQ1
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7SK SnRNA:cyclinT1:Cdk9:Tat
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Cyclin T1
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protein remnants
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proteasome inhibitors
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MIP1beta
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NEF
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cyclin T2b
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--
csml-variable:Double
m60
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e8
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Cell_WithoutCellWall_
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--
--
csml-variable:Double
m8
0
infinite
0
--
--
e9
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Cytoplasm
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--
--
csml-variable:Double
m9
0
infinite
0
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c1 : 1
stoichiometry:c3 : 1
stoichiometry:c2 : 1
m5*m14*0.1
nodelay
--
0
PMID: 15183343 In the absence of the viral Tat protein, RNA polymerase II initiates transcription from the viral LTR, but is defective for elongation and few productive transcripts are made. PMID: 15183343, 11713532, 11713533 A small nuclear RNA known as 7SK snRNA has been found to associate with a significant portion of P-TEFb and negatively regulate kinase activity in vitro, leading to the proposal that 7SK snRNA is a negative regulator of P-TEFb function.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c29 : 1
stoichiometry:c31 : 1
stoichiometry:c30 : 1
m5*m21*0.1
nodelay
--
0
PMID: 15183343, 2654643 NF-¦ÊB is induced under viral infected conditions and contributes to an increase in LTR transcription and viral replication. PMID: 15183343, 11713532, 11713533 A small nuclear RNA known as 7SK snRNA has been found to associate with a significant portion of P-TEFb and negatively regulate kinase activity in vitro, leading to the proposal that 7SK snRNA is a negative regulator of P-TEFb function.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c33 : 1
stoichiometry:c35 : 1
stoichiometry:c34 : 1
m24*m22*0.1
nodelay
--
0
PMID: 15183343 PMA treatment of U937 and HL-60 cells produced an increase of cyclin T1 protein expression from very low levels
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c36 : 1
stoichiometry:c38 : 1
stoichiometry:c37 : 1
m25*0.1
nodelay
--
0
PMID: 15183343, 15254183 Using proteasome inhibitors, we have recently observed that the shut off of cyclin T1 in uninfected late-differentiated macrophages involves proteasome-mediated proteolysis.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c39 : 1
stoichiometry:c40 : 1
stoichiometry:c41 : 1
m24*m28*0.1
nodelay
--
0
PMID: 15183343, 12368300 We observed that treatment of macrophages with lipopolysaccharide (LPS) at late time points of differentiation re-induces cyclin T1 protein expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c44 : 1
stoichiometry:c49 : 1
stoichiometry:c45 : 1
m34*m36*0.1
nodelay
--
0
PMID: 15183343 HIV-infected macrophages secrete at least two chemokines, MIP1¦Á and MIP1¦Â, which recruit and activate resting CD4+ T lymphocytes.Analysis of viral genes involved in the secretion of these chemokines revealed that the HIV-1 Nef protein is responsible for the induction of chemokines.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c46 : 1
stoichiometry:c48 : 1
stoichiometry:c47 : 1
m35*m36*0.1
nodelay
--
0
PMID: 15183343 HIV-infected macrophages secrete at least two chemokines, MIP1¦Á and MIP1¦Â, which recruit and activate resting CD4+ T lymphocytes.Analysis of viral genes involved in the secretion of these chemokines revealed that the HIV-1 Nef protein is responsible for the induction of chemokines.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c50 : 1
stoichiometry:c51 : 1
stoichiometry:c52 : 1
m37*m38*0.1
nodelay
--
0
PMID: 15183343 CDK9 is also found in other complexes that contain regulatory subunits other than cyclin T1; these additional cyclin partners of CDK9 are cyclins T2a, T2b, and K.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c53 : 1
stoichiometry:c54 : 1
stoichiometry:c55 : 1
m40*m37*0.1
nodelay
--
0
PMID: 15183343 CDK9 is also found in other complexes that contain regulatory subunits other than cyclin T1; these additional cyclin partners of CDK9 are cyclins T2a, T2b, and K.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c56 : 1
