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 clinical success of suicide gene therapy using herpes simplex virus type 1 thymidine kinase (TK) is largely dependent on the capacity of this enzyme to effectively induce the death of bystander cells. We have shown that fusion of TK to an 11-amino acid peptide from the basic domain of the human immunodeficiency virus type 1 Tat protein (Tat11) imparts cell membrane-translocating ability to the enzyme and significantly increases its cytotoxic activity. Here we report on the efficacy of this strategy in two different mouse models of adoptive tumorigenesis, based on the implantation of human Kaposi sarcoma (KS-IMM) cells in nude mice or of B16F10 melanoma cells in syngeneic C57BL/6J mice. Experiments were performed by the subcutaneous injection of mixtures of unmodified tumor cells containing different fractions of TK or Tat11-TK producing cells followed by animal treatment with ganciclovir (GCV). In both systems we consistently found that mice bearing tumors containing Tat11-TK cells displayed significantly retarded tumor growth and prolonged survival as compared with mice inoculated with cells expressing unmodified TK. Collectively, these results demonstrate that fusion of Tat11 to TK imparts remarkable intercellular trafficking capability to the enzyme. This modification of TK might constitute an important step in the optimization of TK suicide gene strategy for gene therapy of cellular proliferation.
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PMID:Fusion of the human immunodeficiency virus type 1 tat protein transduction domain to thymidine kinase increases bystander effect and induces enhanced tumor killing in vivo. 1639 Feb 70

Insufficient immunosurveillance is an important aspect in early tumorigenesis and in the pathogenesis of malignant disease. In the later course of cancer, the development of immunodeficiency is considered the major reason for disease progression and death. Within the anti-tumoral host defense reaction, Th1-type cytokine interferon-gamma (IFN-gamma) is of particular relevance. IFN-gamma stimulates several anti-proliferative and thus tumoricidal biochemical pathways in macrophages and other cells and also in tumor cell lines. These include inducible nitric oxide synthase, indoleamine (2, 3)-dioxygenase, an enzyme degrading the essential amino acid tryptophan, and the production of reactive oxygen species and neopterin in human macrophages and dendritic cells. Although the anti-proliferative strategy of the immune system aims to inhibit the growth of malignant cells, it can also affect T-cell response and thus contribute to the development of immunodeficiency. Accelerated degradation of tryptophan and increased production of neopterin were found to parallel the course of malignant diseases. Moreover, a higher degree of these metabolic changes characterizes poor prognosis and is associated with the development of anemia, weight loss and depressive mood in patients. Available data suggest that immunodeficiency in cancer patients may develop as a long-term side-effect of the antiproliferative and pro-apoptotic mechanisms elicited within Th1-type immune response, and enhanced production of pro-inflammatory cytokine IFN-gamma seems to be critically involved.
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PMID:Antitumoral activity of interferon-gamma involved in impaired immune function in cancer patients. 1691 15

Azidothymidine (AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) that is used for reducing mother-to-child transmission of human immunodeficiency virus I. Combinations of AZT and 3'-thiacytidine (3TC) are even more effective than AZT alone. AZT, however, is a mutagen and carcinogen in rodent models and 3TC can increase the genotoxicity of AZT. Since p53 plays a key role in human and mouse tumorigenesis, p53-haplodeficient mice are currently being evaluated as a model for assessing the carcinogenicity of perinatal exposure to NRTIs. In the present study, male C57BL/6 p53(+/+) and p53(-/-) mice were mated with C3H p53(+/+) females; the pregnant females were treated on gestation day 12 through parturition with 40, 80, and 160 mg/kg of AZT or a combination of 160 mg/kg AZT and 100 mg/kg 3TC (AZT-3TC); the p53(+/+) and p53(+/-) offspring were treated daily after birth through postnatal day (PND) 28. The frequencies of micronucleated reticulocytes (MN-RETs) and micronucleated normochromatic erythrocytes (MN-NCEs) were determined on PND1, PND10, and PND28; the frequency of Hprt mutant lymphocytes was measured on PND28. The frequencies of MN-RETs and MN-NCEs were increased in treated animals at all time points; there were no differences in the responses of p53(+/+) and p53(+/-) animals treated with identical doses of NRTIs. After correction for clonal expansion, both AZT and AZT-3TC treatments induced small but significant increases in the frequency of Hprt mutant lymphocytes in p53(+/-) mice, but not in p53(+/+) mice. The data indicate that p53 haplodeficiency affects the genotoxicity of NRTIs; thus, p53(+/-) mice may be a sensitive model for evaluating the carcinogenicity of perinatal exposure to NRTIs.
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PMID:Frequency of Hprt mutant lymphocytes and micronucleated erythrocytes in p53-haplodeficient mice treated perinatally with AZT and AZT in combination with 3TC. 1735 30

