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 rhesus monkey experimentally inoculated with simian immunodeficiency virus (SIV) mac251 was killed 42 months later because of poor general condition. CD4 lymphocyte count which was 3,430/mm3 before inoculation, had decreased to 638/mm3 2 months before death. Neuropathological examination revealed changes characteristic of progressive multifocal leukoencephalopathy (PML) in the white matter of the cerebral hemispheres and brain stem. In situ hybridization was negative for JC virus but markedly positive for simian virus 40 (SV40) in the nuclei of many oligodendrocytes. Many oligodendrocytes also expressed p53. Within an area involved by PML, there was a densely cellular tumor with honeycomb appearance and elongated vessels characteristic of oligodendrogliomas. Within the tumor in situ hybridization for SV40 and immunocytochemistry for p53 were negative. Opportunistic infection by SV40 has been occasionally reported in experimentally SIV-infected monkeys resulting in PML or malignant astrocytoma. Association of JC virus-induced PML and astrocytomas has been reported in three human cases without AIDS. In those cases, as in our monkey, polyomaviruses (SV40 or JC virus) were expressed in the areas with PML but not in the glial tumor. Association of PML and oligodendroglioma has not been reported previously to our knowledge. The relationship between oligodendrocyte proliferation and polyomavirus infection of oligodendrocytes is unclear. Our findings suggest that binding of the viral protein to p53 may result in inactivation of the pro-apoptotic protein favoring the proliferation of a randomly occurring tumoral clone of oligodendrocytes.
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PMID:Progressive multifocal leukoencephalopathy and oligodendroglioma in a monkey co-infected by simian immunodeficiency virus and simian virus 40. 1096 4

Apoptosis (programmed cell death) is a genetically programmed active cell death process for maintaining homeostasis under physiological conditions and for responding to various stimuli. Many human diseases have been associated with either increased apoptosis (such as AIDS and neurodegenerative disorders) or decreased apoptosis (such as cancer and autoimmune disorders). In an attempt to understand apoptosis signaling pathway and genes associated with apoptosis, we established two cell model systems on which apoptosis is induced either by DNA damaging agent, etoposide or by redox agent, 1,10-phenanthroline (OP). DNA chip profiling or mRNA differential display (DD) was utilized to identify genes responsive to apoptosis induced by these two agents. In etoposide model with chip hybridization, we defined signaling pathways that mediate apoptosis in p53 dependent manner (through activation of p53 target genes such as Waf-1/p21, PCNA, GPX, S100A2 and PTGF-beta) as well as in p53-independent manner (through activation of ODC and TGF-beta receptor, among others). In OP model with DD screening, we cloned and characterized two genes: glutathione synthetase, encoding an enzyme involved in glutathione synthesis and Sensitive to Apoptosis Gene (SAG), a novel evolutionarily conserved gene encoding a zinc RING finger protein. Both genes appear to protect cells from apoptosis induced by redox agents. Further characterization of SAG revealed that it is a growth essential gene in yeast and belongs to a newly identified gene family that promotes protein ubiquitination and degradation. Through this activity, SAG regulates cell cycle progression and many other key biological processes. Thus, SAG could be a valid drug target for anti-cancer and anti-inflammation therapies.
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PMID:Identification and characterization of genes responsive to apoptosis: application of DNA chip technology and mRNA differential display. 1100 51

Expression of Tax in the mature lymphoid compartment of transgenic mice resulted in a lymphoproliferative malignancy of natural killer cells and cytotoxic T lymphocytes. Transgenic mouse tumors exhibited mutations in the p53 tumor suppressor gene, and functional inactivation of wild-type p53 protein. Tax transgenic mice heterozygous for the p53 gene exhibited more rapid tumor dissemination and accelerated mortality. Studies of Tax trans-activation in an infectious clone of HTLV-1 demonstrated a critical role for nuclear factor B activation in lymphocyte immortalization. A mutant disrupting Tax activation of the cAMP response element binding (CREB) protein resulted in preferential immortalization of CD8(+) lymphocytes, rather than preferential immortalization of CD4(+) lymphocytes seen with the wild-type infectious clone. A mutation disrupting Tax interaction with CREB-binding protein, CBP, did not affect lymphocyte immortalization by the infectious molecular clone. These models provide new insights into the molecular details of HTLV-1 leukemogenesis.
AIDS Res Hum Retroviruses 2000 Nov 01
PMID:Studies of the immortalizing activity of HTLV type 1 Tax, using an infectious molecular clone and transgenic mice. 1108 Aug 5