stoichiometry:c57 : 1
stoichiometry:c58 : 1
m37*m42*0.1
nodelay
--
0
PMID: 15183343 CDK9 is also found in other complexes that contain regulatory subunits other than cyclin T1; these additional cyclin partners of CDK9 are cyclins T2a, T2b, and K.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c5 : 1
stoichiometry:c4 : 1
stoichiometry:c6 : 1
m6*m13*0.1
nodelay
--
0
PMID: 15183343 Tat binds to TAR RNA in a complex with a cellular protein kinase complex termed TAK/P-TEFb (Tat-associated kinase/positive transcriptional elongation factor b). TAK/P-TEFb is composed of cyclin T1 as a regulatory subunit and CDK9 as the catalytic subunit.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c59 : 1
stoichiometry:c64 : 1
stoichiometry:c60 : 1
m24*m46*0.1
nodelay
--
0
PMID: 15183343, 12368300 The transient increase of cyclin T1 expression is specific to macrophage differentiation, as monocytes induced to differentiate to dendritic cells by GM-CSF and IL-4 sustain cyclin T1 expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c61 : 1
stoichiometry:c62 : 1
stoichiometry:c63 : 1
m45*m44*0.1
nodelay
--
0
PMID: 15183343, 12368300 The transient increase of cyclin T1 expression is specific to macrophage differentiation, as monocytes induced to differentiate to dendritic cells by GM-CSF and IL-4 sustain cyclin T1 expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c65 : 1
stoichiometry:c66 : 1
stoichiometry:c67 : 1
m47*m48*0.1
nodelay
--
0
PMID: 15183343, 12368300 The transient increase of cyclin T1 expression is specific to macrophage differentiation, as monocytes induced to differentiate to dendritic cells by GM-CSF and IL-4 sustain cyclin T1 expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c68 : 1
stoichiometry:c70 : 1
stoichiometry:c69 : 1
m24*m49*0.1
nodelay
--
0
PMID: 15183343, 12368300 The transient increase of cyclin T1 expression is specific to macrophage differentiation, as monocytes induced to differentiate to dendritic cells by GM-CSF and IL-4 sustain cyclin T1 expression.
p3
p3
cso30:i:ME_Phosphorylation
cso30:i:CC_Nucleoplasm
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c7 : 1
stoichiometry:c19 : 1
stoichiometry:c24 : 1
stoichiometry:c20 : 1
stoichiometry:c8 : 1
m14*m13*0.1
nodelay
--
0
PMID: 15183343, 11145967, 10757782, 11713532, 11713533 Binding of Tat complexed with TAK/P-TEFb to TAR RNA is believed to activate transcriptional elongation through the phosphorylation of the carboxyl terminal domain of RNA polymerase II, the Spt5 subunit of a negative factor termed DSIF, and perhaps other substrates in the polymerase complex. A small nuclear RNA known as 7SK snRNA has been found to associate with a significant portion of P-TEFb and negatively regulate kinase activity in vitro, leading to the proposal that 7SK snRNA is a negative regulator of P-TEFb function. PMID: 15183343 Association of TAK/P-TEFb with 7SK snRNA and MAQ1 reduces CDK9 kinase activity in vitro.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c10 : 1
stoichiometry:c11 : 1
stoichiometry:c12 : 1
m16*m15*0.1
nodelay
--
0
PMID: 15183343 Tat makes direct protein-protein complex with cyclin T1 and can therefore only target the cyclin T1-containing P-TEFb complex. PMID: 15183343 TAK/P-TEFb is composed of cyclin T1 as a regulatory subunit and CDK9 as the catalytic subunit.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c13 : 1
stoichiometry:c15 : 1
stoichiometry:c14 : 1
m5*m11*0.1
nodelay
--
0
PMID: 15183343 phosphorylation overcomes the active of negative factors (DSIF, NELF) that repress elongation
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c16 : 1
stoichiometry:c17 : 1
stoichiometry:c18 : 1
m13*m18*0.1
nodelay
--
0
PMID: 15183343, 11713532, 11713533 A small nuclear RNA known as 7SK snRNA has been found to associate with a significant portion of P-TEFb and negatively regulate kinase activity in vitro, leading to the proposal that 7SK snRNA is a negative regulator of P-TEFb function.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c21 : 1
stoichiometry:c9 : 1
stoichiometry:c22 : 1
m19*m23*0.1
nodelay
--
0
PMID: 15183343, 12832472 A recent study has identified an additional protein termed MAQ1 that is associated with the 7SK/P-TEFb complex, and this association is dependent upon active RNA polymerase II transcription.
