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)

The nef gene product of human immunodeficiency virus type 1 (HIV-1) is important for the induction of AIDS, and key to its function is its ability to manipulate T-cell function by targeting cellular signal transduction proteins. We reported that Nef coprecipitates a multiprotein complex from cells which contains tumor suppressor protein p53. We now show that Nef interacts directly with p53. Binding assays showed that an N-terminal, 57-residue fragment of Nef (Nef 1-57) contains the p53-binding domain. Nef also interacted with p53 during HIV-1 infection in vitro. As p53 plays a critical role in the regulation of apoptosis, we hypothesized that Nef may alter this process. Nef inhibited UV light-induced, p53-dependent apoptosis in MOLT-4 cells, with Nef 1-57 being as effective as its full-length counterpart. The inhibition by Nef of p53 apoptotic function is most likely due its observed ability to decrease p53 protein half-life and, consequently, p53 DNA binding activity and transcriptional activation. These data show that HIV-1 Nef may augment HIV replication by prolonging the viability of infected cells by blocking p53-mediated apoptosis.
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PMID:Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. 1186 36

Infection with the human immunodeficiency virus (HIV) invariably leads to the development of acquired immunodeficiency syndrome (AIDS) in most infected humans, yet does so rarely, if at all, in HIV-infected chimpanzees. The differences between the two species are not due to differences in cellular receptors or an inability of the chimpanzee to be infected, but rather to the lack of pan-immune activation in the infected primate. This results in reduced apoptotic death in CD4+ T-helper lymphocytes and a lower viral load. In humans the degree of chronic immune activation correlates with virus load and clinical outcome with high immune activation leading to high viral loads and the more rapid progression to AIDS and death. The type of immune perturbation seen in HIV-associated AIDS is similar to that of chronic graft-versus-host disease (GVHD) where reduced cell-mediated immune (CMI) responses occur early in the course of the disease and where humoral responses (HI) predominate. A reduced CMI response occurs in a number of chronic infectious diseases, including tuberculosis and leishmaniasis. More recently, it has become increasingly apparent that the CMI response is suppressed in virtually all malignant diseases, including melanoma and colorectal and prostate cancer. This raises the possibility that, as the malignant process develops, the cancer cells evolve to subvert the CMI response. Moreover, the reduced CMI response seen in colorectal cancer (CRC) patients is completely reversed following curative surgery strongly supporting the hypothesis that CRC can suppress the systemic immune response. Wound healing, ovulation, embryo implantation, and fetal growth are all associated with suppressed CMI and neovascularization (the formation of new blood vessels) or angiogenesis (the formation of new blood vessels from an existing vasculature). If unresolved, wound healing results in chronic inflammation, which can give rise to the phenomenon of "scar cancers." Indeed all the chronic inflammatory conditions known to be associated with the subsequent development of malignant disease, including chronic obstructive airway disease (COPD), ulcerative colitis (UC), and asbestosis, give rise to similar proangiogenic, suppressed CMI, and HI-predominant environments. In keeping with this CMI-associated cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma tend to be antiangiogenic, whereas HI cytokines such as IL-6 tend to be proangiogenic. Furthermore, chronic immune activation leads to the synthesis and release of factors such as macrophage inflammatory protein (MIP)-1 that inhibit apoptosis through suppression of p53 activity. The "Golden Triangle" of suppressed CMI, angiogenesis, and reduced apoptosis would provide the ideal environment for the serial mutations to occur that are required for the development of malignant disease. If the observed association is relevant to carcinogenesis, then treatments aimed at reducing the components of these inflammatory conditions may be useful both in the setting of chemoprevention and the therapeutic management of established disease.
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PMID:Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. 1188 29

Infection with human immunodeficiency virus type 1 (HIV-1) is associated with dramatic depletion of CD4(+) T cells, the major HIV-1-induced pathogenesis. Apoptosis has been suggested to play an important role for the T cell depletion and a number of mechanisms have been proposed for the apoptosis in T cells. Here, we compared the levels for apoptosis induction in primary peripheral blood mononuclear cells (PBMCs) among several laboratory strains and primary isolates of the HIV-1 subtypes B and E. The results showed that apoptosis in infected PBMCs, preferentially in CD4+ T cell population, became detectable around the time for virus production by flow cytometric terminal transferase dUTP nick end labeling (TUNEL) technique and staining with the nuclear dye Hoechst 33342. The abilities to induce apoptosis in PBMCs were highly variable in individual isolates. The increase of p53 protein in infected PBMCs, which was initiated before virus production, was observed in infected PBMCs and the levels of p53 protein were almost proportional to the rates of the isolates to induced apoptosis. The cells infected and cultured in the presence of Z-VAD-FMK had significantly decreased cell mortalities, indicating that activated caspases also played a significant role in the apoptosis. Thus, HIV-1-induced apoptosis in primary T cells was accompanied by the p53 protein and caspase activation at varied levels in primary isolates.
AIDS Res Hum Retroviruses 2002 Apr 10
PMID:Ability to induce p53 and caspase-mediated apoptosis in primary CD4+ T cells is variable among primary isolates of human immunodeficiency virus type 1. 1195 87

