Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A retrospective study was performed to characterize malignant lymphomas of 16 Simian immunodeficiency virus (SIV)-infected rhesus monkeys (Macaca mulatta), 2-9 years of age, on the basis of clinical data, histologic and immunophenotypic results, and cell death indices compiled with the TdT-mediated X-duTP nick end labeling method. We particularly focused on providing immunohistochemical evidence of expression products of EBNA2, Bc12, c-Myc, P21, P53, and Bc16. Results were compared with data from the literature on human HIV-associated lymphomas. According to the updated Kiel classification, the lymphomas were classified as 11 centroblastic lymphomas, three immunoblastic lymphomas, one Burkitt-like lymphoma, and one immunocytoma. Using antibodies to CD20, the B-cell origin of tumor cells was demonstrated. SIV antigen was not demonstrated in the tumor cells. Infection with rhesus lymphocryptovirus was present in 94% of the monkeys. Lymphomas revealed expression of Bc12 in 15/16 (94%), c-Myc in 14/16 (88%), P21 in 10/ 16 (63%), P53 in 12/16 (75%), and Bc16 in 1/16 (6%) monkeys. This study provided evidence that the expression of these gene products, which are thought to play an important role in cell proliferation and apoptosis in HIV- and non-HIV-associated lymphomas, are also involved in the pathogenesis of lymphomas in SIV-infected rhesus monkeys. A tentative relationship between the described gene products and the cell death indices was established for the expression of Bc12. The present primate model represents a suitable animal model for studying the pathogenesis of AIDS-associated lymphomas.
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PMID:SIV-associated lymphomas in rhesus monkeys (Macaca mulatta) in comparison with HIV-associated lymphomas. 1210 18

Ataxia-telangiectasia (AT) syndrome (cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, susceptibility to infections, and neoplasia) is associated with cyto- and nucleomegaly in several organ systems. Our aim was to determine (1) whether such cellular abnormalities in the pituitary selectively involve specific cell types, and (2) the proliferation and DNA ploidy status of such cells. Three AT autopsy pituitaries were studied by histology, immunohistochemistry (pituitary hormones, MIB-1, p53 protein), in situ hybridization (pituitary hormones), and Feulgen stain image analysis for ploidy. Results indicated that, in adenohypophyses the scattered pleomorphic, bizarre nuclei were mainly those of somatotrophs and corticotrophs, growth hormone (GH), or adrenocorticotropic hormone (ACm) immunoreactive and expressing the GH or ACTH gene, respectively. Cyto- and nucleomegaly were less frequent in other secretory cells but were also noted in pituicytes of the posterior lobe. Affected cells were immunonegative for MIB-1 and for p53 protein. Image morphometric DNA analysis showed the bizarre cells to be aneuploid with complex histogram patterns, including many nuclei with DNA contents >8 n. No adenomas were found. We conclude that in AT adenohypophyseal cells with cyto- and nucleomegaly, as well as pleomorphism, synthesize and store adenohypophyseal hormones, mainly GH or ACTH. They and affected pituicytes are nonproliferative and are aneuploid.
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PMID:Pituitary Changes in Ataxia-Telangiectasia Syndrome: An Immunocytochemical, In Situ Hybridization, and DNA Cytometric Study of Three Cases. 1211 23

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

The Vpr gene of human immunodeficiency virus type 1 (HIV-1) encodes a 14-kDa protein that prevents cell proliferation by causing arrest in the G2/M phase of the cell cycle. Here we report the first evidence that Vpr activates the expression and transcription of the cyclin-dependent kinase inhibitor p21/Waf1/Cip1 (hereafter p21), an inhibitor of the G1 and G2/M phase transitions in T lymphoid and myeloid cells. Vpr activated p21 protein expression in a dose-dependent manner. Vpr also caused a three- to eightfold induction of the p21 promoter. This induction was dose- and time-dependent and was comparable to levels of p21 induction induced by p53. Of note, Vpr activated p21 transcription in endogenous p53 positive cells, but not in p53-deleted or p53 nonfunctional cells. Vpr and p53 had an additive effect on p21 transcription. Mutational analysis indicated that wt Vpr, but not cell cycle inactive Vpr mutants, activated the p21 promoter. These data demonstrate that HIV-1 Vpr utilizes the cyclin-dependent kinase inhibitor p21, in addition to cdc2, to arrest cells in G2/M.
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PMID:HIV-1 Vpr activates cell cycle inhibitor p21/Waf1/Cip1: a potential mechanism of G2/M cell cycle arrest. 1257 82

