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)

Organ and cell cultures of the small intestine serve as excellent in vitro models for programmed cell death (PCD). Cells cultured in serum-free, minimal medium rapidly died, as evidenced by histological changes, internucleosomal DNA cleavage, and TdT-mediated dUTP nick end labeling. Cell death was pervasive, although nonepithelial cells within the fibrovascular villus core were spared. PCD did not require a functional p53 gene. Serine and cysteine protease inhibitors, but not FCS, suppressed it. Relative to structural and functional proteins, dying enterocytes rapidly downregulated Ras-convergent proteins, including epidermal growth factor receptor, Erb-B2, and the son of sevenless guanine nucleotide exchangers. Reductions in the steady-state levels of both protein and mRNA were observed. These reductions were prevented by a combination of death-defying serine and caspase inhibitors, indicating a requirement for the initiation of death. Thus, during catastrophic PCD, intestinal epithelial cells delete cell surface signaling pathways responsible for Ras activation.
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PMID:Dying enterocytes downregulate signaling pathways converging on Ras: rescue by protease inhibition. 961 24

Defective regulation of apoptosis may play a role in the development of autoimmune diseases such as systemic lupus erythematosus, in which the skin is a prominent target. To our knowledge, however, the nature of epidermal changes in cutaneous lupus erythematosus (LE) has not previously been investigated. We investigated the involvement of apoptosis in cutaneous LE. A total of 44 lesional skin samples from patients with cutaneous LE, 44 skin samples from patients with scleroderma, five skin specimens from patients suffering from dermatomyositis, and 13 normal skin samples were stained immunohistochemically with monoclonal antibodies to Ki-67, p53 (DO-7), and bcl-2. The lesional skin from cutaneous LE, except LE profundus, showed a marked increase in Ki-67- and p53-positive keratinocytes, which were predominantly located in the basal layer of the epidermis and follicle, and a drastic reduction in the number of bcl-2-positive cells localized in the basal cell compartment. With TdT-mediated dUTP-biotin nick end-labeling staining, we demonstrated that extensive apoptosis occurred in almost the whole epidermis of cutaneous LE, except in cases of LE profundus. This abnormal expression of Ki-67, p53, and bcl-2 and the occurrence of apoptosis in the epidermis was also observed in epidermis from patients with dermatomyositis, but not in that from patients with scleroderma.
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PMID:Apoptosis in the pathogenesis of cutaneous lupus erythematosus. 965 Jun 94

1. The possible mechanisms of the antiproliferative and apoptotic effects of curcumin (diferuloylmethane), a polyphenol in the spice turmeric, on vascular smooth muscle cells were studied in rat aortic smooth muscle cell line (A7r5). 2. The proliferative response was determined from the uptake of [3H]-thymidine. Curcumin (10(-6)-10(-4) M) inhibited serum-stimulated [3H]-thymidine incorporation of both A7r5 cells and rabbit cultured vascular smooth muscle cells in a concentration-dependent manner. Cell viability, as determined by the trypan blue dye exclusion method, was unaffected by curcumin at the concentration range 10(-6) to 10(-5) M in A7r5 cells. However, the number of viable cells after 10(-4) M curcumin treatment was less than the basal value (2 x 10(5) cells). 3. To analyse the various stages of the cell cycle, [3H]-thymidine incorporation into DNA was determined every 3 h. After stimulation with foetal calf serum, quiescent A7r5 cells started DNA synthesis in 9 to 12 h (G1/S phase), then reached a maximum at 15 to 18 h (S phase). Curcumin (10(-6)-10(-4) M) added during either the G1/S phase or S phase significantly inhibited [3H]-thymidine incorporation. 4. Following curcumin (10(-6)-10(-4) M) treatment, cell cycle analysis utilizing flow cytometry of propidium iodide stained cells revealed a G0/G1 arrest and a reduction in the percentage of cells in S phase. Curcumin at 10(-4) M also induced cell apoptosis. It is suggested that curcumin arrested cell proliferation and induced cell apoptosis, and hence reduced the [3H]-thymidine incorporation. 5. The apoptotic effect of 10(-4) M curcumin was also demonstrated by haematoxylin-eosin staining, TdT-mediated dUTP nick end labelling (TUNEL), and DNA laddering. Curcumin (10(-4) M) induced cell shrinkage, chromatin condensation, and DNA fragmentation. 6. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by curcumin at the concentration range 10(-5) to 10(-4) M. On the other hand, the cytosolic protein kinase C activity stimulated by phorbol ester was reduced by 10(-4) M curcumin, but unaffected by lower concentrations (10(-6)-10(-5) M). 7. The levels of c-myc, p53 and bcl-2 mRNA were analysed using a reverse transcription-polymerase chain reaction (RT-PCR) technique. The level of c-myc mRNA was significantly reduced by curcumin (10(-5)-10(-4) M) treatment. And, the level of bcl-2 mRNA was significantly reduced by 10(-4) M curcumin. However, the alteration of the p53 mRNA level by curcumin (10(-5)-10(-4) M) treatment did not achieve significance. The effects of curcumin on the levels of c-myc and bcl-2 mRNA were then confirmed by Northern blotting. 8. Our results demonstrate that curcumin inhibited cell proliferation, arrested the cell cycle progression and induced cell apoptosis in vascular smooth muscle cells. Curcumin may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis. Our results suggest that the antiproliferative effect of curcumin may partly be mediated through inhibition of protein tyrosine kinase activity and c-myc mRNA expression. And, the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase activity, protein kinase C activity, c-myc mRNA expression and bcl-2 mRNA expression.
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PMID:Effect of curcumin on cell cycle progression and apoptosis in vascular smooth muscle cells. 972 Jul 70

