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)

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous telangiectasias of the face, sun sensitivity, stunted growth infertility and immunodeficiency. In addition, BS patients are highly predisposed to cancers. Although recently the causative gene of BS (BLM) was identified as a DNA helicase homologue, the function of BLM in DNA replication has not been elucidated. In this study, p53 mutation and microsatellite instability in B-cell lymphomas originating from 2 sibling BS patients were investigated. In the originally developed tumor of both patients, no p53 mutation was detected. In one patient, however, after treatment by ionizing radiation the B-cell lymphoma recurred, showing a 9-bp deletion in exon 7. In lymphoma cells and an EB-virus-transformed cell line from BS lymphocytes of this patient, microsatellite instability was also detected from the reduced length of microsatellite DNA markers, although in the other patient microsatellite instability was not detected. Thus, 2 B-cell lymphomas, despite having the same BLM mutation, showed different phenotypes in terms of p53 mutation and microsatellite instability.
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PMID:Microsatellite instability in B-cell lymphoma originating from Bloom syndrome. 898 Feb 51

Keratinocyte apoptosis may be induced by ultraviolet-B radiation and represents a potential source of fragmented autoantigens in autoimmune diseases. This study investigates whether excessive keratinocyte apoptosis occurs in the skin lesions of cutaneous lupus (CLE) and dermatomyositis (DM) and the potential mechanisms responsible for this phenomenon. Skin biopsies have been studied from 19 patients with CLE and DM, eight with scleroderma, and five healthy controls. Apoptosis was detected by in situ end-labelling of fragmented DNA. The expression of Bcl-2, PCNA, p53, and Ki-67 proteins was studied by immunohistochemistry. In DM and CLE skin, the number of apoptotic keratinocytes was significantly increased (p=0.008) compared with normal skin. In both diseases, a large accumulation of apoptotic keratinocytes and apoptotic bodies was present in the disrupted basal zone. Unlike normal skin, a large number of keratinocytes, particularly those morphologically apoptotic, expressed p53 protein. A significant increase in the number of proliferating Ki-67 positive (p=0.0007) and PCNA-positive (p=0.0008) nuclei was also observed. In both CLE and DM, exaggerated and inappropriate keratinocyte apoptosis occurs. It is associated with increased expression of p53 and PCNA. This suggests that normal solar radiation alone or in combination with additional local factors induces DNA damage and excessive keratinocyte apoptosis in these autoimmune diseases of the skin. Apoptosis can mediate the severe epidermal lesions observed in both diseases and the release of fragmented autoantigens into the dermis.
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PMID:Keratinocyte apoptosis and p53 expression in cutaneous lupus and dermatomyositis. 1039 42

Cell death by apoptosis is exerted by the coordinated action of many different gene products. Mutations in some of them, acting at different levels in the apoptosis process, have been identified as cause or contributing factor for human diseases. Defects in the transmembrane tumor necrosis factor receptor 1 (TNF-R1) lead to the development of familial periodic fever syndromes. Mutations in the homologous receptor Fas (also named CD95; Apo-1) are observed in malignant lymphomas, solid tumors and the autoimmune lymphoproliferative syndrome type I (ALPS I). A mutation in the ligand for Fas (Fas ligand; CD95 ligand, Apo-1 ligand), which induces apoptosis upon binding to Fas, was described in a patient with systemic lupus erythematodes and lymphadenopathy. Perforin, an other cytotoxic protein employed by T- and NK-cells for target cell killing, is mutated in chromosome 10 linked cases of familial hemophagocytic lymphohistiocytosis. Caspase 10, a representative of the caspase family of proteases, which plays a central role in the execution of apoptosis, is defect in autoimmune lymphoproliferative syndrome type II (ALPS II). The intracellular pro-apoptotic molecule bcl-10 is frequently mutated in mucosa-associated lymphoid tissue (MALT) lymphomas and various non-hematologic malignancies. The p53, an executioner of DNA damage triggered apoptosis, and Bax, a pro-apoptotic molecule with the ability to perturb mitochondrial membrane integrity, are frequently mutated in malignant neoplasms. Anti-apoptotic proteins like bcl-2, cellular-inhibitor of apoptosis protein 2 (c-IAP2) and neuronal apoptosis inhibitory protein 1 (NAIP1) are often altered in follicular lymphomas, MALT lymphomas and spinal muscular atrophy (SMA), respectively. This article reviews the current knowledge on mutations of apoptosis genes involved in the pathogenesis of human diseases and summarises the gradual transformation of discoveries in apoptosis research into benefits for the clinical management of diseases.
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PMID:Mutations in apoptosis genes: a pathogenetic factor for human disease. 1139 50

