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 cis-acting control elements of the interleukin-2 receptor alpha-chain (IL-2R alpha) gene contain a potent kappa B-like enhancer whose activity can be induced by various mitogenic stimuli. Recent cloning of the p50 and p65 subunits of the kappa B-binding protein NF-kappa B complex revealed a striking sequence homology of these proteins with the c-rel proto-oncogene product (c-Rel). On the basis of this homology, we examined the potential role of c-Rel in controlling IL-2R alpha transcription. We now demonstrate that the recombinant human c-Rel protein binds to the kappa B element in the IL-2R alpha promoter and results in alteration of the DNA structure in the adjacent downstream regulatory elements containing the CArG box and the GC box. We found that human c-Rel can activate transcription from the IL-2R alpha promoter, but not the kappa B-containing human immunodeficiency virus type 1 promoter, upon cotransfection into Jurkat T cells. Furthermore, truncation of the carboxyl terminus of c-Rel results in a c-Rel mutant (RelNA) that (i) localizes exclusively in the nucleus and (ii) acts in synergy with wild-type c-Rel in activating transcription from the kappa B site of the IL-2R alpha promoter. Finally, induction of surface IL-2R alpha expression coincides with the induced levels of endogenous c-Rel and induced c-Rel binding to the IL-2R alpha kappa B site. Our study identified c-Rel as one component of the Rel/NF-kappa B-family proteins involved in the kappa B-dependent activation of IL-2R alpha gene expression. Furthermore, our results suggest that a Re1NA-like cellular factor (e.g., NF-kappa B p50 or p49 subunit) acts in synergy with c-Re1 during T-cell activation.
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PMID:Kappa B site-dependent activation of the interleukin-2 receptor alpha-chain gene promoter by human c-Rel. 150 3

The effects of human immunodeficiency virus 1 (HIV-1) infection on cellular differentiation and NF-kappa B DNA binding activity have been investigated in a new model of myeloid differentiation. PLB-985 cells represent a bipotential myelomonoblastic cell population capable of either granulocytic or monocytic differentiation after induction with appropriate inducers. By virtue of the presence of CD4 on the cell surface, PLB-985 cells were chronically infected with HIV-1 strain IIIB. PLB-IIIB cells clearly possessed a more monocytic phenotype than the parental myeloblasts, as determined by differential staining, increased expression of the myeloid-specific surface markers, and transcription of the c-fms proto-oncogene. NF-kappa B binding activity was inducible by tumor necrosis factor and phorbol myristate acetate in PLB-985. However, in PLB-IIIB cells, constitutive expression of a novel NF-kappa B complex was detected, composed of proteins ranging between 70 and 110 kD. These proteins interacted specifically with the symmetric NF-kappa B site from the interferon beta (IFN-beta) promoter. Mutations affecting the 5' guanine residues of the kappa B site were unable to compete for these NF-kappa B-related proteins. Inducibility of endogenous IFN-beta and IFN-alpha RNA was also increased in PLB-IIIB cells. These studies indicate that HIV-1 infection of myelomonoblastic cells may select for a more mature monocytic phenotype and that unique subunit associations of NF-kappa B DNA binding proteins may contribute to differential NF-kappa B-mediated gene expression.
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PMID:Induction of monocytic differentiation and NF-kappa B-like activities by human immunodeficiency virus 1 infection of myelomonoblastic cells. 174 Jun 63

