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)

Characteristics of human hepatoma cell lines with the wild-type p53 were compared with those of human hepatoma cell lines with the mutant-type p53. The p21 protein located downstream of p53 was expressed in cell lines with the wild-type p53 but was not expressed in cell lines with the mutant-type p53. As to other tumor suppressor genes such as p16 and p27, there was no difference in their expression between both types of cell lines. In addition, no marked difference was observed in the activities of CDK2 and CDK4 between cell lines with the wild-type and the mutant-type p53. Phosphorylated Rb protein was detected in all cell lines except the HLE line, indicating that this cell line may have a deletion of and/or a mutation of the Rb gene. These results indicate that abnormalities of tumor suppressor genes other than p53, p16, p27, and Rb may be involved in hepatocarcinogenesis. The population doubling time of the wild-type p53 cells was significantly longer than that of the mutant p53 cells. Neither type of cell line showed a specific chromosome distribution which would indicate karyotype instability. The cell lines expressing the wild-type p53 produced tumors at lower frequency than those with the mutant p53 gene. Although there was no significant difference in effects of TGF-beta 1, EGF, cholera toxin, and db-cAMP on cell growth between the two types of cells, all three cell lines with the wild-type p53 were resistant to cytotoxicity of TNF-alpha, while two of the three with the mutant p53 were very sensitive to its cytotoxic effects.
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PMID:Comparison of cellular characteristics between human hepatoma cell lines with wild-type p53 and those with mutant-type p53 gene. 943 73

Glucocorticoids can induce a G1 arrest in the cell cycle progression of BDS1 rat hepatoma cells. In these cells, dexamethasone, a synthetic glucocorticoid, stimulated a rapid and selective increase in expression of the p21 cyclin-dependent kinase (CDK) inhibitor mRNA and protein and virtually abolished CDK2 phosphorylation of the retinoblastoma protein. Expression of the p27 CDK inhibitor, and other G1-acting cell cycle proteins, remained unaffected. Dexamethasone stimulated p21 promoter activity in a p53-independent manner that required functional glucocorticoid receptors. Transforming growth factor-beta, which also induced a G1 cell cycle arrest of the hepatoma cells, failed to elicit this response. Analysis of 5' deletions of the p21 promoter uncovered a glucocorticoid responsive region between nucleotides -1481 and -1184, which does not contain a canonical glucocorticoid response element but which can confer dexamethasone responsiveness to a heterologous promoter. Fine mapping of this region uncovered three distinct 50-60-base pair transcriptional elements that likely function as targets of glucocorticoid receptor signaling. Finally, ectopic expression of p21 had no effect on hepatoma cell growth in the absence of glucocorticoids but facilitated the ability of dexamethasone to inhibit cell proliferation. Thus, our results have established a direct transcriptional link between glucocorticoid receptor signaling and the regulated promoter activity of a CDK inhibitor gene that is involved in the cell cycle arrest of hepatoma cells.
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PMID:Glucocorticoids stimulate p21 gene expression by targeting multiple transcriptional elements within a steroid responsive region of the p21waf1/cip1 promoter in rat hepatoma cells. 944 36

Apoptosis requires the activation of caspases (formerly interleukin 1beta-converting enzyme-like proteases), in particular those related to the caspase-3/7/6 subfamily. Recent data, however, revealed that, although caspase-specific inhibitors delay apoptosis, they are often incapable of preventing it. To obtain evidence for caspase-independent steps of apoptosis, we artificially created a high amount of short-lived or aberrant proteins by blocking the ubiquitin degradation pathway. A temperature-sensitive defect in the ubiquitin-activating enzyme E1 induced apoptosis independent of the activation of caspase-3 and -6 and the cleavage of their respective substrates poly(ADP-ribose) polymerase and lamin A. In addition, neither the caspase 3/7-specific inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone nor the general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone were capable of blocking this type of cell death. By contrast, Bcl-2 overexpression effectively protected cells from apoptosis induced by a defect in the E1 enzyme at the nonpermissive temperature. Bcl-2 acted downstream of the accumulation of short-lived or aberrant proteins because it did not prevent the overexpression of the short-lived proteins p53, p27(kip1), and cyclins D1 and B1 under conditions of decreased ubiquitination. These results suggest the existence of short-lived proteins that may serve the role of caspase-independent effectors of apoptosis and attractive targets of the death-protective action of Bcl-2.
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PMID:Defects in the ubiquitin pathway induce caspase-independent apoptosis blocked by Bcl-2. 949 30