In response to changes in the external environment cells must initiate a coordinated program of gene expression for them to adapt. IEX-1 (immediate early response gene X-1) is precisely regulated by multiple transcription factors among which p53, NF-kappaB/rel, Sp1 and c-Myc play central roles, to ensure rapid and transient expression of IEX-1 in cells under a variety of stress conditions. Overexpression of IEX-1 renders some cells sensitive to apoptosis and accelerates cell cycle progression, but reduces proliferation of other cells, whereas disruption of IEX-1 expression is associated with decreases in both apoptosis and cell cycle progression. In sharp contrast to in vitro studies, in vivo constitutive expression of IEX-1 prevents activated T cells but not B cells from apoptosis, as shown using IEX-1-transgenic mice that target IEX-1 expression specifically to lymphocytes driven by the Emu enhancer. The animals developed a lupus-like disease and subsequently a high incidence of T cell lymphomas when they aged, due to insufficient apoptosis of T cells. These varied effects of IEX-1 on cell death and cell cycle progression in a cell-context dependent fashion implicate that IEX-1 is involved in more than one signaling pathway, understanding of which will certainly improve our knowledge with respect to cancer biology, cell death and cell cycle regulation.
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PMID:Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis. 1251 Jan 47

A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21-/- lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.
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PMID:Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity. 1497 Jan 81

The p53 tumor suppressor molecule triggers a key pathway of apoptosis in injured cells, in part through induction of Fas. The importance of Fas as a receptor mediating apoptosis is highlighted by the lupus-like systemic autoimmunity seen in animals and humans with nonfunctional Fas molecules. We set out to see if the absence of p53, superimposed on the Fas defect of lpr mice, might further accelerate or exacerbate their systemic autoimmunity. We generated double mutant mice (p53(-/-) lpr) having defects in both p53- and Fas-dependent pathways, hypothesizing that animals with lesions in both Fas- and p53-dependent pathways would show reduced ability to delete autoreactive or injured cells, thereby producing more severe autoimmune disease. Surprisingly, these mice have lower autoantibody levels than the single mutant lpr mice. These studies suggest an unanticipated role for p53 in the progression of autoimmunity and the production of autoantibodies.
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PMID:p53 is required for spontaneous autoantibody production in B6/lpr lupus mice. 1578 37

After administration to normal mice, a subset of monoclonal (m) anti-DNA antibodies (Ab) derived from MRL-lpr/lpr mice was identified that enter cells, in vivo. In the kidneys, this was associated with glomerular hypercellularity and proteinuria. In cultured cells, the same mAb bound to myosin 1 on the cell surface, prior to internalization, nuclear localization and inhibition of apoptosis. The present study focuses on the mechanisms underlying the observed functional effects. Subcellular localization studies revealed that following internalization, a prototypic, nuclear localizing, m antibody (Ab; termed H7) co-localized with myosin 1, shortly after internalization, within caveolae, near the cell membrane. Cell fractionation studies confirmed the presence of both H7 and myosin within the caveolar fraction. Since variations in caveolin protein expression have been associated with apoptotic events in cancer cells, through p53 dependent and independent pathways, modulation of caveolin by intracellular H7 was evaluated. Cellular entry of the anti-DNA Ab resulted in an increase in caveolin protein expression. Furthermore, after exposure of cells to dexamethasone to induce apoptosis, the usual increase in p53 was inhibited in the presence of intracellular H7. Taken together, the results suggest that upregulation of caveolin and inhibition of p53 induction are involved in H7-induced, inhibition of apoptosis. Furthermore, they suggest that this inhibition contributes to the glomerular hypercellularity observed in normal mice with intranuclear H7. The results also raise the possibility that inhibition of apoptotic pathways during inflammation or/and autoimmunity could influence subsequent disease events. The novel mechanism of cellular perturbation is indirect and dependent on apoptotic stimuli, and it may account for the presence of intranuclear antibodies in inflammatory and normal tissues of individuals with lupus.
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PMID:Nuclear localizing anti-DNA antibodies enter cells via caveoli and modulate expression of caveolin and p53. 1582 7

