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 mdm2 oncogene encodes p90(MDM2), which binds to and inactivates the p53 tumor suppressor protein. p90(MDM2) inhibits p53 by blocking the transcriptional activation domain of p53 as well as by stimulating its degradation. Recently, we showed that another product of the wild-type mdm2 gene, p76(MDM2), lacks the first 49 amino acids of p90(MDM2) and cannot bind p53. Here, we report that, like p90(MDM2), p76(MDM2) is expressed in both the nuclear and cytoplasmic compartments. Overexpression of p76(MDM2) antagonizes the ability of p90(MDM2) to stimulate the degradation of p53 and leads to an increase in the levels and activity of p53. Seven murine tissues express an alternatively spliced mdm2 mRNA that can encode p76(MDM2) but not p90(MDM2), as well as the normally spliced mdm2 mRNA that encodes both MDM2 proteins. All seven tissues express both MDM2 proteins. p90(MDM2) is much more abundant than p76(MDM2) in the testis, brain, heart, and kidney. However, in those tissues known to undergo p53-mediated apoptosis in response to gamma-irradiation, the thymus, spleen, and intestine, the levels of the MDM2 proteins are roughly equivalent. Our results indicate that the ratio of the two MDM2 proteins may regulate the response of tissues to DNA damage.
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PMID:p76(MDM2) inhibits the ability of p90(MDM2) to destabilize p53. 1068 59

The cyclic chalcone analogue, E-2-(4'-methoxybenzylidene)-1-benzosuberone (MBB), was found to show outstanding in vitro antineoplastic activity against P388, L1210, Molt 4/C8 and CEM cells as well as against a panel of human tumor cell lines. In order to determine whether this promising antineoplastic activity would extend to anticarcinogenic properties, the effects of MBB on the 7,12-dimethylbenz[alpha] anthracene (DMBA)-induced expression of c-myc, Ha-ras and p53 genes in isolated RNA from liver, lung, kidney, spleen, thymus, lymph nodes and bone marrow of CBA/Ca inbred mice was investigated. DMBA is a well-known chemical carcinogen, which can act as an initiator by causing point mutations in certain oncogenes and tumor suppressor genes. Elevated expression of oncogenes after treatment with DMBA and other carcinogenic chemicals has been noted previously. Administration of MBB simultaneously with DMBA, 24 hours prior to or 24 hours after the DMBA treatment characteristically modified the DMBA-induced expression of the three genes in the 24-hour experiments. The most pronounced suppression effect of MBB could be observed in almost all the investigated tissues when it was administered simultaneously with DMBA. These "short-term" in vivo results support our previous conclusion that MBB can serve as a model molecule for subsequent structural modifications in searching for new effective anticarcinogenic agents.
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PMID:Effect of E-2-(4'-methoxybenzylidene)-1-benzosuberone on the 7,12-dimethylbenz[alpha]anthracene-induced onco/suppressor gene action in vivo. I: A 24-hour experiment. 1076 99

p27Kip1 (p27) controls cell cycle progression by binding to and inhibiting the activity of cyclin dependent kinases. Disruption of the p27 gene in mice (p27-/-) results in increased body growth with a disproportionate enlargement of the spleen, thymus, testis, ovary and pituitary. The increase in pituitary size is due to selective hyperplasia of the intermediate lobe (IL) while the anterior lobe (AL) is not overtly affected. p27 heterozygous mice (p27+/-), as well as p27-/- mice, are hypersensitive to radiation- and chemical-induced tumors compared to wildtype (p27+/+) littermates. Therefore, unlike classical tumor suppressors, only a reduction in p27 levels is necessary to predispose tissues to secondary tumor promoters. Consistent with these studies is the fact that the p27 gene sequence and mRNA levels appear normal in human pituitary adenomas while p27 protein levels are decreased. Therefore, a reduction in p27 levels could be sufficient to sensitize pituitary cells to tumorigenic factors. To test this hypothesis, metallothionein promoter-driven, human growth hormone-releasing hormone (MT-hGHRH) transgenic mice, that exhibit somatotrope hyperplasia before 9 months of age and subsequent adenoma formation with 30 - 40% penetrance, were crossbred with p27+/- mice for two successive generations to produce p27+/+, p27+/- and p27-/- mice that expressed the hGHRH transgene. At 10 - 12 weeks of age, p27-/- and p27+/+, hGHRH mice were larger than their p27+/+ littermates and displayed characteristic hyperplasia of the IL and AL, respectively. Expression of the hGHRH transgene in both p27+/- and p27-/- mice selectively expanded the population of somatotropes within the AL, where pituitaries of p27+/-, hGHRH and p27-/-, hGHRH mice were two- and fivefold larger than p27+/+, hGHRH pituitaries, respectively. There was also a synergistic effect of hGHRH transgene expression and p27-deficiency on liver, spleen and ovarian growth. At 6 - 8 months of age, 83% of p27+/-, hGHRH mice displayed macroscopic AL adenomas (>100 mg), while all pituitaries from p27+/+, hGHRH mice remained hyperplastic (<20 mg). In contrast to the dramatic effects of p27-deficiency on hGHRH-induced organ growth, elimination of p53, by crossbreeding MT-hGHRH mice to p53-deficient mice, did not augment the hyperplastic/tumorigenic effects of hGHRH transgene expression. Taken together these results demonstrate that a reduction in p27 expression is sufficient to sensitize somatotropes to the proliferative actions of excess GHRH, resulting in the earlier appearance and increased penetrance of hGHRH-induced pituitary tumors.
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PMID:p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation. 1077 77