The majority of AIDS-related non-Hodgkin's lymphomas are clinically aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, or immunoblastic lymphomas. In contrast, the lymphoid proliferations arising in solid organ transplant recipients, collectively referred to as posttransplantation lymphoproliferative disorders (PT-LPDs), represent a clinically and histopathologically heterogeneous group of Epstein-Barr virus (EBV)-driven B-cell proliferations of variable clonal composition. During a retrospective histopathologic review of lymphoid proliferations associated with human immunodeficiency virus (HIV) infection we identified 10 cases that morphologically resemble the polymorphic PT-LPDs. They arose in lymph nodes (five), lungs (two), and the parotid gland, perineum, and skin (one each). They exhibit a diffuse growth pattern and are composed of a polymorphic lymphoid cell population exhibiting a variable degree of plasmacytic differentiation, cytologic atypia, and numbers of atypical immunoblasts. A clonal B-cell population was detected by immunoglobulin heavy and light chain gene rearrangement and/or EBV terminal repeat analysis in 8 of the 10 (80%) cases by Southern blotting. The nongermline hybridizing bands were usually faint, however, suggesting that the clonal B-cell population represented only a subpopulation within the polymorphic lesion. Strong clonal rearrangement bands were present in one case in which there was clear morphologic evidence of transformation to diffuse large cell lymphoma. This case exhibited C-MYC, BCL-6, and p53 gene mutations. One other case exhibited a p53 gene mutation. The remaining eight cases lacked C-MYC, BCL-6, RAS, and p53 gene alterations. Clonal EBV infection was detected in 4 of the 10 (40%) lesions. Like EBV-containing PT-LPDs, all four EBV-positive HIV-associated polymorphic lesions were associated with type A EBV. The Kaposi's sarcoma-associated herpesvirus was detectable in two cases by polymerase chain reaction analysis, but not by Southern blotting. In situ hybridization demonstrated Kaposi's sarcoma-associated herpesvirus in some of the cytologically malignant-appearing cells. In conclusion, polymorphic B-cell lymphoproliferative disorders comparable morphologically and molecularly to those arising after solid organ transplantation also occur in association with HIV infection. As in the case of their polymorphic PT-LPD counterparts, their malignant status, biologic significance, and relationship to monomorphic B-cell lymphomas remain to be elucidated.
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PMID:Human immunodeficiency virus (HIV)-associated polymorphic lymphoproliferative disorders. 1260 85

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, immunodeficiency, cancer predisposition, genome instability, and radiation sensitivity. Previous research has shown that it is possible to correct the hereditary deficiency A-T by DNA transfection in cell culture, but the large size of the ATM cDNA (9 kb) limits the use of many vector types for gene replacement. HSV-1 amplicon vectors provide a means to deliver large genes to cells efficiently and without toxicity. In this study, the FLAG-tagged cDNA for human ATM was inserted into an HSV-1 amplicon under control of the CMV promoter (designated as HGC-ATM). FLAG-ATM expression was confirmed in 293T/17 cells and human A-T fibroblasts (GM9607) after transduction, by immunoprecipitation, Western analysis, and immunocytochemistry. Functional recovery was assessed by two independent assays. First, in vitro kinase assay showed that vector-derived ATM in GM9607 cells could successfully phosphorylate wt p53 using recombinant GST-p53(1-101). Second, in A-T cells infected with the HGC-ATM vector, the extent of accumulation in G2/M phase at 24 h postirradiation was similar to that observed in cells with wild-type endogenous ATM and lower than that observed in A-T cells infected with a control vector. Thus, these vectors provide a tool to test the feasibility of HSV-amplicons as gene therapy vectors for A-T.
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PMID:HSV-1 amplicon vector-mediated expression of ATM cDNA and correction of the ataxia-telangiectasia cellular phenotype. 1288 28