In the highly active antiretroviral therapy (HAART) era, AIDS-related non-Hodgkin's lymphomas (AIDS-NHL) and their treatment still represent an open issue, because HAART may not be sufficient to prevent the development of NHL. The present spectrum of AIDS-NHL includes systemic lymphomas, primary central nervous system lymphomas, and 2 rare entities, primary effusion lymphomas (PEL) and plasmablastic lymphomas of the oral cavity. The vast majority of systemic AIDS-NHL belongs to 3 high-grade B-cell lymphomas: Burkitt's lymphoma (BL), immunoblastic lymphoma (IBL), and large-cell lymphoma (LCL). The pathologic heterogeneity of AIDS-NHL is correlated with the heterogeneity of the molecular lesions associated with these lymphomas. The molecular lesions associated with AIDS-BL involve activation of c-MYC inactivation of p53, and infection by Epstein-Barr virus (EBV). EBV infection occurs in 40% of LCL cases and in 90% of IBL cases. Rearrangements of BCL-6 are detected in 20% of AIDS-LCL cases. In the presence of EBV infection, BCL-6 expressing AIDS-LCL fails to express the latent membrane protein 1 (LMP1) antigen. Conversely, AIDS-IBL are characterized by absent BCL-6 expression, absence of BCL-6 rearrangements, and frequent expression of LMP1. Consistently, the molecular pathways of viral infection and lesions of cancer-related genes associated with AIDS-NHL vary substantially in different clinicopathologic categories of the disease. The marked degree of biologic heterogeneity of AIDS-NHL is highlighted by their histogenetic differences, because AIDS-NHL are related to distinct B cell subsets (ie, germinal center [GC] or post-GC B cells). The phenotypic pattern of AIDS-BL and systemic AIDS-LCL closely reflects B cells residing in the GC, namely centroblasts and centrocytes. Conversely, the phenotype of AIDS-IBL, either systemic or localized primarily to the central nervous system, and AIDS-PEL reflects post-GC B cells in all cases. New information on the molecular and virologic pathogenesis of AIDS-NHL may serve as a point of attack for pathogenic-driven therapies. Moreover, a greater knowledge of other biologic features of these tumors may help investigators identify new potential targets for "intelligent" therapies.
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PMID:AIDS-related non-Hodgkin's lymphomas: from pathology and molecular pathogenesis to treatment. 1205 73

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

Human papillomavirus (HPV) plays a central rule in uterine cervix carcinogenesis. Other factors direct or indirectly influence the installation of this mechanism in cervical squamous epithelium. Investigations regarding mechanisms of interaction of these factors with viral elements are found in the literature of the last 20 years. The present review article discusses possible co-factors of HPV in the genesis of the squamous carcinoma of uterine cervix, taking into account only the factors whose association with the virus or cervical cancer has been documented by experimental studies, and not based just on clinical or epidemiological data. Among the approached parameters are immunological factors (local and humoral immune response), the association with Acquired Immune Deficiency Syndrome, genetic factors as protein p53 polymorphism, tabagism and the use of oral contraceptives. All these factors interact in variable intensity with oncoproteins and other HPV elements, increasing and facilitating the virus action in host cells, leading to the development of immortalization and carcinogenesis.
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PMID:[Hpv cofactors in cervical carcinogenesis]. 1218 39