Tumor progression and metastasis are complex processes involving intricate interplay among multiple gene products. Astrocyte elevated gene (AEG)-1 was cloned as an human immunodeficiency virus (HIV)-1-inducible and tumor necrosis factor-alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes (PHFA) by a rapid subtraction hybridization approach. AEG-1 down-regulates the expression of the glutamate transporter EAAT2; thus, it is implicated in glutamate-induced excitotoxic damage to neurons as evident in HIV-associated neurodegeneration. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells, and AEG-1 cooperates with Ha-ras to augment the transformed phenotype of normal immortal cells. Moreover, AEG-1 is overexpressed in >95% of human malignant glioma samples when compared with normal human brain. Overexpression of AEG-1 increases and siRNA inhibition of AEG-1 decreases migration and invasion of human glioma cells, respectively. AEG-1 contains a lung-homing domain facilitating breast tumor metastasis to lungs. These findings indicate that AEG-1 might play a pivotal role in the pathogenesis, progression and metastasis of diverse cancers. Our recent observations indicate that AEG-1 exerts its effects by activating the nuclear factor kappa B (NF-kappaB) pathway and AEG-1 is a downstream target of Ha-ras and plays an important role in Ha-ras-mediated tumorigenesis. These provocative findings are intensifying interest in AEG-1 as a crucial regulator of tumor progression and metastasis and as a potential mediator of neurodegeneration. In this review, we discuss the cloning, structure and function(s) of AEG-1 and provide recent insights into the diverse actions and intriguing properties of this molecule.
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PMID:Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration. 1739 30

A simple, quantitative assay for measuring the oncogenic potential of integrating vectors is needed in order to improve vector design and safety. In this study, we have developed a transient plasmid-based assay to measure the activation of a reporter gene by an adjacent vector provirus. Plasmid pACT contains a luciferase cassette driven by a minimal, enhancerless promoter, into which vector proviruses are inserted upstream for evaluation by luciferase assays and northern blots. In a comparison of analogous vectors based on murine leukemia virus (MLV), human immunodeficiency virus (HIV), and foamy virus (FV), we observed significant enhancer activity and read-through transcription from MLV proviruses, and significant read-through transcription from HIV proviruses. HIV and FV proviruses containing an internal MLV long-terminal repeat (LTR) promoter also had significant enhancer activity, which was not observed with an internal promoter from the murine phosphoglycerate kinase-1 gene, PGK. These results demonstrate that neighboring gene activation can be limited by using internal promoter(s) lacking enhancer activity, especially when present in an FV vector backbone that prevents read-through transcription. Although the pACT assay does not measure oncogenesis directly, it should be useful for screening vectors before more time-consuming and costly animal studies are undertaken.
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PMID:A rapid and quantitative assay for measuring neighboring gene activation by vector proviruses. 1820 33

Lymphocyte maturation requires generation of a large diversity of antigen receptors, which involves somatic rearrangements at the antigen receptor genes in a process termed V(D)J recombination. Upon encountering specific antigens, B-lymphocytes undergo rearrangements in the constant region of the immunoglobulin genes to optimize immune responses in a process called class switch recombination. Activated B-cells also undergo somatic hypermutation in the variable regions of the immunoglobulin genes to enhance their antigenic affinity. These somatic events are initiated by the infliction of DNA lesions within the antigen receptor genes that are strictly confined to a specific developmental window and cell-cycle stage. DNA lesions are then repaired by one of the general DNA repair mechanisms, such as non-homologous end-joining. Mutations in key factors of these pathways lead to the interruption of these processes and immunodeficiency, making it possible to study the mechanisms of cellular response to DNA lesions and their repair. This review briefly summarizes some of the recently developed animal models with focus on current advances in the understanding of the mechanism of DNA end-joining activities, and its role in the maintenance of genomic stability and the prevention of tumorigenesis.
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PMID:DNA damage and repair during lymphoid development: antigen receptor diversity, genomic integrity and lymphomagenesis. 1821 91