Four Epstein-Barr virus-positive lymphoblastoid cell lines (LCL) were successfully infected in vitro with immunodeficiency virus type 1 (HIV-1) as demonstrated by reverse transcriptase activity and p24 HIV antigen in culture supernatants, positive cell staining for gag-encoded HIV proteins, presence of viral HIV genome by Southern blot analysis and ulstrastructural observations. In addition, both HIV-1-infected B cells and their supernatants efficiently transactivated the chloramphenicol acetyl transferase reporter gene which is under the control of the HIV-1 long terminal repeat. The LCL cells displayed long-term HIV-1 infection and production, but no cytopathic effects were observed. Cytofluorimetric analysis did not detect membrane CD4 presence in the LCL cells before and after HIV-1 infection; moreover, a minute amount of CD4 mRNA was observed only in one of the LCL. A monoclonal antibody specific for the viral binding site of the CD4 molecule delayed, but did not block, HIV-1 infection of the LCL cells. Following HIV-1 infection, changes in LCL phenotype were observed, consisting of a decrease in CD23- and CD39-positive cells, and a concomitant increase of cells with surface CD10 and Bac-1. Furthermore, HIV-1-infected LCL cells did not grow in tight clumps, as usually observed in uninfected LCL, but as disperse suspensions, and formed more agar colonies than control LCL. However, despite this apparent acquisition of a malignant-like phenotype, c-myc proto-oncogene rearrangement was not detected. The appearance of cells with new characteristics did not seem due to clone selection by HIV-1 infection, since all the LCL conserved their clonotypic pattern of IgH chain rearrangement. The acquisition of malignant-like features by HIV-infected B cells might be clinically significant in terms of the pathogenesis of non-Hodgkin's B cell lymphomas, which occur frequently in AIDS patients.
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PMID:Infection of Epstein-Barr virus-transformed lymphoblastoid B cells by the human immunodeficiency virus: evidence for a persistent and productive infection leading to B cell phenotypic changes. 217 Jan 47

Epstein-Barr virus and HTLV-1 are both lymphotropic viruses, capable of immortalizing lymphocytes in vitro (Fig. 1). Both viruses have been sequenced and subjected to intense molecular biologic scrutiny, and in both cases genes believed to be important in lymphocyte immortalization have been identified. These viral genes are not homologues of cellular oncogenes, nor is there any evidence to suggest insertional mutagenesis. Rather, these genes alter the expression of a variety of cellular genes and, in so doing, alter the growth characteristics of the host cell. Infection with either virus is most likely to be asymptomatic, associated with a benign self-limited lymphoproliferation, or both, but in a small fraction of instances these benign lymphoproliferations give rise to a lymphoma or leukemia. In the case of the Epstein-Barr virus, a variety of cofactors have been identified that are important to the evolution of malignancy. These cofactors include immunosuppression in transplant recipients, cogenital immunodeficiency in the X-linked lymphoproliferative syndrome, human immunodeficiency virus infection in AIDS patients, and malaria in patients with endemic Burkitt's lymphoma. In the case of HTLV-1, cofactors have not been identified. Nonetheless, the importance of cofactors is suggested by the small fraction of the population infected by the virus who actually develop lymphoproliferative disease, and the long latency period between infection and the development of frank lymphoproliferative disease. In organ transplant recipients with lymphomas associated with Epstein-Barr virus infection, the EBV immortalizing/transforming genes are expressed in the malignant tissue. But in Burkitt's lymphoma and in adult T-cell leukemia/lymphoma, the EBV and HTLV-1 immortalizing/transforming genes are not detectably expressed. In Burkitt's lymphoma, it is suggested that the dysregulated myc gene renders the growth effects of Epstein-Barr virus latency genes superfluous. No comparable proto-oncogene translocation or activation has yet been identified in HTLV-1 lymphoma/leukemia.
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PMID:Human lymphotropic viruses associated with lymphoid malignancy: Epstein-Barr and HTLV-1. 217 3

Protein myristoylation was first discovered in the catalytic subunit of adenosine 3',5'-cyclic monophosphate-dependent protein kinase. Subsequently, various cellular and viral myristoylated proteins were detected. In each case, the myristoyl moiety was found in an amide linkage with the amino terminal glycine residue of the modified proteins. The biological functions of protein myristoylation of various cellular protein, oncogene product, and viral structural proteins have been studied by many biochemists. Two of the most thoroughly studies myristoylated proteins are the transforming protein of Rous sarcoma virus, pp60v-src, and the proto-oncogene product, pp60c-src. Deletion, modification of the first 14 NH2-terminal amino acid of pp60v-src, or chemical antimyristoylation of the protein with N-myristoyl glycinal diethylacetal does not affect intrinsic tyrosine src-kinase activity, but prevents myristoylation and membrane association, and abolishes the transforming activity of the protein. Protein myristoylations of some viral structural proteins were also studied by many investigators, and X-ray crystallographic studies of poliovirus suggest that myristate moiety may play a central role in capsid assembly. Recently, human immunodeficiency virus, HIV-I, process a myristoylated p17gag protein, which is proteolytically derived from the NH2-terminus of a gag precursor protein, and its myristate moiety may be important for virus assembly. In this review, we detailed recent studies of the protein myristoylation in cellular regulation and virus proliferation.
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PMID:[Function of protein myristoylation in cellular regulation and viral proliferation]. 254 55

