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)

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

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

The human immunodeficiency virus type 1 (HIV-1) Tat protein has been reported to transactivate several cellular genes, including the potent chemotactic factor interleukin-8 (IL-8). Consistent with these in vitro assays, elevated levels of IL-8 protein are found in the serum of HIV-infected individuals. We now extend these observations by demonstrating that Tat induction of IL-8 is linked to the cell cycle. Cells that constitutively express the Tat(1-86) protein (eTat) and control cells (pCEP) were reversibly blocked at the G(1)/S border with hydroxyurea or thymidine. The cells were subsequently released, and IL-8 expression was monitored by RNase protection assays and enzyme-linked immunosorbent assay (ELISA). RNase protection assays demonstrated that IL-8 mRNA expression is transiently induced, approximately fourfold, as the Tat-expressing cells enter S phase. Consistent with the RNase protection assay, an increase in IL-8 protein was observed in the cell supernatant using an IL-8 ELISA. Similar experiments were performed following a reversible block at the G(2)/M border with nocodazole and release into G(1). Using the RNase protection assay and ELISA, little or no increase in IL-8 expression was observed during G(1). Using gel shift as well as an immobilized DNA binding assay, we demonstrate that the increase in IL-8 gene expression correlates with a specific increase in p65 NF-kappa B binding activity only in the nucleus of the Tat-expressing cells. Moreover, the CREB-binding protein coactivator is present in the complex in the Tat cell line. Finally, we demonstrate that the presence of the proteasome inhibitor MG-132 inhibits the induction of NF-kappa B binding, as well as IL-8 expression, supporting the role of NF-kappa B.
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PMID:Cell cycle regulation of human interleukin-8 gene expression by the human immunodeficiency virus type 1 Tat protein. 1116 Jun 71

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

Kaposi's sarcoma-associated herpesvirus (KSHV) open reading frame K8 encodes a basic region-leucine zipper protein of 237 amino acids that homodimerizes with its bZIP domain. KSHV K8 shows significant homology to the Epstein-Barr virus (EBV) immediate-early protein Zta, a key regulator in the reactivation and replication of EBV. In this study, we report that K8, like its homolog EBV Zta, interacts with cellular CREB-binding protein (CBP) in vivo and in vitro. This interaction requires the C/H3 domain of CBP and the basic region of K8. K8 represses CBP-mediated transcription by competing with limited amounts of cellular CBP, exemplified by the reduced expression from the AP-1 and human immunodeficiency virus long terminal repeat promoters.
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PMID:The Kaposi's sarcoma-associated herpesvirus K8 protein interacts with CREB-binding protein (CBP) and represses CBP-mediated transcription. 1153 13

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

Human immunodeficiency virus, type 1-encoded transactivator protein Tat is known to be a substrate of and to interact with several nuclear histone acetyltransferases (HATs). Here we show that Tat is a general inhibitor of histone acetylation by cellular HATs and that for at least one of them, the CREB-binding protein (CBP), it induces a substrate selectivity. Indeed, in the presence of Tat, the acetylation of histones by CBP was severely inhibited, while that of p53 and MyoD remained unaffected. The C-terminal domain of Tat, dispensable for the activation of viral transcription, was found to be necessary and sufficient to interfere with histone acetylation. These results demonstrate that Tat is able to selectively modulate cellular protein acetylation by nuclear HATs and therefore to take over this specific signaling system in cells.
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PMID:Tat-controlled protein acetylation. 1215 97

Patients with AIDS are at increased risk for developing various neoplasms, including Hodgkin's and non-Hodgkin's lymphomas, Kaposi's sarcomas, and anal-rectal carcinomas, suggestive that human immunodeficiency virus type-1 infection might promote establishment of AIDS-related cancers. Tat, the viral trans-activator, can be endocytosed by uninfected cells and has been shown to inhibit p53 functions, providing a candidate mechanism through which the human immunodeficiency virus type-1 might contribute to malignant transformation. Because Tat has been shown to interact with histone acetyltransferase domains of p300/cAMP-responsive element-binding protein (CREB)-binding protein and p300/CREB-binding protein-associated factor, we have investigated whether Tat might alter p53 acetylation and tumor suppressor-responsive transcription. Here, we demonstrate that both Tat and p53 co-localize with p300/CREB-binding protein-associated factor and p300 in nuclei of IMR-32 human neuroblastoma cells and in PC-12 pheochromocytoma cells. Further, p53 trans-activation of the 14-3-3varsigma promoter was markedly repressed by Tat-histone acetyltransferase interactions, and p53 acetylation by p300/CREB-binding protein-associated factor on residue Lys(320) was diminished as a result of Tat-histone acetyltransferase binding in vivo and in vitro. Tat also inhibited p53 acetylation by p300 in a dosage-dependent manner in vitro. Finally, HIV-1-infected Molt-4 cells displayed reduced p53 acetylation on lysines 320 and 373 in response to UV irradiation. Our results allude to a mechanism whereby the human immunodeficiency virus type-1 trans-activator might impair tumor suppressor functions in immune/neuronal-derived cells, thus favoring the establishment of neoplasia during AIDS.
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PMID:Human immunodeficiency virus type-1 Tat/co-activator acetyltransferase interactions inhibit p53Lys-320 acetylation and p53-responsive transcription. 1250 Dec 50

Vpr (Viral protein-R) of the Human Immunodeficiency Virus type-1 is a 14-kDa virion-associated protein, conserved in HIV-1, -2 and the Simian Immunodeficiency Virus (SIV). Vpr is incorporated into the virion, travels to the nucleus, and has multiple activities including promoter activation, cell cycle arrest at the G2/M transition and apoptosis induction. Through these activities, Vpr is thought to influence not only viral replication but also numerous host cell functions. These functions may be categorized in three groups depending on the domains of Vpr that support them: (1) functions mediated by the amino terminal portion of Vpr, like virion packaging; (2) functions mediated by the carboxyl terminal portion such as cell cycle arrest; and (3) functions that depend on central alpha-helical structures such as transcriptional activation, apoptosis and subcellular shuttling. Association of these activities to specific regions of the Vpr molecule appears to correlate to the host/viral molecules that interact with corresponding portion of Vpr. They include Gag, host transcription factors/coactivators such as SP1, the glucocorticoid receptor, p300/CREB-binding protein and TFIIB, apoptotic adenine nucleotide translocator, cyclophilin A and 14-3-3 proteins. The properties of Vpr molecule has made it difficult to assess its function and determine the true cellular interactors. Further studies on Vpr function are needed to fully assess the function of this important early regulatory molecule of HIV and other lentiviruses.
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PMID:Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1. 1514 77

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a systemic disease with autoimmune characteristics caused by mutations in a single gene called AIRE. Although a defect in negative selection has been emphasized for the pathogenesis of the autoimmune symptoms on the basis of studies of Aire-targeted mice, the function of the gene in the peripheral immune system and the cause of immunodeficiency noted in the disease have not been clarified yet. In this study, we demonstrated using murine Aire transfectants that Aire downregulates IL-1 receptor antagonist (IL-1Ra), which is important for immune suppression, and major histocompatibility complex (MHC) class II molecules, which are critical for acquired immunity. It was surprising to learn that Aire, which has been supposed to positively regulate transcription, downregulates multiple molecules. This downregulation of IL-1Ra and MHC class II molecules seems to be caused by the competition for transcriptional coactivator, CREB-binding protein (CBP), and may explain part of the contradictory (i.e., both autoimmune and immunodeficient) nature of APECED.
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PMID:Aire downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressive functions. 1514 62


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