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)

Transcription of human immunodeficiency virus (HIV) type 1 and other viruses is regulated by the transcription factor NF-kappaB, which interacts with the multifunctional cellular protein p300. p300, originally identified by its ability to bind adenovirus early region 1A (E1A), has also been shown to regulate HIV transcription through its interaction with NF-kappaB. The 13S form of E1A activates HIV gene expression, while the 12S form represses its transcription. In this report, we have investigated whether these divergent effects of E1A are dependent upon common or distinct cellular cofactors, including p300, pRb, and the TATA box-binding protein (TBP). Unlike activation in the absence of E1A, cooperative stimulation of HIV gene expression by 13S E1A and RelA was independent of the ability of E1A to bind p300 but was critically dependent on the E1A CR3 region which associates with TBP. In contrast, inhibition of basal HIV gene expression by the 12S form of E1A was dependent on p300 but not pRb or TBP. Interestingly, mutation of the CR2 region of 12S E1A responsible for pRb binding abolished the repression of HIV transcription stimulated by tumor necrosis factor alpha, suggesting that repression of cytokine-activated transcription involves cofactors different from those used in unstimulated cells. Repression and activation of HIV transcription by different forms of E1A are mediated by distinct sets of cellular cofactors. These findings suggest that E1A has evolved to interact by alternative mechanisms with a transcriptional coactivator and its associated cofactors to differentially modulate cellular and viral gene expression.
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PMID:Distinct domains of adenovirus E1A interact with specific cellular factors to differentially modulate human immunodeficiency virus transcription. 903 32

A unique aspect of the retrovirus life cycle is the obligatory integration of the provirus into host cell chromosomes. Unlike viruses that do not integrate, retroviruses must conserve an ability to activate transcription from a chromatin context. Human immunodeficiency virus (HIV)-1 encodes an unusual and an unusually potent transcriptional transactivator, Tat, which binds to a nascent viral leader RNA, TAR. The action of Tat has been well studied in various reductive model systems; however, the physiological mechanism through which Tat gains access to chromatin-associated proviral long terminal repeats (LTRs) is not understood. We show here that a nuclear histone acetyltransferase activity associates with Tat. Intracellularly, we found that Tat forms a ternary complex with p300 and P/CAF, two histone acetyltransferases (HATs). A murine cell defect in Tat transactivation of the HIV-1 LTR was linked to the reduced abundance of p300 and P/CAF. Thus, overexpression of p300 and P/CAF reconstituted Tat transactivation of the HIV-1 LTR in NIH3T3 cells to a level similar to that observed for human cells. By using transdominant p300 or P/CAF mutants that lack enzymatic activity, we delineated a requirement for the HAT component from the latter but not the former in Tat function. Finally, we observed that Tat-associated HAT is preferentially important for transactivation of integrated, but not unintegrated, HIV-1 LTR.
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PMID:Activation of integrated provirus requires histone acetyltransferase. p300 and P/CAF are coactivators for HIV-1 Tat. 973 96

The androgen receptor (AR) is a member of the nuclear hormone receptor superfamily. Recent work in this field has been focused upon defining the mechanisms of transcriptional control exacted by members of this superfamily. Using a COOH-terminal region of the human AR in a yeast two-hybrid screen, we have identified Tip60 as an AR-interacting protein. In this report, we show that Tip60, which was originally identified as a coactivator for the human immunodeficiency virus TAT protein, can enhance AR-mediated transactivation in a ligand-dependent manner in LNCaP and COS-1 cell lines. In addition, our experiments show that Tip60 can also enhance transactivation through the estrogen receptor and progesterone receptor in a ligand-dependent manner; thus identifying Tip60 as a nuclear hormone receptor coactivator. Our studies also demonstrate that Tip60 co-immunoprecipitates with the full-length AR in vitro and that, in our system, Tip60 enhances transactivation to levels observed with the coactivators steroid receptor coactivator 1, p300, and CREB-binding protein. The importance of such proteins in enhancing nuclear hormone receptor-mediated transcriptional activation is widely accepted, and this work suggests that Tip60 may have an equally important role to play.
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PMID:Tip60 is a nuclear hormone receptor coactivator. 1036 96