The p53 protein plays a pivotal role in transmitting signals from many forms of genotoxic stress to genes and factors that control aspects of the cell cycle and death. Although mutated in approximately 60% of all human cancers, only a minority of human T-lymphotropic virus type 1 (HTLV-1)-transformed cells carry p53 mutations. Nevertheless, the p53 protein in HTLV-1-transformed cells is functionally inactive. We have previously demonstrated that the HTLV-1 Tax protein can inhibit p53 trans-activation function. Tax does not accomplish this by directly binding to p53, but rather by a unique mechanism that includes constitutive phosphorylation of p53 at Ser-15 and Ser-392. Analysis of Tax mutants in lymphocytes demonstrates that Tax-induced p53 inhibition correlates with the ability of Tax to activate NF-kappaB, but not p300 binding or CREB trans-activation. Consistent with these results, expression of the I-kappaBalpha(S32,36A) mutant that blocks NF-kappaB activation blocks Tax-mediated p53 inhibition. We further demonstrate the importance of Tax activation of NF-kappaB in p53 inhibition, using p65 knockout (KO) mouse embryo fibroblasts (MEFs). In the absence of p65 Tax could not inhibit p53. Tax does activate IKKbeta in the p65 KO MEFs, indicating that prenuclear events of NF-kappaB activation are not sufficient for Tax-mediated p53 inhibition, but rather NF-kappaB transcriptional activation is critical. Importantly, using phosphospecific antibodies, we demonstrate that phosphorylation of p53 at Ser-15 and Ser-392 correlates with Tax-mediated inhibition. In addition, mutation of p53 at Ser-15 and Ser-392 to alanines renders p53 resistant to Tax inhibition. This report reviews p53 inhibition by Tax and presents our current model.
AIDS Res Hum Retroviruses 2000 Nov 01
PMID:Insights into the molecular mechanism of p53 inhibition by HTLV type 1 Tax. 1108 Aug 8

Human T cell lymphotropic virus type II (HTLV-2) was originally isolated from a patient with a hairy T cell leukemia. It has been associated with rare cases of CD8(+) T lymphoproliferative disorders, and has a controversial role as a pathogen. The loss of p53 function, as a consequence of mutation or inactivation, increases the chances of genetic damage. Indeed, the importance of p53 as a tumor suppressor is evident from the fact that over 60% of all human cancers have a mutant or inactive p53. p53 status has been extensively studied in HTLV-1-infected cell lines. Interestingly, despite the fact that p53 mutations have been found in only a minority of cells, the p53 functions were found to be impaired. We have analyzed the functional activity of the p53 tumor suppressor in cells transformed with HTLV-2 subtypes A and B. As with HTLV-1-infected cells, abundant levels of the p53 protein are detected in HTLV-2 virus-infected cell lines. Using p53 reporter plasmid or induction of p53-responsive genes in response to gamma-irradiation, the p53 was found to be transcriptionally inhibited in HTLV-2-infected cells. Interestingly, although Tax-2A and-2B inactivate p53, the Tax-2A protein appears to inhibit p53 function less efficiently than either Tax-1 or Tax-2B in T cells, but not in fibroblasts.
AIDS Res Hum Retroviruses 2000 Nov 01
PMID:Inactivation of p53 by HTLV type 1 and HTLV type 2 Tax trans-activators. 1108 Aug 9