Keloids are the result of a dysregulated wound-healing process and are characterized by formation of excess scar tissue that proliferates beyond the boundaries of the inciting wound. In this study, we investigated the expression of key proteins involved in regulating apoptosis in keloids. Twenty archival paraffin-embedded keloid samples were randomly selected for an immunoperoxidase assay with antibodies against fas, p53, bcl-2, and bcl-x proteins using the target antigen-retrieval technique. Apoptosis was assessed in keloids and normal skin and in keloid and normal fibroblasts by the TdT-mediated dUTP nick-end labeling (tunel) assay on tissue sections, fibroblast cultures, and by flow cytometry for cell suspensions. We found that 18 of 20 keloids expressed p53 protein; bcl-2 was expressed by keloid fibroblasts in 19 of 20 keloids, and all specimens had prominent fas expression throughout the tissue. The distribution of these three antigens was regional within each lesion and followed a consistent pattern of p53 and bcl-2 expression colocalized to the hypercellular, peripheral areas of each keloid in a perinuclear pattern (p < .001). In contrast, an inverse distribution of fas expression was shown, with staining being more diffuse across the cell surfaces and limited to the central, more hypocellular regions in16 of 17 keloids (p < .001). There was no specific staining pattern in these keloids with antihuman bcl-x. In vitro studies on cultured keloid fibroblasts (derived from six patients) revealed maintenance of the p53+, bcl-2+ phenotype up to passage 10. Neither neonatal nor normal adult skin fibroblasts expressed either antigen but could be induced to express p53 by exposure to adriamycin. Keloid lesions and keloid fibroblasts were found to have lower rates of apoptosis than normal controls. Keloid fibroblasts displayed enhanced apoptosis rates in response to hydrocortisone, gamma interferon, and hypoxia treatment as compared with normal adult fibroblasts. Focal dysregulation of p53 combined with upregulation of bcl-2 may help produce a combination of increased cell proliferation and decreased cell death in the younger, hypercellular areas of the keloid. This phenotype is reversed in the older areas of the keloid and may prevent malignant degeneration, thus favoring normal apoptosis as evidenced by prominent fas expression.
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PMID:p53 and apoptosis alterations in keloids and keloid fibroblasts. 977 48

Lymphomas in 10 cynomolgus monkeys infected with a simian immunodeficiency virus (SIVsm) were studied with regard to proliferative activity and apoptosis-related gene expression. All were diffuse large-cell lymphomas, showed mono or oligoclonality and a 9/10 diploid cellular DNA content. Expression of a simian homologue to Epstein-Barr virus (HVMF-1) was shown in nine cases. The lymphomas showed moderate to high proliferative activity by Ki67 immunostaining and DNA flow cytometry, and a low number of apoptotic cells detected by TdT-mediated dUTP nick-end labeling (TUNEL). Immunohistochemistry showed abundant tumor infiltrating TIA-1(+) cytotoxic lymphocytes (CTL) and macrophages. Bcl-2, Mcl-1, and also Bax and Bak, but not p53 were demonstrable in the tumor cells by immunostaining. Our findings suggest a causal relationship between HVMF-1 infection and a low apoptotic index of the lymphomas due to the expression of Bcl-2. The apparent inefficient function of tumor-infiltrating CTL could be due to inactivation of CTL and/or resistance of the lymphoma cells to CTL effects. The tumors showed immunoreactivity for CD18, CD29, and CD49d, but not for CD11a, mimicking the phenotype of human Epstein-Barr virus (EBV)-related lymphomas. In summary, our observations indicate a high similarity between this simian model of acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL) and human ARL and other immunosuppression-related lymphomas.
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PMID:Proliferation and apoptosis-related gene expression in experimental acquired immunodeficiency syndrome-related simian lymphoma. 994 80

