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 effects of the novel vitamin D analogue, EB1089 alone, or in combination with the retinoid, 9-cis retinoic acid (9-cis RA) on indices of apoptosis in MCF-7 breast cancer cells have been examined. EB1089 was capable of reducing bcl-2 protein, a suppressor of apoptosis, and increasing p53 protein levels in MCF-7 cell cultures following 96h treatment. In the presence of 9-cis RA, EB1089 acted to further enhance the down-regulation and up-regulation of bcl-2 and p53 respectively. Furthermore, EB1089 induces DNA fragmentation in MCF-7 cells, a key feature of apoptosis, alone and in combination with 9-cis RA in situ. The observation that EB1089 and 9-cis RA act in a cooperative manner to enhance induction of apoptosis in these cells may have therapeutic implications.
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PMID:Vitamin D derivatives in combination with 9-cis retinoic acid promote active cell death in breast cancer cells. 766 28

Germinal centre cell lymphomas (GCCL) show a wide range of clinical outcomes from persistent indolent disease to large cell transformation. To investigate possible mechanisms of this heterogeneity, a combined morphometric and immunohistological study of p53, bcl-2 and cell proliferation was carried out. There was wide variation in p53 expression between biopsies and between individual follicles in the same tumour. A similar pattern of variation was seen using the cell-cycle marker MIB1, but this did not correlate with p53 expression. Even in cases in which a t(14;18) was demonstrated by PCR, variation occurred in the number of cells expressing bcl-2. On the basis of these results, we suggest that the probability of the clonal expansion of GCCL tumour cells carrying additional genetic abnormalities depends on a complex interaction of cell proliferation with p53 and bcl-2 expression, and that this may account for variation seen in the clinical behaviour seen in this group of tumours.
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PMID:Heterogeneity in cell proliferation and expression of p53 and bcl-2 during the indolent phase of germinal centre cell lymphoma: an explanation for clinical variability. 766 61

The effects of dolastatin 10 (Dol10) and dolastatin 15 (Dol15) alone, and after treatment with bryostatin 1 (Bryo1), on human diffuse large cell lymphoma cell line (WSU-DLCL2) were studied. At a concentration of 1.0 ng/ml Dol10 and Dol15 showed significant growth inhibition (p < 0.05). This inhibition was intensified when the cells were pretreated for 24 h with 200 nM Bryo1. Bryo1, Dol10 and Dol15 induced apoptosis which was seen on morphological examination, by flow cytometry and DNA fragmentation on agarose gel electrophoresis. Cells pretreated with Bryo1 and then exposed to Dol10 showed an increase in apoptosis compared with cells that were treated with the Dol10, Dol15 alone. Immunocytochemistry revealed that WSU-DLCL2 cells express the bcl-2 oncoprotein constitutively. bcl-2 expression was decreased when cells were treated with Bryo1, Dol10 or Dol15 and abolished with the Bryo1/Dol10 combination. WSU-DLCL2 cells were negative for p53 protein expression, upon treatment with Bryo1 or Dol10, the expression of p53 was weak and moderate with the Bryo1/Dol10 combination. The inverse correlation between bcl-2 and p53 oncoprotein expression seems to be related to induction of apoptosis in this lymphoma cell line.
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PMID:The bcl-2 and p53 oncoproteins can be modulated by bryostatin 1 and dolastatins in human diffuse large cell lymphoma. 767 Jan 36

Bcl-2 expression has been evaluated immunocytochemically in a series of 33 medullary thyroid carcinomas (MTC) with long-term (mean, 10.3 years) follow-up. Twenty-six of 33 cases showed intense bcl-2 immunoreactivity in more than 25% neoplastic cells. Bcl-2 immunoreactivity did not correlate with several clinicopathologic parameters including sex and age of the patients, sporadic or familial disease, tumor size and stage, amount of amyloid stroma, and immunoreactivity for calcitonin, chromogranin A, proliferating cell nuclear antigen (PCNA), N-myc, and p53. Lack of bcl-2 immunoreactivity, however, correlated significantly (P = .0001) with a shorter survival. Indeed, the seven patients with tumors devoid of bcl-2 immunoreactivity all died of disease within 8 years from the diagnosis. In multivariate analysis, lack of bcl-2 immunoreactivity was an independent predictor of worse prognosis (P = .001 for disease-free survival and P = .0001 for overall survival). None of the other clinicopathologic variable investigated proved to be an independent prognostic parameter. It is concluded that down-regulation of bcl-2 expression in MTC may identify a subset of tumors with a more aggressive clinical course.
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PMID:Prognostic value of bcl-2 immunoreactivity in medullary thyroid carcinoma. 767 94