Increased expression of p202 protein (encoded by the Ifi202 gene) in splenocytes derived from B6.Nba2 mice (congenic for the Nba2 interval derived from the New Zealand Black mice) was correlated with defects in apoptosis of splenic B cells and increased susceptibility to develop systemic lupus erythematosus. We have now investigated the molecular mechanisms by which increased expression of p202 in B6.Nba2 cells contributes to defects in apoptosis. In this study, we report that increased expression of p202 in the B6.Nba2 splenocytes, as compared with cells derived from the parental C57BL/6 (B6) mice, was correlated with increased levels of p53 protein and inhibition of p53-mediated transcription of target genes that encode proapoptotic proteins. Conversely, knockdown of p202 expression in B6.Nba2 cells resulted in stimulation of p53-mediated transcription. We found that p202 bound to p53 in the N-terminal region (aa 44-83) comprising the proline-rich region that is important for p53-mediated apoptosis. Consistent with the binding of p202 to p53, increased expression of p202 in B6.Nba2 mouse embryonic fibroblasts inhibited UV-induced apoptosis. Taken together, our observations support the idea that increased expression of p202 in B6.Nba2 mice increases the susceptibility to develop lupus, in part, by inhibiting p53-mediated apoptosis.
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PMID:Increased expression of Ifi202, an IFN-activatable gene, in B6.Nba2 lupus susceptible mice inhibits p53-mediated apoptosis. 1667 Feb 93

The gross and histopathologic findings for a primary tonsillar squamous cell carcinoma in a captive 11-yr-old male polar wolf (Canis lupus arctos) are described. The carcinoma had metastasized to regional lymph nodes of the pharynx, the precardial mediastinum, and the lungs. Tumor suppressor protein TP53 was detected by immunohistochemistry in the nuclei of poorly differentiated, cytokeratin-positive cells of the primary neoplasm and the metastases. Canine oral papillomavirus DNA was not detectable by polymerase chain reaction (PCR).
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PMID:Tp53 expressing squamous cell carcinoma of the tonsil in a captive polar wolf (Canis lupus arctos). 1731 81

A dysregulation of apoptosis or an ineffective clearance of apoptotic material is suspected to be involved in the pathogenesis of systemic lupus erythematodes. Subcellular fragments such as apoptotic bodies (ABs) have been recognized as modulators of intercellular communication and immune function. In this context, we have been interested whether nuclear and cytoplasmic antigens are relocated into ABs. In the present study, we characterized ABs isolated from apoptozing lymphoblasts. We found an accumulation of the linker-histone (histone 1) as well as the core-histones (histone 2A, histone 2B, histone 3, histone 4) in ABs. Further, they contained DNA, RNA and the ribonuclear protein La/SSB. Proteins such as cytochrome c, HSP 70, prohibitin, p53, nuclear matrix antigen or lamin B were excluded from ABs. The content of ABs differed from that observed in membrane microparticles isolated from viable cells. Formation of ABs occurred early during apoptosis. It was observed before DNA-degradation or phosphatidylserine exposure was detected. ABs were engulfed by monocyte-derived phagocytes. These findings suggest that immunogenic molecules are actively translocated into ABs followed by a rapid engulfment of the latter by environmental phagocytes. In autoimmune diseases, a defect in the clearance of ABs or AB formation may contribute to the development of autoimmunity.
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PMID:Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis. 1793 98


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