The present studies were initiated to investigate whether p53 transactivated target genes are induced in a rat model of focal cerebral ischemia. Therefore, we applied in situ hybridization, immunocytochemistry and western blotting to study the temporal and spatial expression of p53 and its transcriptional targets Bax, p21 and cyclin G1 following permanent middle cerebral artery occlusion in the rat. Cyclin G1 immunoreactivity was constitutively expressed in the nuclei of cells in the choroid plexus and ependymal cell layer and in the cytoplasm of cell bodies and dendrites of pyramidal neurons of the cerebral cortex. Cyclin G1 messenger RNA and protein levels transiently increased to 150% of contralateral levels in neurons of the ipsilateral frontal and parietal cortex and striatum 3 h following middle cerebral artery occlusion. A low level of constitutively expressed p21 messenger RNA and protein was found in nuclei of cells in the choroid plexus, oligodendrocytes and neurons. p21 messenger RNA and protein levels gradually increased to 250% and 140% of contralateral levels in areas bordering the infarct core up to 6 h following middle cerebral artery occlusion. In contrast, p53 and Bax messenger RNA and protein levels, and protein levels of p27, cyclin-dependent kinase 5, p35 and cyclin E decreased in the infarct core and border areas with time after middle cerebral artery occlusion. The selective up-regulation of cyclin G1 and p21 in neurons in the border zone of a focal ischemic infarct indicates their involvement in an adaptive response to ischemic injury. The possible participation of cyclin G1 and p21 in a signal transduction pathway associated with ischemia-induced cellular stress is discussed.
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PMID:Cell cycle-related gene expression in the adult rat brain: selective induction of cyclin G1 and p21WAF1/CIP1 in neurons following focal cerebral ischemia. 957 98

To characterize the biological features of breast cancer associated with germ-line mutations in BRCA1 and BRCA2, invasive tumors were studied from 58 Jewish women ascertained through studies of early-onset breast cancer. All women were tested for the BRCA1 founder mutations 187delAG (commonly known as 185delAG) and 5385insC (commonly known as 5382insC) and the BRCA2 founder mutation 6174delT. Mutations were detected in 17 of 58 (29.3%) women. Comparing BRCA-associated breast cancers (BABCs) to cases arising in women without founder mutations, no differences were noted in tumor size, tumor stage, or frequency of axillary nodal involvement. Infiltrating ductal carcinoma was the predominant histological type in both groups. BABCs were significantly more likely to be of histological grade III (100 versus 63%; P = 0.04), estrogen receptor negative (75 versus 35%; P = 0.004), and HER2/neu negative (87 versus 58%; P = 0.04). An associated intraductal component was present in 59% of BABCs and 76% of cancers not associated with mutations (P = not significant). A high Ki-67 labeling index was more commonly observed in BABCs than in cases without mutations (83 versus 48%; P = 0.09). There were no differences between the two groups in the frequency of expression of epidermal growth factor receptor, cathepsin D, bcl-2, p27, p53, or cyclin D. There were no significant differences in relapse-free or overall survival. These observations suggest that breast cancers arising in Jewish women with germ-line BRCA founder mutations have a greater proliferative potential than cancers in women without such mutations. Additional studies of BABC are required to determine the nature and implications of additional genetic abnormalities occurring in these tumors.
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PMID:BRCA-associated breast cancer: absence of a characteristic immunophenotype. 958 22

In recent two years, a group of protein factors have been found to combine with the cyclin-dependent kinases (CDKs) and block the activation of cyclin/CDK complexes. They are named CDK inhibitors (CKIs) as p21, p16, p15, p27 and CDI1. The p21 and p27 have certain homology and can inhibit the activity of multiple CDKs; p16 and p15 have higher homology and can specifically combine with CDK4 and CDK6; and the combination specificity of CDI1 needs further research. The expression of p21 is regulated positively by p53. TGF-beta can upregulate the expression of p15 and the inhibitory activity of p27. The above findings demonstrate that CKIs are not only the regulators of CDKs' activity but also the direct linkers between cancer inhibitors and cell-cycle regulation.
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PMID:[Cyclin-dependent kinase inhibitors in mammal cells]. 959 31