The regulatory NEMO (NF-kappaB essential modulator) protein has a crucial role in the canonical NF-kappaB signaling pathway notably involved in immune and inflammatory responses, apoptosis and oncogenesis. The regulatory domain is located in the C-terminal half of NEMO and contains a classical CCHC-type zinc finger (ZF). We have investigated the structural and functional effects of a cysteine to phenylalanine point mutation (C417F) in the ZF motif, identified in patients with anhidrotic ectodermal dysplasia with immunodeficiency. The solution structures of the wild type and mutant ZF were determined by NMR. Remarkably, the mutant adopts a global betabetaalpha fold similar to that of the wild type and retains thermodynamic stability, i.e., the ability to bind zinc with a native-like affinity, although the last zinc-chelating residue is missing. However, the mutation induces enhanced dynamics in the motif and leads to an important loss of stability. A detailed analysis of the wild type solution structure and experimental evidences led to the identification of two possible protein-binding surfaces that are largely destabilized in the mutant. This is sufficient to alter NEMO function, since functional complementation assays using NEMO-deficient pre-B and T lymphocytes show that full-length C417F pathogenic NEMO leads to a partial to strong defect in LPS, IL-1beta and TNF-alpha-induced NF-kappaB activation, respectively, as compared to wild type NEMO. Altogether, these results shed light onto the role of NEMO ZF as a protein-binding motif and show that a precise structural integrity of the ZF should be preserved to lead to a functional protein-recognition motif triggering full NF-kappaB activation.
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PMID:Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation. 1831 93

Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a(+) LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor-beta1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor-beta1 indirectly reduces antigen-presenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis.
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PMID:Transforming growth factor-beta1-mediated Slug and Snail transcription factor up-regulation reduces the density of Langerhans cells in epithelial metaplasia by affecting E-cadherin expression. 1838 19

The PI3K-AKT network, which is activated by cytokines or growth factors, mediates intracellular signals to regulate a variety of cellular responses, including antiapoptosis, proliferation, cell cycling, protein synthesis, glucose metabolism, and telomere activity. Genomic mutations, alterations of the PI3K-AKT regulatory network, underlie such diseases as cancer, glucose intolerance (diabetes mellitus), schizophrenia, and/or autoimmune diseases. In addition to direct tumorigenesis involvement by genetically altering human cancer, the PI3K-AKT network underlies the clinical manifestation of different stages of tumorigenic viral infection, such as latent and chronic infection, and malignant transformation of Epstein-Barr, hepatitis C, hepatitis B, and human immunodeficiency virus (HIV) viruses. We summarize updated knowledge on the PI3K-AKT network underlying different phathological viral and/or bacterial infections. Antiviral activity engendered by suppressing of PI3K-AKT activity, rather than directly targeting anticancer activity via oncogenes, may thus open up ways to prevent malignant transformation by tumorigenic viral infection.
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PMID:[PI3K-AKT network roles in infectious diseases]. 1854 44

Given the fact that infectious agents contribute to around 18% of human cancers worldwide, it would seem prudent to explore their role in neoplasms of the ocular adnexa: primary malignancies of the conjunctiva, lacrimal glands, eyelids, and orbit. By elucidating the mechanisms by which infectious agents contribute to oncogenesis, the management, treatment, and prevention of these neoplasms may one day parallel what is already in place for cancers such as cervical cancer, hepatocellular carcinoma, gastric mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma. Antibiotic treatment and vaccines against infectious agents may herald a future with a curtailed role for traditional therapies of surgery, radiation, and chemotherapy. Unlike other malignancies for which large epidemiological studies are available, analyzing ocular adnexal neoplasms is challenging as they are relatively rare. Additionally, putative infectious agents seemingly display an immense geographic variation that has led to much debate regarding the relative importance of one organism versus another. This review discusses the pathogenetic role of several microorganisms in different ocular adnexal malignancies, including human papilloma virus in conjunctival papilloma and squamous cell carcinoma, human immunodeficiency virus in conjunctival squamous carcinoma, Kaposi sarcoma-associated herpes virus or human herpes simplex virus-8 (KSHV/HHV-8) in conjunctival Kaposi sarcoma, Helicobacter pylori (H. pylori,), Chlamydia, and hepatitis C virus in ocular adnexal mucosa-associated lymphoid tissue lymphomas. Unlike cervical cancer where a single infectious agent, human papilloma virus, is found in greater than 99% of lesions, multiple organisms may play a role in the etiology of certain ocular adnexal neoplasms by acting through similar mechanisms of oncogenesis, including chronic antigenic stimulation and the action of infectious oncogenes. However, similar to other human malignancies, ultimately the role of infectious agents in ocular adnexal neoplasms is most likely as a cofactor to genetic and environmental risk factors.
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PMID:The role of infectious agents in the etiology of ocular adnexal neoplasia. 1857 51


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