By utilizing a human cDNA expression array blot (588 genes), we have observed overexpression of various transcription factors, cell cycle regulated kinases, and DNA repair genes in HTLV-1-infected T cells. One of the genes of interest, and focus in this study, is the cyclin-dependent kinase inhibitor, p21/waf1. The p21/waf1 transcription and protein is overexpressed in all HTLV-1-infected cell lines tested as well as ATL and HAM/TSP patient samples. While p21/waf1 has been shown to display a selectivity for G(1)/S cyclin/cdk complexes, we have observed p21/waf1 to be complexed with cyclin A/cdk2. Functionally, the association of p21/cyclin A/cdk2 decreased the histone H1 phosphorylation in vitro, as observed in immunoprecipitations followed by kinase assays, as well as affecting other substrates such as the C-terminus of Rb protein involved in c-Abl and HDAC1 regulation. Wild-type, but not a mutant form (M47) of Tax, was found to be able to transactivate the p21/waf1 promoter in a p53-independent manner. We found that the minimal p21/waf1 promoter (-49 to +49 sequence) was activated by Tax and the minimal promoter contained two E2A transcription factor binding sites located between the TATA box and the initiation site. E2A proteins, E12 and E47, as well as a related helix-loop-helix protein, HEB, are all up-regulated in HTLV-1-infected T cells. When using band shift analysis, we found that only the E1 site (overlapping the transcription start site) was a functional DNA binding site. By using a chromatin immunoprecipitation (ChIP) assay, we observed that histone H4, and not histone H3, was acetylated from the endogenous p21/waf1 promoter in vivo, implying that CBP/p300, and not the SAGA complex, was critical in complexing with E2A in up-regulation of p21/waf1 in HTLV-1-infected cells.
AIDS Res Hum Retroviruses 2000 Nov 01
PMID:Gene expression array of HTLV type 1-infected T cells: Up-regulation of transcription factors and cell cycle genes. 1108 Aug 12

Kaposi's sarcoma (KS) is a multifocal lesion that occurs predominantly in the skin, most frequently in people infected with HIV-1, and that evolves through early stages (patch and plaque) to a tumor-like late stage (nodular). Both, endemic African (EKS) and AIDS-associated (AKS) KS expressed human herpesvirus 8 (HHV-8) as shown by PCR. By immunohistochemistry the expression of cellular Bcl-2 and c-myc was confined in early stages of both EKS and AKS to relatively few endothelial cells (EC) whereas in nodular KS most of spindle cells (SC) strongly expressed both genes. CD40 was usually strongly expressed in SC at all KS stages as well as in EC of non-involved tissue whereas CD40L (CD154) was not demonstrable. Fas (CD95) was moderately to weakly expressed by SC whereas p53 and Waf-1 were found in less than 5% of the SC. In both AKS and EKS at nodular stage almost no apoptotic SC were detected. In most AKS and EKS low levels of cell proliferation were seen but AKS showed consistently higher values compared to EKS. All clinical types and stages of KS showed a diploid cellular DNA content by flow cytometric analysis of microselected lesions. Thus, we conclude that KS during evolution represents diploid, probably reactive, cell proliferation, which progressively increases the expression of strong cellular and also viral (HHV-8) antiapoptotic factors.
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PMID:Proliferation and apoptosis in the evolution of endemic and acquired immunodeficiency syndrome-related Kaposi's sarcoma. 1111 13

Considerable progress has been made in the transfer of foreign genes into salivary glands in vivo using adenovirus vectors in rats. In an attempt to avoid the transient expression inherent, when using these vectors, retroviral vectors and human cell lines where used here in attempt to develop an in vitro model of HIV-associated salivary gland disease. The HIV-1-tat protein is increasingly implicated in the pathogenesis of the AIDS through altering the expression of strategic cellular genes. The purpose of this study was to transfect human salivary gland (HSG) cell lines in vitro, with the pHIV-1/LTR-tat plasmid, and examine the effect of tat on expression of matrix and basement membrane genes known to be important in the pathogenesis of salivary gland disease. HSG cells were transfected with HIV-1-tat plasmid by the lipofection method. Transfection was confirmed by polymerase chain reaction (PCR) and Southern blot, which verified that tat-specific DNA was present. Tat-mRNA was analysed by Northern blotting and quantified by reverse transcriptase polymerase chain reaction (RT-PCR) to demonstrate its expression. Numerous clones were found to contain integrated tat DNA sequences and analysis of mRNA showed stable expression of tat-specific RNA. Further analysis of mRNA expression for various marker proteins important in HIV pathogenesis showed that the HSG cell line transfected with HIV-1-tat, was associated with significant induction of mRNA expression for extracellular matrix protein. Tat-amplified transcription of the major basement membrane protein laminin, as well as of fibronectin, collagen I and III, and c-myc oncogene was demonstrated. Conversely, expression of p53 suppressor gene mRNA was reduced. Post-transfection expression of collagen IV was erratic and inconclusive. It was concluded that the presence of HIV-tat in this in vitro model of salivary ductal epithelial cell model alters the mRNA expression of several matrix, basement membrane and oncoproteins known to be involved in HIV pathogenesis. These cell lines provide a useful system for studying the role of tat in the immunopathogenesis of HIV-associated salivary gland disease.
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PMID:Amplification of extracellular matrix and oncogenes in tat-transfected human salivary gland cell lines with expression of laminin, fibronectin, collagens I, III, IV, c-myc and p53. 1131 Dec 2