p3
p8
cso30:i:ME_Phosphorylation
cso30:i:CC_Nucleoplasm
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c23 : 1
stoichiometry:c25 : 1
stoichiometry:c42 : 1
stoichiometry:c43 : 1
stoichiometry:c26 : 1
m12*m14*0.1
nodelay
--
0
PMID: 15183343, 11145967, 10757782, 11713532, 11713533 Binding of Tat complexed with TAK/P-TEFb to TAR RNA is believed to activate transcriptional elongation through the phosphorylation of the carboxyl terminal domain of RNA polymerase II, the Spt5 subunit of a negative factor termed DSIF, and perhaps other substrates in the polymerase complex. A small nuclear RNA known as 7SK snRNA has been found to associate with a significant portion of P-TEFb and negatively regulate kinase activity in vitro, leading to the proposal that 7SK snRNA is a negative regulator of P-TEFb function. PMID: 15183343 Association of TAK/P-TEFb with 7SK snRNA and MAQ1 reduces CDK9 kinase activity in vitro.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c27 : 1
stoichiometry:c32 : 1
stoichiometry:c28 : 1
m17*m22*0.1
nodelay
--
0
PMID: 15183343, 2654643 NF-¦ÊB is induced under viral infected conditions and contributes to an increase in LTR transcription and viral replication.
cso30:c:InputAssociation
threshold
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0
1,
--
cso30:c:InputProcess
threshold
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0
1,
--
cso30:c:OutputProcess
threshold
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0
1,
--
cso30:c:InputAssociation
threshold
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0
1,
--
cso30:c:InputAssociation
threshold
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0
1,
--
cso30:c:OutputProcess
threshold
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0
1,
--
cso30:c:InputInhibitor
threshold
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0
1,
--
cso30:c:InputInhibitor
threshold
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0
1,
--
cso30:c:InputProcess
threshold
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0
1,
--
cso30:c:OutputProcess
threshold
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0
1,
--
cso30:c:InputAssociation
threshold
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0
1,
--
cso30:c:InputAssociation
threshold
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0
1,
--
cso30:c:InputProcess
threshold
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0
1,
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cso30:c:OutputProcess
threshold
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0
1,
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cso30:c:InputAssociation
threshold
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0
1,
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cso30:c:InputAssociation
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0
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cso30:c:OutputProcess
threshold
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0
1,
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cso30:c:InputAssociation
threshold
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0
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cso30:c:InputAssociation
threshold
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0
1,
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cso30:c:InputAssociation
threshold
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0
1,
--
cso30:c:OutputProcess
threshold
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0
1,
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cso30:c:InputAssociation
threshold
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0
1,
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cso30:c:InputProcess
threshold
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0
1,
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cso30:c:OutputProcess
threshold
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0
1,
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cso30:c:InputAssociation
threshold
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0
1,
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cso30:c:InputAssociation
threshold
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0
1,
--
cso30:c:OutputProcess
threshold
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0
1,
--
cso30:c:InputInhibitor
threshold
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0
1,
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cso30:c:InputInhibitor
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--