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 clinicopathological range of AIDS-related non-Hodgkin lymphomas (NHLs) includes systemic lymphomas, primary central-nervous-system lymphomas, primary effusion lymphoma, and plasmablastic lymphoma of the oral cavity. Most AIDS-related NHLs belong to one of three categories of high-grade B-cell lymphomas: Burkitt's lymphoma, centroblastic lymphoma, and immunoblastic lymphoma. The pathological heterogeneity of AIDS-related NHL reflects the heterogeneity of their associated molecular lesions. In AIDS-related Burkitt's lymphoma, the molecular lesions involve activation of c-MYC, inactivation of p53, and infection with Epstein-Barr virus (EBV). AIDS-related immunoblastic lymphomas infected with EBV are characterised by frequent expression of latent membrane protein 1-an EBV oncoprotein. The biological heterogeneity of AIDS-related NHLs is highlighted by their histogenetic differences; AIDS-related NHLs are related to distinct B-cell subgroups (eg, germinal-centre or post-germinal-centre B cells). The phenotypic pattern of AIDS-related Burkitt's lymphomas and systemic AIDS-related centroblastic lymphomas closely reflects that of B cells in germinal centres. Conversely, the phenotype of AIDS-related immunoblastic lymphomas and AIDS-related primary effusion lymphomas reflects post-germinal-centre B cells in all cases. Despite their clinicopathological, genetic, and phenotypic heterogeneity, most lymphomas in patients with AIDS carry somatic mutations of immunoglobulin and BCL-6 genes. However, the somatic hypermutation mechanism functions aberrantly in a significant proportion of AIDS-related NHLs, causing the mutation of many genes, and possibly favouring chromosomal translocation, which may be a powerful contributor to malignant transformation. New molecular and virological evidence of such pathways and a greater knowledge of other biological features of AIDS-related NHLs may lead to new targets for pathogenetically and biologically oriented therapies.
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PMID:Emerging pathways in the development of AIDS-related lymphomas. 1251 36

Germ-line mutations (present in all cells) in genes that are crucial for the cell cycle cause cancer only in specific cell lines (e.g. mismatch repair genes in the colon; BRCA1-2 in breast and ovary; other cancers in Bloom syndrome, neurofibromatosis and xeroderma pigmentosum). The mutation rate of genes other than mismatch repair or p53 is the same in colon cancer and in normal cells, indicating that a 'mutator phenotype', increasing the rate of mutations in many genes, is not an essential feature of sporadic cancers; conversely, fusion genes, TEL-AML1/AML1-ETO, typical of leukemia, are 100 times more frequent at birth than in overt leukemia in children, indicating that further selective events are needed to cause malignancy. The devastating impairment of immunity, as in AIDS patients, does not cause cancer other than Kaposi's sarcoma and non-Hodgkin's lymphoma, although immunological control is considered to be an essential mechanism in preventing the spread of cancer cells. These observations suggest that cell-specific additional events are needed to explain carcinogenesis. Carcinogenesis has been traditionally interpreted as the sequence of initiation (mutation) and promotion (clone expansion), with an interesting similarity with the neo-Darwinian theory of evolution, based on a first stage of genetic change (including recombination) and a second stage of selection. I propose that carcinogenesis consists in two general phases (not necessarily stages), i.e. genetic change followed by clone expansion (selective advantage). As in neo-Darwinian theory selection is chiefly represented by the elimination of the less fit, the selection of mutated cells would mainly consist in resistance to apoptosis or other types of 'bottlenecks' that hamper a cell's survival; an example of such a bottleneck is the autoimmunity that induces paroxysmal nocturnal hemoglobinuria in individuals with PIG-A mutations. Cancer rates show great variation in different countries around the world, a variation only marginally explained by genetic differences. More interestingly, migrants change their risk of cancer by adapting to that of the population into which they move: as these changes are not likely to be entirely due to mutagens in the environment, we have to invoke selective pressure over mutated cells to explain them. My theory is that mutated cells adapt to environmental 'niches' better than normal cells, in a 'gene-environment interaction' that involves the history of the genetic changes the cell has undergone and the kind of environment in which it happens to live.
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PMID:Cancer as an evolutionary process at the cell level: an epidemiological perspective. 1253 42

Antigenic stimuli increase ROS that influence T-cell activation by interfering with the oxidant-antioxidant balance. Oxidative stress takes place when excess of ROS production is not counterbalanced by antioxidant mechanisms and bcl-2 gene product that inhibits apoptosis by interacting with mitochondrial superoxide dismutase. ROS Excess induces apoptosis both by activation of NF-kB-dependent genes and DNA damage. The latter has been shown to elicit the activation of poly-ADP-ribose transferase and the accumulation of p53, thus determining apoptosis. Additionally, oxidative stress may induce formation of cell membrane oxidized lipids, potent inducers of apoptosis. Oxidative stress is also involved in immune diseases. In AIDS, ROS excess and deficiency of antioxidants lead to apoptosis and virus activation. ROS produced at sites of chronic inflammation, have genotoxic effects. As a consequence, abnormalities of the p53 genes might explain the conversion from an inflammatory phase into autonomous progression of rheumatoid arthritis or other chronic inflammatory disorders.
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PMID:Oxidative stress and apoptosis in immune diseases. 1257 15


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