Transient transfection of ras expression vectors into human fibroblasts and astrocytes has been used to test the hypothesis that p21 ras, a known membrane signal transductor, may participate in pathways linking cellular activation and human immunodeficiency virus (HIV) reactivation. Expression vectors carrying the chloramphenicol acetyl transferase coding sequence under the control of various fragments of the long terminal repeat (LTR) of HIV were co-transfected with expression vectors of the mutated (val 12) c-Ha-ras gene or of its normal counterpart. Both forms of the ras gene induced transactivation of the HIV-LTR via the two direct repeat sequences which constitute the HIV enhancer. This repeat sequence was shown to be sufficient for ras-induced LTR transactivation. Other LTR sequences tested were not found to be responsive to co-transfected ras expression vectors. Deletion of the TAR sequence impaired the response to tat, but not to ras co-transfection. The mutated ras gene was more efficient than the proto-oncogene in activating the HIV enhancer. Transfection of ras was shown to enhance transcription of a complete provirus DNA clone of HIV-1. Such findings may shed new light on the mechanisms through which cell membrane activation signals result in HIV reactivation.
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PMID:c-Ha-ras transfection induces human immunodeficiency virus (HIV) transcription through the HIV-enhancer in human fibroblasts and astrocytes. 268 62

Lymphomas occurred in 3 of 16 Japanese patients with ataxia telangiectasia (AT) and Wiskott-Aldrich syndrome (WAS). The patients had a persistently reactivated Epstein-Barr virus (EBV) infection with a remarkable decrease in virus-specific cellular immunity. In these patients, the B lymphocytes were more sensitive to EBV-induced events and to cellular proto-oncogene activation than seen in the healthy counterparts. This immunologic and genetic background was considered to explain the massive lymphoproliferation in these primary immunodeficiency disorders.
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PMID:Epstein-Barr virus infection and oncogenesis in primary immunodeficiency. 303 Mar 41

The purpose of this study was to characterize the clinical and histological features of intraoral squamous cell carcinoma in men who were seropositive for the human immunodeficiency virus and to evaluate viral cofactors (human papillomavirus, herpes simplex virus, Epstein-Barr virus), proliferative index (proliferating cell nuclear antigen), a factor associated with invasion (cathepsin D), and mutated tumor suppressor gene and proto-oncogene products (mutated p53, c-erbB-2). Four men who were seropositive for the human immunodeficiency virus and had acquired immunodeficiency syndrome presented with painful oral lesions of variable duration. Oral cancer risk factors included heavy tobacco use (four of four), heavy alcohol use (three of four), and previous radiotherapy (one of four). The lesions consisted of ulcers (two of four), a fungating mass (one of four), and papillary erythroplakia (one of four). Incisional biopsy specimens were obtained. High-stringency in situ hybridization was performed with DNA probes to the human papillomavirus (types 6/11; 16/18; 31/33/35) and Epstein-Barr virus: Immunocytochemical studies for the herpes simplex virus, proliferating cell nuclear antigen, cathepsin D, mutated p53, and c-erbB-2 were performed. Two lesions were moderately differentiated squamous cell carcinoma, one lesion was a basaloid squamous cell carcinoma, and one was carcinoma in situ. Stage of disease at diagnosis was II (one of four), III (two of four), and IV (one of four). Three cases were positive for the human papillomavirus, one case was positive for Epstein-Barr virus, and three cases were positive for the herpes simplex virus. C-erbB-2 was focally positive in one case, and mutated p53 was positive in a separate case.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intraoral squamous cell carcinoma in human immunodeficiency virus infection. A clinicopathologic study. 755 63