The cell-positional incidence of both spontaneous and damage-induced apoptosis of epithelial cells was assessed in longitudinal sections of the crypts of small intestine and colon of BDF1 mice. This was compared, using immunohistochemistry, with the pattern of expression of bcl-2, a suppressor of apoptosis. In the small intestine, apoptosis was maximal around cell position 4 from the base of the crypt; this closely corresponds to the position considered to contain the stem cells. In the colon, however, apoptosis was not confined to the area considered to harbour the stem cells (position 1 and 2). Instead, apoptosis was attenuated and distributed along the length of the crypt. Some cells at the base of murine colonic crypts expressed bcl-2 protein, whereas bcl-2 was absent in the crypts of the small intestine. Most pertinently, bcl-2 was absent from small intestinal crypt cells at positions 4-5 (the stem cell region). The importance of the expression of bcl-2 to the attenuation of apoptosis in stem cells was confirmed by analysis of the levels of both spontaneous and induced apoptosis in homozygously bcl-2 null C57BL/6 mice: in colonic crypts the level of spontaneous apoptosis rose significantly, and selectively at the base of the crypt, in comparison with crypts from wild-type animals. In contrast, there was no rise in spontaneous apoptosis in the small intestinal crypts from the bcl-2 null animals. Analysis of sections of human colon and small intestine also showed that expression of bcl-2 was confined to the base of the colonic crypt. The attenuation of apoptosis by bcl-2 in the region of the stem cells of the colonic crypts may dispose these to neoplastic transformation. Indeed, analysis of human carcinomas revealed expression of bcl-2, which in some samples was reciprocal with the expression of p53.
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PMID:Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia. 767 46

Systemic administration of kainate induces cell death in vulnerable regions of the rodent brain. Neuronal degeneration is associated with internucleosomal DNA fragmentation and induction of presumptive cell death effector genes (e.g. p53, c-fos) suggesting that kainate activates an apoptotic pathway. In the present study, kainate-induced DNA damage has been demonstrated at the cellular level by in situ nick translation in the mouse hippocampus and neocortex at 24 h and 48 h after intraperitoneal injections. In the same regions, the intensity of Bcl-2 immunoreactivity decreased by about 45% as measured by digital image analysis. Most important, kainate treatment evoked a nearly 3-fold increase in bax mRNA levels within the mouse brain. The down-regulation of bcl-2, which promotes cell survival, and the up-regulation of bax, which promotes programmed cell death, may have functional significance in kainate-mediated excitotoxicity and in the selective vulnerability of specific brain regions.
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PMID:Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain. 767 27

Gastric cancer involves changes in multiple oncogenes and multiple suppressor genes, and it causes genetic instability. Aberrant expression and amplification of the c-met gene, inactivation of the p53 gene, and CD44 abnormal transcripts are common events of both well differentiated and poorly differentiated gastric cancers. Amplification of the cyclin E gene is also observed in gastric cancer regardless of histologic type. Decreased expression of the pic1 (p21) gene occurs independent of the p53 mutations. In addition, K-ras mutations, c-erbB-2 gene amplification, loss of heterozygosity (LOH) and mutations of the APC gene, LOH of the bcl-2 gene, and LOH at the DCC locus are preferentially associated with well differentiated gastric cancer. Moreover, LOH on chromosome 1q is involved in the progression of well differentiated cancer. Precancerous lesions, including hyperplastic polyp, intestinal metaplasia, and adenoma, share genetic changes found in well differentiated cancers. Conversely, genetic instability may be involved in the first step of stomach carcinogenesis of the poorly differentiated type. Reduction or loss of cadherin and catenins, K-sam gene amplification, and c-met gene amplification are necessary for the development and progression of poorly differentiated or scirrhous carcinoma. Interaction between cell-adhesion molecules in the c-met expressed tumor cells and hepatocyte growth factor from stromal cells is implicated in the morphogenesis of two types of gastric cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular biology of gastric cancer. 767 88