Opiates such as morphine or heroin may promote cell apoptosis and cause dysfunction of immune cells. In simian immunodeficiency virus (SIV)-infected lymphocytic cells, however, morphine may protect the cells from apoptotic lysis and allow the virus to continue to replicate. To further explore this apparently antithetical effect of opiates, we evaluated in the present study the effects of morphine on human lymphocytic CEM x174 cells induced to undergo apoptosis in the presence of actinomycin D. It was found that induction of apoptosis (characterized by DNA laddering) by actinomycin D was accompanied by a stimulation of the expression of active (phosphorylated) form of p53. Pretreatment of the cells with 10nM morphine caused a transient, naloxone-reversible suppression of the appearance of activated p53 and the generation of DNA laddering. Parallel evaluation of the growth of CEM x174 indicated that morphine treatment delays the inception of cell death triggered by actinomycin D. Inasmuch as Bcl-2 suppresses while Bax accelerates apoptosis, treatment of cells with morphine reduced the expression of Bax and enhanced the expression of Bcl-2. Taken together, morphine, through binding at the opioid receptor, may protect lymphocytic cells from apoptotic lysis if cell death is initiated by apoptosis-inducing agents such as human immunodeficiency virus (HIV), SIV or actinomycin D.
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PMID:Morphine suppresses lymphocyte apoptosis by blocking p53-mediated death signaling. 1292 89

Cells expressing the envelope glycoprotein complex (Env) encoded by the human immunodeficiency virus can fuse with cells expressing Env receptors (CD4 and CXCR4). The resulting syncytia undergo apoptosis. We developed a cytofluorometric assay for the quantitation of syncytium formation and syncytial apoptosis. Using this methodology, we show that caspase activation in syncytia is inhibited by pharmacological or genetic intervention on cyclin-dependent kinase-1, p53, and mitochondrial membrane permeabilization (MMP). Thus, transfection of fusing cells with the viral mitochondrial inhibitor of apoptosis encoded by cytomegalovirus, a specific inhibitor of MMP, prevented the mitochondrial cytochrome c release and abolished simultaneously the activation of caspase-3. Conversely, inhibition of caspases did not prevent MMP. These results indicate that Env-elicited syncytial apoptosis involves the intrinsic (mitochondrial) pathway.
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PMID:Mitochondrion-dependent caspase activation by the HIV-1 envelope. 1455 4

Growth hormone (GH) is neuroprotective, presumably through its actions on GH receptor-mediated pathways. Here, we examined the effects of GH using in vitro and in vivo assays of human immunodeficiency virus (HIV)-induced neuronal injury. Neuronal cultures were in assays of neurotoxicity induced by supernatants from HIV-1 tat-transfected monocytoid cells (Tat supernatant). GH treatment reduced neuronal death compared with untreated cultures (p < 0.001), which was blocked by a GH receptor antagonist, B2036. Tat supernatant-induced p53 expression in neurons was also reduced by GH treatment. Expression of both p53 and GH receptor were increased in brain tissue from HIV-infected persons compared with controls (p < 0.05). Mice receiving intrastriatal implants of Tat supernatant and treated with GH showed less neurobehavioral abnormalities together with reduced neuroinflammation and neuronal injury compared with untreated animals (p < 0.01). Three acquired immunodeficiency syndrome-defined patients with neurocognitive impairment were serially evaluated during daily GH treatment showing a sustained improvement in neuropsychological performance (p < 0.01). GH prevents neuronal death through its actions on neurons involving a p53-mediated pathway and also improved in vivo neurological function, indicating that GH may have a role in the treatment of HIV-induced neurodegeneration.
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PMID:Growth hormone prevents human immunodeficiency virus-induced neuronal p53 expression. 1459 50


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