The p53 tumor suppressor gene, which is considered the guardian of the genome, encodes a phosphoprotein, which is a sequence-specific transcriptional activator or repressor of target genes. The role of p53 in developmental processes has not been studied extensively, although its expression appears to undergo temporal and spatial changes during prenatal and postnatal development. In the present study, we assessed the levels of p53 mRNA and protein in the developing rat brain and its relation to developmental cell death. Furthermore, we investigated the potential role of n-methyl-d-aspartate (NMDA) receptors in regulating p53 expression, since these receptors are involved in the control of cell death. We found that p53 mRNA and protein were detectable in the rat brain throughout perinatal development. In embryos, p53 immunoreactivity was mainly localized in the nuclei of neuroepithelial cells, with a maximum in staining at embryonic day (E)12. In the neuroepithelium, we also found significant numbers of TdT-mediated dUTP nick end labeling (TUNEL)-positive cells, both in dividing periventricular cells and in migrating neurons. In neonates, immediately after birth there was a reduction in the number of apoptotic cells, which then increased to reach a maximum at postnatal day (P)5. Postnatally, apoptotic as well as p53-positive cells were detected in most brain areas. P53 immunoreactivity was also highest on P5. In most cells, p53 immunoreactivity and the TUNEL signal colocalized. P53 immunoreactivity as well as the number of TUNEL- positive cells were dramatically decreased in the brains of newborns treated with MK-801, an NMDA receptor antagonist. Our results show that p53 is involved in the control of developmental cell death, and that NMDA receptors play a regulatory role in the expression of the p53 gene, and thus in apoptosis occurring in the developing rat brain.
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PMID:p53 expression and regulation by NMDA receptors in the developing rat brain. 1034 Jul 50

Apoptosis and the expression of p53 protein, an apoptosis-related protein, in the process of healing of a full-thickness burn wound in guinea-pig skin were studied with the terminal deoxynucleotide transferase nick-end labelling method, electron microscopy, and immunohistochemistry, respectively. Apoptosis was detected in the peripheral zone of heat-injured skin from 12 h until day 10 after the burn, with the peak occurring on day 2. The peripheral zone of heat-injured skin showed p53 protein from 12 h through day 2, with the peak occurring on day 2. Apoptosis was also detected in tissues regenerated for covering skin defects. The peak of apoptosis in the regenerated epidermis occurred at days 7-10, when the epidermis was most acanthotic. p53 protein reactivity was also detected in the acanthotic regenerated epidermis, with a peak on day 7. The peak of apoptosis in the granulation and scar tissue took place from day 10 to 14, when the granulation tissue started diminishing, but p53 protein reactivity was not detected there. These findings suggest that apoptosis plays an important part in the elimination of dying and/or dead cells resulting from heat stress, the terminal differentiation of the regenerated epidermis, and the decrease in cellularity during remodelling. The apoptotic process during remodelling may be mediated by some p53-independent pathway.
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PMID:Apoptosis and p53 protein expression increase in the process of burn wound healing in guinea-pig skin. 1035 18

Apoptotic macrophages are regularly found in atherosclerotic plaques indicating programmed cell death as one of their regulatory controls. The objective of this study was to characterize in more detail apoptotic macrophages in atherosclerotic lesions of humans and heritable hyperlipidemic (HHL) rabbits. Macrophages were immunohistochemically analyzed using antibodies directed against alphaMbeta2-integrins (CD11b/CD18), CD44, major histocompatibility complex (MHC) class I and II, inducible nitric oxide synthase (iNOS), manganese superoxide dismutase (MnSOD), tumor necrosis factor alpha (TNFalpha), p53, c-jun/AP-1 and rabbit macrophages (RAM-11) and the TUNEL (TdT-mediated dUTP nick end labeling) technique. Colocalization studies of human atherosclerotic carotid and aortic tissue showed apoptotic plaque macrophages also being MnSOD-, alphaMbeta2-integrin-, CD44-, MHC class I- and II-, iNOS-, TNFalpha- and p53-immunoreactive. Similar results occurred in atherosclerotic aortas of HHL rabbits. Computer-assisted morphometric analyses revealed a positive correlation of the area density of MnSOD-immunoreactive macrophages with those of alphaMbeta2-integrin- and CD44-immunoreactive ones, but not with those of MHC class I- and II- as well as of RAM-11-immunoreactive macrophages. We conclude that apoptotic macrophages located in atherosclerotic vessel wall are activated, antigen-presenting, integrin-expressing and oxidatively stressed cells. Since all these processes have been demonstrated to cause apoptosis of macrophages in vitro, we propose their potency accelerates the susceptibility of the macrophages to programmed cell death in atherosclerotic lesions.
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PMID:Characterization of apoptotic macrophages in atheromatous tissue of humans and heritable hyperlipidemic rabbits. 1038 Dec 75