The regulatory Tat protein of human immunodeficiency virus type-1 (HIV-1) exerts a pleyotropic activity on the survival and proliferation of different cell types in culture. In this report, we investigated the effect of either endogenous or exogenous Tat on Bcl-2 proto-oncogene expression and cell survival in Jurkat T-cell lines and primary peripheral blood mononuclear cells. Stable and transient transfections of Jurkat cells with the cDNA of tat and a plasmid containing Bcl-2 promoter in front of CAT (Bcl-2 Pr/CAT) stimulated CAT activity and showed an increase of Bcl-2 mRNA and protein expression. This effect was specifically related to tat, because Jurkat cells transfected with the cDNA of tat in antisense orientation, tat carrying a mutation in the amino acid cys22-gly22, or the control vector alone (pRPneo-SL3) did not show any significant difference in Bcl-2 promoter activity with respect to parental Jurkat cells. We also observed a specific correlation between tat-induced Bcl-2 gene expression and inhibition of apoptosis induced by serum withdrawal. Our results suggest that the structural integrity of the activation domain of Tat was required for the promotion of the Bcl-2 promoter and Jurkat cell survival, because a single mutation in the aminoacid cys22 was sufficient to completely block the upregulation of Bcl-2 and inhibition of apoptosis. Moreover, picomolar concentrations of native or recombinant Tat were able to upregulate Bcl-2 expression both in Jurkat and primary peripheral blood mononuclear cells, suggesting that extracellular Tat, actively released by infected cells, may also play a significant role in suppressing apoptosis. An aberrant cell survival of lymphoid cells consequent to the upregulation of Bcl-2 may represent an additional pathogenetic mechanism that could help explain both the dysregulated immune response and the frequent occurrence of hyperplastic/neoplastic disorders in HIV-1-seropositive individuals.
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PMID:The human immunodeficiency virus type-1 Tat protein upregulates Bcl-2 gene expression in Jurkat T-cell lines and primary peripheral blood mononuclear cells. 757 50

BHRF1, one of many Epstein-Barr virus (EBV)-encoded proteins, shows strong functional homology to the human bcl-2 proto-oncogene product, a protein involved in the pathogenesis of a subset of B-cell lymphomas, ie, follicle center cell lymphomas (FCCL). We have investigated the presence of possible latent and lytic transcripts of BHRF1 using a reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay in a group of EBV-associated B-cell lymphomas in patients with (N = 5) or without overt immunodeficiency (N = 4), in T-cell lymphomas (N = 9), and in cases of Hodgkin's disease (N = 6). BHRF1 transcription was found consistently in EBV-associated (ie, diffuse EBER 1/2-positive) B-cell lymphomas in patients with or without immune deficiency, whereas in EBV-associated T-cell lymphomas or in EBV-associated Hodgkin's disease, BHRF1 transcription was only detected in two T-cell lymphomas and one case of Hodgkin's disease, which also harbored EBER 1/2-positive reactive cells. Moreover, weak BHRF1 signals were found in two T-cell lymphomas where EBER 1/2 expression was detected mainly in sporadic reactive lymphocytes and in one reactive tonsil with sporadic EBER 1/2-positive lymphocytes. BHRF1 transcripts were found to be generated by the C or W promoter (associated with viral latency) and/or by the H promoter (associated with the virus lytic cycle). In all cases with H promoter-derived BHRF1 transcripts, transcripts encoding ZEBRA were also detected, suggesting a reactivation of the virus lytic cycle. Analysis of other EBV genes revealed transcription of BARFO in all tested EBV-harboring tissues. Transcription of EBNA1 and LMP1 was usually detected, whereas EBNA2 transcription was found exclusively in B-cell lymphomas in immunocompromised patients. These data demonstrate that BHRF1 transcripts are exclusively found in EBV-associated B-cell lymphomas. When BHRF1 transcripts are detected in T-cell lymphomas or in Hodgkin's disease, it is probably due to the presence of reactive EBER 1/2-positive lymphocytes. The consistent transcription of BHRF1 in EBV-associated B-cell lymphomas suggests a possible pathogenic role for this gene product in EBV-positive B-cell lymphomas analogous to bcl-2.
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PMID:BHRF1, the Epstein-Barr virus (EBV) homologue of the BCL-2 protooncogene, is transcribed in EBV-associated B-cell lymphomas and in reactive lymphocytes. 765 18


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