The human immunodeficiency virus (HIV) trans- activator protein, Tat, stimulates transcription from the viral long-terminal repeats (LTR) through an RNA hairpin element, trans-activation responsive region (TAR). We and others have shown that trans-activator protein (Tat)-associated histone acetyltransferases (TAHs), p300 and p300/CBP-associating factor (PCAF), assist functionally in the activation of chromosomally integrated HIV-1 LTR. Here, we show that p300 and PCAF also directly acetylate Tat. We defined two sites of acetylation located in different functional domains of Tat. p300 acetylated Lys50 in the TAR RNA binding domain, while PCAF acetylated Lys28 in the activation domain of Tat. In support of a functional role for acetylation in vivo, histone deacetylase inhibitor (trichostatin A) synergized with Tat in transcriptional activation of the HIV-1 LTR. Synergism was TAR-dependent and required the intact presence of both Lys28 and Lys50. Mechanistically, acetylation at Lys28 by PCAF enhanced Tat binding to the Tat-associated kinase, CDK9/P-TEFb, while acetylation by p300 at Lys50 of Tat promoted the dissociation of Tat from TAR RNA that occurs during early transcription elongation. These data suggest that acetylation of Tat regulates two discrete and functionally critical steps in transcription, binding to an RNAP II CTD-kinase and release of Tat from TAR RNA.
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PMID:HIV-1 tat transcriptional activity is regulated by acetylation. 1054 21

The human immunodeficiency virus 1 (HIV-1) Tat protein activates transcriptional elongation by recruiting the positive transcription elongation factor (pTEFb) complex to the TAR RNA element, which is located at the 5' extremity of all viral transcripts [1-3]. Tat also associates in vitro and in vivo with the transcriptional coactivator p300/CBP [4-6]. This association has been proposed to recruit the histone acetyltransferase (HAT) activity of p300 to the integrated HIV-1 promoter. We have observed that the purified p300 HAT domain acetylates recombinant Tat proteins in vitro and that Tat is acetylated in vivo. The major targets of acetylation by p300 are lysine residues (Lys50 and Lys51) in the arginine-rich motif (ARM) used by Tat to bind RNA and for nuclear import. Mutation of these residues in full-length recombinant Tat blocked its acetylation in vitro. Furthermore, mutation of these lysine residues to arginine markedly decreased the synergistic activation of he HIV promoter by Tat and p300 or by Tat and cyclin T1. These results demonstrate that acetylation of Tat by p300/CBP is important for its transcriptional activation of the HIV promoter.
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PMID:Acetylation of the HIV-1 Tat protein by p300 is important for its transcriptional activity. 1060 94

Upon infection of susceptible cells, the RNA genome of the human immunodeficiency virus type 1 (HIV-1) is reverse transcribed into double-stranded DNA, which can be subsequently integrated into the cellular genome. After integration, the viral long terminal repeat (LTR) promoter is present in a nucleosome-bound conformation and is transcriptionally silent in the absence of stimulation. Activation of HIV-1 gene expression is concomitant with an acetylation-dependent rearrangement of the nucleosome positioned at the viral transcription start site. Thus, similar to most cellular genes, the transcriptional state of the integrated HIV-1 provirus is closely linked to histone acetylation. This enzymatic activity results from the function of histone-specific nuclear acetyltransferase (HAT) enzymes. Efficient viral transcription is strongly dependent on the virally-encoded Tat protein. the mechanism by which Tat increases the rate of transcriptional initiation has been recently demonstrated and involves the interaction of Tat with the transcriptional coactivator p300 and the closely related CREB-binding protein (CBP), having histone acetyltransferase activity.
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PMID:Chromatin control of HIV-1 gene expression. 1071 Jul 18

p73 has been shown to transcriptionally activate genes positively responsive to wild-type p53. In order to undertake a comparative study of functions of p53 and p73 we have cloned the cDNA of p73 from MCF-7 cells. Adenovirus onco-protein E1A inhibits the transactivation by p73; a deletion mutant of E1A incapable of interacting with p300 and CREB-binding protein (CBP) fails to disrupt the transactivation. Furthermore, CBP increases the transactivation mediated by p73 suggesting that CBP may function as a co-activator and E1A inhibits p73-mediated transactivation by sequestering p300 or CBP. We show that p73 can transcriptionally inhibit a number of cellular and viral promoters. However, wild-type p53, p73 alpha and p73 beta differ in their ability to inhibit transcriptional activity of different promoters. While wild-type p53 inhibits the promoters of the human cytomegalovirus (CMV) immediate-early gene, the long terminal repeat of human immunodeficiency virus type 1 (HIV LTR), human cyclin A (cyc A) gene, and insulin-like growth factor receptor I (IGF-I-R), p73 alpha only inhibits the HIV LTR and cyc A promoters significantly; and p73 beta inhibits the CMV, HIV LTR and cyc A promoters. A mutant of p73 alpha having amino acid substitutions at positions 268 and 300 on the presumptive DNA-binding domain fails to transactivate the p21 promoter but represses the CMV and the HIV LTR promoter quite efficiently showing that the mechanisms of transactivation and repression by p73 are different. Interestingly, p73 alpha transactivates the IGF-I-R promoter, which is inhibited by wild-type p53; p73 beta has no significant effect on this promoter. This is a unique situation where p73 alpha differs from p73 beta as well as p53.
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PMID:Differential modulation of cellular and viral promoters by p73 and p53. 1117 10