Nasal NK/T-cell lymphoma is a unique form of lymphoma highly associated with Epstein-Barr virus (EBV). These lymphomas are rare in Western populations and much more prevalent in some Asian and Latin American countries. Although there are several sizable studies from Asian countries, the same is not true from South America. The aim of this study was to analyze a series of 32 cases of nasal T-cell lymphoma from Peru and to further extend the characterization of this disease. Immunohistochemistry was performed on paraffin sections using the following antibodies: CD20 (L26), CD45RO, CD3, Ki67, CD57, CD56, TIA-1, bcl-2, and p53. The presence of EBV was investigated with immunohistochemical analysis for latent membrane protein (LMP)-1 and in situ hybridization using an antisense riboprobe to EBER 1. The 32 patients included 18 men and 14 women (M:F ratio, 1.2:1), with a median age of 43 years (11 to 72). Three categories were identified: (1) Nasal NK/T cell lymphomas (28 cases): The morphology ranged from small or medium-sized cells to large transformed cells. Necrosis was present in 86% of the cases, and angioinvasion was seen in 36% of the cases. All cases were positive for CD45RO, CD3, and for TIA-1. CD56 was positive in 21 of 27 cases (78%), and CD57 was negative in all cases. EBER 1 positivity was identified in most of the tumor cells in 27 of 28 cases (96%), including the six cases in which CD56 was negative. Overexpression of p53 was detected in 24 cases (86%). (2) Blastic NK cell lymphoma (1 case): The neoplastic cells resembled those of lymphoblastic lymphoma. CD56 and CD45RO were positive; TIA-1, TdT, and EBER-1 were negative. (3) Peripheral T-cell lymphoma (PTCL) unspecified (3 cases): CD56, TIA-1, and EBER-1 were negative. Nasal lymphomas from Peru with a T cell phenotype are predominantly EBV-associated NK/T cell lymphomas, similar to those described in Asian countries. The expression of CD56, TIA-1, and EBER-1, in combination, are very useful markers for the diagnosis of nasal NK/T cell lymphoma in paraffin-embedded tissue. The differential diagnosis of T-cell lymphomas in the nasal region should include rare cases of PTCL unspecified and the blastic variant of NK cell lymphoma. P53 is overexpressed in 86% of the cases. The significance of this finding with regard to clinical behavior and prognosis remains to be determined.
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PMID:Histological and immunophenotypic profile of nasal NK/T cell lymphomas from Peru: high prevalence of p53 overexpression. 1041 5

The induction of apoptosis by contrast media (CM) and mannitol (M) was investigated in the hearts and kidneys of 12-mo-old male SHR rats. Ten groups of 3 SHR rats received a dose of 5 ml/kg of one of the following: Hypaque (H)-30, H-60, H-76, Omnipaque (O)-140, O-350, mannitol (M)-4%, M-9%, M-19%, M-27%, or saline (S). DNA fragmentation was detected using the terminal deoxynucleotidyl transferase-mediated [TdT] dUTP nick-end labeling (TUNEL) method, and the morphology characteristics of apoptosis were confirmed in cardiac and renal cells. The immunoreactivities of Bcl-2, Bax, and p53 were assessed immunohistochemically in the kidneys. Apoptosis occurred in cardiac myocytes and renal tubular and glomerular cells as well as in vascular endothelial and smooth muscle cells of the heart and kidneys. The high frequency of apoptosis correlated significantly with the increase in the osmolality of the H, O, and M. The increased Bax, the increased p53, and the decreased Bcl-2 immunoreactivities were detected in H- or O-treated, but not in M-treated, rats. These findings suggest that CM and M activate cardiac and renal apoptosis by different mechanisms and that the apoptotic process may be implicated in acute heart and renal damage.
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PMID:Contrast medium- and mannitol-induced apoptosis in heart and kidney of SHR rats. 1048 23


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