Primary malignant melanoma of the mediastinum is extremely rare. We report a case not previously reported of primary malignant melanoma located in the mediastinum in a 11-year-old boy. The tumor could not be completely resected as a result of extensive invasion of the large blood vessels. Histologically, the tumor was heavily pigmented and composed of vague fascicles of spindle cells intermingled with epithelioid cells. Immunohistochemical analysis showed vimentin, S-100 protein, Melan-A, and HMB-45 immunoreactivity in most of the tumor cells. Nearly 50% of the tumor cells were also positive for p53. It is suggested that primary malignant melanoma of the anterior mediastinum may have a histogenetic relationship to the recently described aggregates of nevus cells in the thymus or mediastinal lymph nodes.
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PMID:Primary malignant melanoma of the anterior mediastinum in a child. 1080 Sep 95

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a newly proposed clinicopathologic entity; a few cases of LCNEC have been reported in other sites, such as the uterine cervix and the thymus. In the salivary glands, LCNEC is extremely rare and is not recognized as a specific entity in the World Health Organization classification. We retrospectively reviewed from our files 1675 cases of surgically resected primary parotid gland tumors and found 2 cases of LCNEC that fulfilled the criteria of pulmonary LCNEC. These cases occurred in 72- and 73-year-old men who had short histories of enlarging parotid gland tumors. The tumors were composed of large cells that exhibited organoid, solid, trabecular, and rosette-like growth patterns with a high mitotic rate and a conspicuous tendency for necrosis. The tumor cells were polygonal and characterized by a moderate nuclear:cytoplasmic ratio, coarse chromatin, and conspicuous nucleoli. Immunohistochemical examination revealed that the tumor cells were positive for six general neuroendocrine markers, cytokeratin, p53, bcl-2, epidermal growth factor receptor, and cyclin D1. Markedly reduced expressions of p21Waf1 and p27Kip1 were also noticed. The Ki-67 labeling index was more than 50% in both cases. One case showed loss of heterozygosity at TP53 accompanied by a p53 gene point mutation. Loss of heterozygosity at chromosome 9p21 was detected in both cases; one was accompanied by a p16 gene silent point mutation. Both patients died of the disease, with recurrence 5 months and 4 years after surgery, respectively. These findings indicate that LCNEC is a rare but distinct salivary gland tumor with highly aggressive biologic behavior. Multiple alterations of cell cycle regulators and tumor suppressor genes may play an important role in presenting the biologic characteristics of this rare parotid gland tumor.
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PMID:Primary large-cell neuroendocrine carcinoma of the parotid gland: immunohistochemical and molecular analysis of two cases. 1082 28

Generally, the process of apoptosis does not cause leakage of noxious cytosolic contents and is therefore non-inflammatory. However, as previously shown, macrophages ingesting apoptotic CTLL-2 cells produced pro-inflammatory cytokines, particularly interleukin-8 (IL-8) and macrophage inflammatory protein-2 (MIP-2), a murine IL-8 homolog. This predicted that rapid and massive apoptosis may induce neutrophil accumulation in vivo. In this study, we tested this prediction by inducing apoptosis by whole-body X-irradiation in mice. After exposure to 4 Gy X-ray irradiation, mice exhibited considerable apoptosis of thymic cells, which was associated with transient infiltration of neutrophils as well as MIP-2 mRNA expression. In contrast, in p53-deficient mice in which irradiation-induced apoptosis was suppressed, as has been reported, infiltration of neutrophils into the thymus was less than that found in p53+/+ mice. Taken together, these results suggest that massive and rapid apoptosis can result in infiltration of neutrophils.
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PMID:Transient infiltration of neutrophils into the thymus in association with apoptosis induced by whole-body X-irradiation. 1085 49

