Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53, a tumour suppressor, is involved in DNA repair and cell death processes and mediates apoptosis in response to death stimuli by transcriptional activation of pro-apoptotic genes and by transcription-independent mechanisms. In the latter process, p53 induces permeabilization of the outer mitochondrial membrane by forming an inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release in several cell line systems. However, it is unclear how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischaemia. We examined interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons using a tGCI (transient global cerebral ischaemia) rat model. We showed mitochondrial translocation of p53 and its binding to Bcl-X(L). Mitochondrial p53 translocation, interaction between p53 and Bcl-X(L), and cytochrome c release from mitochondria and subsequent CA1 neuronal death were prevented by pifithrin-alpha, a p53-specific inhibitor. These results suggest that the mitochondrial p53 pathway plays a role in delayed CA1 neuronal death after tGCI.
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PMID:Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischaemia. 1707 2

The apoptosis stimulating proteins of p53 (ASPP) family consists of three members, ASPP1, ASPP2 and iASPP. They bind to proteins that are key players in controlling apoptosis (p53, Bcl-2 and RelA/p65) and cell growth (APCL, PP1). So far, the best-known function of the ASPP family members is their ability to regulate the apoptotic function of p53 and its family members, p63 and p73. Biochemical and genetic evidence has shown that ASPP1 and ASPP2 activate, whereas iASPP inhibits, the apoptotic but not the cell-cycle arrest function of p53. The p53 tumour suppressor gene, one of the most frequently mutated genes in human cancer, is capable of suppressing tumour growth through its ability to induce apoptosis or cell-cycle arrest. Thus, the ASPP family of proteins helps to determine how cells choose to die and may therefore be a novel target for cancer therapy.
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PMID:ASPP: a new family of oncogenes and tumour suppressor genes. 1721 78

Approximately 10% of all colorectal carcinomas are mucinous carcinomas, characterized by extracellular mucin. Occasionally, mucin accumulates intracellularly in these tumours, causing signet ring cell differentiation. We hypothesized that signet ring cells arise from a separate genetic pathway. In this study the molecular background of signet ring cell differentiation was investigated by analysing genetic changes, changes in the expression of adhesion molecules, and mucin content. Furthermore, its clinical relevance was addressed. Cell lines of colorectal tumours with non-mucinous (AC), mucinous (MC), and signet ring cell phenotype (MCSRC) were used for Multiplex Ligation-dependent Probe Amplification to detect deletions and amplifications in specific oncogenes and tumour suppressor genes. Furthermore, the expression of E-cadherin, beta-catenin, ITF (intestinal trefoil factor), and MUC2 in signet ring cells was studied by immunohistochemistry, immunofluorescence, and mRNA in situ hybridization. Results were validated using a large cohort of rectal carcinomas from which clinicopathological data were available. Specific amplifications and deletions in cell lines of AC, MC, and MCSRC were detected. Bcl-2 was amplified in MCSRC and MC cell lines, but not in AC cell lines. Bcl-2 FISH analysis confirmed this in patient material. Signet ring cells had decreased expression of adhesion molecules (E-cadherin, beta-catenin) and were strongly positive for ITF and MUC2, two peptides which are normally only produced by goblet cells. RNA in situ hybridization confirmed the production of ITF. Mucinous carcinomas with signet ring cell differentiation presented at a higher T stage than adenocarcinomas and mucinous carcinomas (16% pT4 versus 3-5%, p<0.001) and were more frequently node positive (77% vs 39-44%; p<0.001). Prognosis was significantly worse. In conclusion, the presence of signet ring cells in carcinomas with mucinous differentiation correlates with increased T-stage and poor prognosis. These cells, characterized by ITF and MUC2 production, show disruption of the E-cadherin/beta-catenin complex, as well as amplification of Bcl-2.
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PMID:Signet ring cell differentiation in mucinous colorectal carcinoma. 1747 75