The anti-HIV agent MAP30 (Momordica anti-HIV protein, 30 kDa) inhibits the proliferation of BC-2, an AIDS-related primary effusion lymphoma (PEL) cell line derived from an AIDS patient. BC-2 cells are latently infected with Kaposi's sarcoma-associated herpes virus (KSHV), also known as human herpes virus 8 (HHV8). We examined the effect of MAP30 on the expression of viral and cellular genes in BC-2 during latent and lytic states of the viral life cycle. By Northern analysis and RT-PCR, we found that MAP30 downregulates the expression of viral cyclin D (vCD), viral interleukin-6 (vIL-6), and viral FLIP (vFLIP), genes involved in cell cycle regulation, viral pathogenesis, and apoptosis. By pathway-specific cDNA microarray analysis, we found that BC-2 cells express high levels of egr-1, ATF-2, hsp27, hsp90, IkappaB, mdm2, skp1, and IL-2, cellular genes involved in mitogenesis, tumorigenesis, and inhibition of apoptosis in NFkappaB and p53 signaling pathways. These results define for the first time the specific cellular pathways involved in AIDS-related tumorigenesis and suggest specific novel targets for the treatment. Furthermore, we found that MAP30 downregulates the expression of egr-1, ATF-2, hsp27, hsp90, IkappaB, mdm2, and Skp1, while it upregulates the pro-apoptotic-related genes Bax, CRADD, and caspase-3. Thus, MAP30 modulates the expression of both viral and cellular genes involved in KS pathogenesis. These results provide valuable insight into the molecular mechanisms of MAP30 anti-KS action and suggest its utility as a therapeutic agent against AIDS-related tumors.
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PMID:Anti-HIV agent MAP30 modulates the expression profile of viral and cellular genes for proliferation and apoptosis in AIDS-related lymphoma cells infected with Kaposi's sarcoma-associated virus. 1157 62

The HIV epidemic in the Asian subcontinent has a significant impact on India. Patients with AIDS have an increased risk of developing non-Hodgkin lymphoma (NHL). In this study, we have investigated the pattern of distribution of lymphoid neoplasms and also studied the Epstein-Barr virus (EBV)-association and p53 expression in 35 HIV-positive patients from India. The biopsy samples were studied for histology and for expression of CD20, CD3, CD15, CD30, light chains, CD138, bcl-6, epithelial membrane antigen, EBV-latent membrane protein-1, and p53 protein. In situ hybridization was performed with digoxigenin-labeled anti-sense EBV-encoded nuclear RNA-1 (EBER-1) probe. Polymerase chain reaction (PCR) was performed on DNA extracted from paraffin sections for EBV-subtype analysis. The 35 cases included 7 cases of Hodgkin disease (HD), 4 cases of plasmacytoma (PL), and 24 cases of NHL. Among the cases of NHL, 3 were Burkitt lymphoma (BL), 4 were diffuse large B-cell lymphoma (DLBL) of centroblastic type (CBL), 10 were DLBL of immunoblastic type (IBL), 4 were high-grade B-cell lymphoma (unspecified) and the rest were other subtypes. EBV-association was noted in all cases of HD, 2 of 3 BL, and 3 of 10 IBL. PCR analysis of the EBNA-3C gene revealed amplimers corresponding to type A. A p53 protein overexpression was noted in 6 of 10 IBLs, 1 of 3 BLs, 2 of 3 CBLs, and 5 of 7 cases of HD. This is the first reported study of lymphoid malignancies in HIV-positive individuals from India.
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PMID:Lymphoid neoplasms in HIV-positive individuals in India. 1183 89


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