A thymic stromal cell line, TFGD, was established from a thymic tumor mass developed spontaneously in p53 knock out mouse, and was found to produce cytokines that could induce bone marrow hematopoietic stem cells (HSCs) to differentiate into macrophages. The cytokines produced by the TFGD line were assessed by immunoassays. High level of macrophage-colony stimulating factor (M-CSF) and interleukin (IL)-6 was detected in the TFGD-culture supernatant, whereas granulocyte/macrophage-colony stimulating factor (GM-CSF), IL-3, IL-4, IL-5, IL-13, or interferon (IFN)-gamma was undetectable. Blocking experiments showed that anti-M-CSF monoclonal antibody could neutralize the differentiation-inducing activity shown by the TFGD-culture supernatant. Dot blot analysis of the total RNA isolated from the cultured fetal thymic stromal cells showed that M-CSF transcripts were expressed in the normal thymus. These observations, together with the earlier finding that M-CSF plus IL-6 is the optimal combination of cytokines for the induction of macrophage differentiation from HSCs in vitro, may indicate that thymic macrophages could be generated within the thymus by cytokines involving M-CSF.
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PMID:A mouse thymic stromal cell line producing macrophage-colony stimulating factor and interleukin-6. 1089 58

In spite of the fact that the deuterium concentration is over 10 mmol/l in all living organisms, its possible role has been ignored for six decades. Recent studies have shown that the depletion of the naturally occurring deuterium can result in tumour regression in mice, dogs, cats and humans. The effect of deuterium depletion on gene expression plays a key part in tumour development. The carcinogen, 7,12-dimethylbenz(alpha)anthracene (DMBA), was used to increase gene expression in "short term" investigations. The expression of c-myc, Ha-ras and p53 gene was followed in CBA/Ca sensitive inbred mice drinking tap water or deuterium-depleted water (DDW) after induction. By detecting the RNA expression 48 hours after exposure to the carcinogen it was found that the expression of all genes investigated was inhibited in six different organs (spleen, lung, thymus, kidney, liver and lymph node) in the DDW-treated group. It is suggested that genes playing a key role in the cell cycle regulation and tumour development are sensitive to deuterium depletion.
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PMID:Deuterium depletion can decrease the expression of C-myc Ha-ras and p53 gene in carcinogen-treated mice. 1090 78

The cyclic chalcone analogue, E-2-(4'-methoxybenzylidene)-1-benzosuberone (MBB), has been found to show outstanding in vitro cytotoxic activity against P388, L1210, Molt 4/C8 and CEM cells, as well as against a panel of human cell lines. In order to determine whether this promising antineoplastic activity would extend to anticarcinogenic properties, the effect of MBB on the 7,12-dimethylbenz [alpha]anthracene (DMBA)-induced expression of the c-myc, Ha-ras and p53 genes in isolated RNA from the liver, lung, kidney, spleen, thymus, lymph nodes and bone marrow of CBA/Ca inbred mice was investigated. Earlier we had found that administration of MBB can reduce the DMBA-induced 24-hour gene expressions most effectively when it is administered prior to, or simultaneously with, the DMBA-treatment to female CBA/Ca inbred mice. As a continuation of this study, we investigated the effect of MBB on the DMBA-induced gene expressions according to the two protocols in a 48-hour experiment. The 48-hour experiment with female and male CBA/Ca inbred mice also determined the compound which effectively reduced the DMBA-induced c-myc and Ha-ras overexpressions in almost all tissues. While the DMBA-induced gene expressions showed very different patterns, the effectiveness of the two different administrations of MBB was found to be very similar in the two sex groups. At the same time, contrary to the 24-hour experiment, increased p53 gene expression levels could be seen in several tissues in both sex groups. In order to get a better understanding of the effects of MBB on the DMBA-induced gene expressions "long-term" and "follow-up" studies should be performed.
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PMID:Effect of E-2-(4'-methoxybenzylidene)-1-benzosuberone on the 7,12-dimethylbenz[alpha]anthracene-induced onco/suppressor gene action in vivo II: A 48-hour experiment. 1092 16

Peptides presented by class I major histocompatibility complex (MHC) molecules and derived from normal self-proteins that are expressed at elevated levels by cells from a variety of human (Hu) malignancies provide, in theory, potential target antigens for a broad-spectrum, cytotoxic T lymphocyte (CTL)-based immunotherapy of cancer and hematologic malignancies. However, as such tumor- and leukemia-associated self-proteins are also expressed at low levels in some types of normal tissues, such as thymus, spleen and lymphohemopoietic cells, these self-MHC-self-peptide complexes may also represent thymic and/or peripheral tolerogens, thereby preventing immune responses. This is particularly true for class I MHC-peptide complexes expressed by bone marrow-derived cells in the thymus, as such expression would cause negative selection of immature thymic T cells with high avidity for self-MHC-self-peptide complexes. This intrathymic deletion of potentially self-reactive T cells could result in a peripheral T cell repertoire purged of CTL precursors with sufficient avidity to recognize natural tumor associated self-epitopes presented by class I MHC molecules on tumor cells. HLA-transgenic (Tg) mice provide the basis of an experimental strategy that exploits species differences between Hu and murine (Mu) protein sequences in order to circumvent self-tolerance and obtain HLA-restricted CTL specific for epitopes derived from tumor- and leukemia-associated Hu self proteins, such as p53, Her-2/neu, hdm2 and CD19.
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PMID:Targeting p53, hdm2, and CD19: vaccination and immunologic strategies. 1093 87


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