The p53 protein is a transcription regulator that is frequently altered by mutation in cancer. Breakthroughs on two fronts shed light on its role in tumor suppression. First, a flurry of biochemical and structural studies (including a partial crystal structure) has sharpened the picture of p53 topology and functional properties. Second, downstream effectors of p53 have been identified including p21Waf-1/Cip-1, an inhibitor of cyclin-dependent kinases, and bax, a dominant-negative inhibitor of bcl-2. This suggest a scenario in which p53 is activated by genotoxic stress and regulates the transcription of at least two sets of genes. One is responsible for transient cell arrest in G1 and the other controls the initiation of apoptosis. Both processes eliminate potential oncogenic mutations, either by proper DNA repair or by inducing damaged cells to commit suicide.
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PMID:The tumor suppressor protein p53: a receptor to genotoxic stress that controls cell growth and survival. 769 67

The expression of 6 different oncoproteins and 2 tumour suppressor gene products in the plasma cells of 63 bone marrow samples was used to determine a profile of the oncogenic phenotype of patients with multiple myeloma. Dual label flow cytometry after periodatelysine paraformaldehyde fixation was used to detect cell surface phenotype and intracellular protein expression simultaneously. The normal range for both the incidence and intensity of expression was determined for each protein by analysing plasma cells (high CD38 intensity) in 22 normal bone marrow samples. The percentage of myeloma patients with a greater than normal incidence of plasma cells expressing these proteins was 53% for c-myc, 28% for Rb, 28% for bcl-2, 27% for c-fos, 24% for p53 wild, 22% for p53 mutant, 13% for c-neu and 13% for pan-ras. When a panel of 8 antibodies was used, 82% of the samples (n = 28) had an increased incidence of expression by at least one oncoprotein or tumour suppressor gene product. The 5 patients with a normal incidence of expression of all 8 proteins were in plateau stage and 4 had not received chemotherapy for more than 12 months. The number of patients with an increased incidence of expression by 2 or more oncoproteins was significantly greater (X2 = 9.0; p < 0.005) in progressive disease (55%) than in stable disease (14%) but there was no specific phenotype pattern associated with progressive disease. All 6 oncoproteins and both tumour suppressor gene products had a greater incidence and intensity of expression in progressive than in stable disease. The expression of c-myc oncoprotein correlated with c-myc mRNA expression in the same samples (n = 10) but c-myc did not correlate with either the plasma cell labelling index (r = -0.15) nor serum thymidine kinase (r = 0.10). Our results suggest that there is a heterogeneous, non-systematic but almost universal presence of activated oncogenes and tumour suppressor genes in the plasma cells of patients with multiple myeloma and that disease progression is associated with the accumulation of a variety of secondary genetic changes which confer increased malignant behaviour.
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PMID:The oncoprotein phenotype of plasma cells from patients with multiple myeloma. 769 21

The blast cells from up to 70% of patients with acute myeloblastic leukaemia exhibit a variable degree of autonomous growth in vitro, which is related to the production of autocrine growth factors. It has recently been established that patients with autonomous blast cell growth have both a lower remission rate and a higher relapse rate, compared to otherwise comparable patients whose blasts exhibit non-autonomous in vitro growth. In a group of 50 patients the actuarial disease-free survival for the autonomous growth group was 11% at 5 years compared to greater than 50% for the non-autonomous growth group. This data suggests that AML blasts with autocrine growth characteristics may be resistant to cytotoxic drug therapy. Here we present further data demonstrating that AML blasts with autonomous growth are relatively resistant to the induction of programmed cell death (apoptosis) and that this is related to the autocrine production of GM-CSF. Also AML blasts with autonomous growths have aberrant expression of genes associated with resistance to apoptosis induced by cytotoxic drugs. These include high expression of the bcl-2 oncoprotein and abnormalities of expression of the p53 tumour suppressor gene. Furthermore bcl-2 expression was found to be unregulated by both exogenous and autocrine GM-CSF suggesting that the documented negative prognostic effect of autonomous growth on treatment outcome in AML, is in part due to the regulatory effect of autocrine GM-CSF on bcl-2 expression, thus protecting cells from apoptosis induced by cytotoxic drug therapy.
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PMID:Biological features of leukaemic cells associated with autonomous growth and reduced survival in acute myeloblastic leukaemia. 771 30


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