Factor acetyltransferase activity associated with several histone acetyltransferases plays a key role in the control of transcription. Here we report that hGCN5, a well known histone acetyltransferase, specifically interacts with and acetylates the human immunodeficiency virus type 1 (HIV-1) transactivator protein, Tat. The interaction between Tat and hGCN5 is direct and involves the acetyltransferase and the bromodomain regions of hGCN5, as well as a limited region of Tat encompassing the cysteine-rich domain of the protein. Tat lysines 50 and 51, target of acetylation by p300/CBP, were also found to be acetylated by hGCN5. The acetylation of these two lysines by p300/CBP has been recently shown to stimulate Tat transcriptional activity and accordingly, we have found that hGCN5 can considerably enhance Tat-dependent transcription of the HIV-1 long terminal repeat. These data highlight the importance of the acetylation of lysines 50 and 51 in the function of Tat, since different histone acetyltransferases involved in distinct signaling pathways, GCN5 and p300/CBP, converge to acetylate Tat on the same site.
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PMID:The histone acetyltransferase, hGCN5, interacts with and acetylates the HIV transactivator, Tat. 1138 67

Nuclear factor (NF)-kappaB transcription factors are involved in the control of a large number of normal cellular and organismal processes, such as immune and inflammatory responses, developmental processes, cellular growth, and apoptosis. Transcription of the human immunodeficiency virus type 1 (HIV-1) genome depends on the intracellular environment where the integrate viral DNA is regulated by a complex interplay among viral regulatory proteins, such as Tat, and host cellular transcription factors, such as NF-kappaB, interacting with the viral long terminal repeat region. CBP (CREB-binding protein) and p300, containing an intrinsic histone acetyltransferase (HAT) activity, have emerged as coactivators for various DNA-binding transcription factors. Here, we show that the p50 subunit as well as the p50/p65 of NF-kappaB, and not other factors such as SP1, TFIIB, polymerase II, TFIIA, or p65, can be acetylated by CBP/p300 HAT domain. Acetylation of p50 was completely dependent on the presence of both HAT domain and Tat proteins, implying that Tat influences the transcription machinery by aiding CBP/p300 to acquire new partners and increase its functional repertoire. Three lysines, Lys-431, Lys-440, and Lys-441 in p50 were all acetylated in vitro, and a sequence similarity among p50, p53, Tat, and activin receptor type I on these particular lysines was observed. All proteins have been shown to be acetylated by the CBP/p300 HAT domain. Acetylated p50 increases its DNA binding properties, as evident by streptavidin/biotin pull-down assays when using labeled NF-kappaB oligonucleotides. Increased DNA binding on HIV-1 long terminal repeat coincided with increases in the rate of transcription. Therefore, we propose that acetylation of the DNA binding domain of NF-kappaB aids in nuclear translocation and enhanced transcription and also suggest that the substrate specificity of CBP/p300 can be altered by small peptide molecules, such as HIV-encoded Tat.
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PMID:Enhancement of nuclear factor-kappa B acetylation by coactivator p300 and HIV-1 Tat proteins. 1173 81

The human immunodeficiency virus type 1 (HIV-1) trans-activator protein Tat stimulates transcription of the integrated HIV-1 genome and promotes viral replication in infected cells. Tat transactivation activity is dependent on lysine acetylation and its association with nuclear histone acetyltransferases p300/CBP (CREB binding protein) and p300/CBP-associated factor (PCAF). Here, we show that the bromodomain of PCAF binds specifically to HIV-1 Tat acetylated at lysine 50 and that this interaction competes effectively against HIV-1 TAR RNA binding to the lysine-acetylated Tat. The three-dimensional solution structure of the PCAF bromodomain in complex with a lysine 50-acetylated Tat peptide together with biochemical analyses provides the structural basis for the specificity of this molecular recognition and reveals insights into the differences in ligand selectivity of bromodomains.
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PMID:Structural basis of lysine-acetylated HIV-1 Tat recognition by PCAF bromodomain. 1193 65


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