Transforming growth factor-beta (TGF-beta) regulates cell proliferation positively or negatively. The mitoinhibition by TGF-beta has been attributed to induction of cyclin-dependent kinase (CDK) inhibitors, such as p15/ Ink4B, p27/Kip1, and p21/Waf1 also known as Cip1 and Sdi1. However, the biological process by which TGF-beta exerts the stimulatory effects on cell growth remains poorly understood. Here we report that TGF-beta 1 stimulates DNA synthesis of IMR-90 human embryonic lung fibroblasts but inhibits that of HuCCT1 human cholangiocarcinoma cells, via down- or up-regulation of p21/Waf1, respectively. TGF-beta 1 markedly suppresses IMR-90 cells to express two different kinds of the p21/Waf1 gene transcription factors, the p53 tumor suppressor and the interferon regulatory factor-1 (IRF-1). This is followed by a marked decrease in expression of p21/Waf1 in a manner consistent with the timing of activation of cyclin E-associated kinase, which normally accompanies the G1-S transition in the cell cycle. Contrarily, TGF-beta 1-induced inhibition of DNA synthesis in HuCCT1 cells is preceded by IRF-1-dependent but p53-independent up-regulation of p21/Waf1 expression followed by inactivation of cyclin E-associated kinase. Thus the cell growth stimulation or inhibition by TGF-beta 1 are mediated by the down- or up-regulation of p21/ Waf1, respectively.
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PMID:Transforming growth factor-beta 1 stimulates or inhibits cell growth via down- or up-regulation of p21/Waf1. 961 5

As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.
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PMID:Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. 969 72

We evaluated the clinical significance of p53, p27 and PCNA expressions in esophageal squamous cell carcinomas. Operative specimens obtained from 70 patients with esophageal squamous cell carcinomas were investigated by staining with antibodies against p53, p27 and PCNA. The correlations among p53, p27 and PCNA expression, clinicopathologic factors and prognosis were studied. The expression of p53 was observed in 55.7%, and it did not correlate to histologic classification, growth pattern, and lymphatic invasion. The expression of p27 was observed in 48.6%, and it correlated to lymph node metastasis. The PCNA positive index (PCNA-PI) was high in the p27 negative cases. The p53 positive and p27 negative group revealed the worst survival rate among groups. Therefore, the p27 positive case, often associated with well differentiated carcinoma, tends to have a slower tumor-growth rate and better prognosis. It is suggested that immunohistochemical assessment on the p53 and p27 expressions would be useful to the recognize the malignant potential and differentiation of squamous cell carcinoma of the esophagus.
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PMID:[Immunohistochemical study of p53, p27 and PCNA expression in esophageal cancer]. 970 5

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell cycle and a potential tumor suppressor gene. Because we had previously demonstrated that loss of p27 protein is associated with aggressive behavior in colorectal adenocarcinomas, we used immunohistochemistry and in situ hybridization to evaluate the potential role of alterations in p27 expression in primary and metastatic colorectal adenocarcinomas. Parallel immunostaining was performed for Ki-67 and p53. We evaluated 13 cases of metachronous and 23 cases of synchronous primary and metastatic colorectal tumor pairs. In the synchronous subgroup (Stage IV tumors), 57% of the primary tumor and metastases pairs did not express p27 protein and the remainder were low expressors. In the metachronous subgroup, 54% of the primary tumors were low expressors and the remainder high expressors of p27 protein. There was a significant reduction in the expression of p27 in the metachronous metastases (mean positive cells: 14.5%) when compared to the corresponding primary tumors (mean positive cells: 41.8%), P = 0.0023. All the primary and metastatic tumors in the metachronous subgroup showed high levels of p27 mRNA expression. There was no association between loss of p27 and either Ki-67 count or p53 expression. Because p27 is known to be up-regulated when epithelial cells are grown in suspension, the down-regulation of p27 in circulating tumor cells may confer the ability to grow in an environment of altered extracellular matrix or intercellular adhesion properties, two situations which may facilitate metastases.
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PMID:Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases. 973 17


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