The aim of this work was to establish the possible involvement of mitochondria in the apoptotic event triggered by nitric oxide (NO) in chromaffin cells. Using bovine chromaffin cells in primary culture and several NO donors (SNP, SNAP, and GSNO) at apoptotic concentrations (50 microM-1 mM), we have shown that NO induces a time-dependent decrease in the mitochondrial transmembrane potential (DeltaPsi(m)), which correlates with the appearance of hypodiploid cells. Disruption in DeltaPsi(m) is followed by cytochrome c release to the cytosol, which in turn precedes caspase 3 activation. In this mechanism participates the Bcl-2 protein family, because NO donors downregulate the expression of anti-apoptotic members of the family such as Bcl-2 and Bcl-XL, and increase the expression of pro-apoptotic members, Bax and Bcl-Xs, inductors of cytochrome c release to cytosol. Different cell signaling pathways seem to regulate Bax induction and Bcl-2 inhibition because decreased Bcl-2 levels are detected later than enhanced Bax expression. The tumour suppressor protein p53 is also upregulated in a very early phase (30 min) of the NO-induced apoptosis and may be responsible for the further induction of Bax expression. Finally, the translocation of NF-kappaB to the nucleus seems to be another early event in NO-induced apoptosis and it may be involved in the regulation of p53 expression. These results support strongly the participation of mitochondrial mechanisms in NO-induced apoptosis in chromaffin cells and suggest that these cells may be good models for the investigation of molecular basis of neurodegeneration and neuroprotection.
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PMID:Mechanisms of nitric oxide-induced apoptosis in bovine chromaffin cells: Role of mitochondria and apoptotic proteins. 1752 67

When Chinese hamster ovary (CHO) cells were grown in suspension and deprived of serum, 40% of them became apoptotic after 72 hours, as determined by flow cytometry analysis of TUNEL-labelled cells. Cell viability, assessed by erythrocin B staining, decreased correspondingly. An increase in the total fraction of cells expressing interleukin converting enzyme (ICE; caspase 1), B-cell lymphoma 2 protein (Bcl-2,) and Bcl-2 associated x protein (Bax) was shown by antibody probing and subsequent flow cytometry. The p53 tumour suppressor gene product level remained low within the cell population. Insulin-like growth factor-1 (IGF-1) inhibited cell death in a concentration-dependent manner, and at 20 ng/ml, cell viability was maintained close to 100% and no apoptotic cells were detected. Also, insulin was shown to inhibit cell death - at 1.0 microg/ml, cell viability was 95%, whereas 10% of the cells stained for apoptosis. At the highest concentrations of IGF-1 and insulin, the expression of ICE, Bcl-2 and Bax was fully suppressed, whereas the p53 product level increased, despite still being detectable in a minority of cells. Under these conditions, IGF-1 may increase p53 expression to restrain abnormal cell proliferation. It is concluded that special attention should be paid to exposure and culture conditions that induce acquired susceptibility to a toxic insult, during the development and validation of cell-based assays.
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PMID:Insulin and IGF-1 mediated inhibition of apoptosis in CHO cells grown in suspension in a protein-free medium. 1765 Sep 54

Apoptosis may be regulated by oxidants such as peroxynitrite (ONOO(-)). The tumour suppressor, p53, has been reported to play a crucial role in apoptosis induced by oxidants, therefore we assessed the ability of a ONOO(-) donor, GEA 3162, to activate caspases and induce mitochondrial permeability in a p53-deficient murine bone marrow cell line, Jaws II. Furthermore, these cells were stably transfected with Bcl-2, in order to investigate the impact of this survival protein on ONOO(-)-induced apoptosis. GEA 3162 activated caspases and induced loss of mitochondrial membrane potential in Jaws II cells. In particular, caspases 3 and 2 were activated, alongside minor activation of caspases 8 and 9, and apoptosis was partially dependent upon p38 MAP kinase activation, with little or no role for JNK. Overexpression of Bcl-2 abolished activation of all caspases and reduced the change in mitochondrial membrane potential. Thus, we have demonstrated that the ONOO(-) donor, GEA 3162, induces apoptosis in Jaws II murine myeloid cells despite lacking functional p53, via a pathway that principally involves caspases 2 and 3 and mitochondrial changes. This is blocked by overexpression of Bcl-2 via a mechanism that does not appear to merely reflect stabilisation of the mitochondrial membrane.
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PMID:GEA 3162, a peroxynitrite donor, induces Bcl-2-sensitive, p53-independent apoptosis in murine bone marrow cells. 1768 Dec 84

Cancers of the lung and pleura remain a major cause of cancer deaths, both in men and women, with strong causal relationships between cigarette smoking and asbestos fibres, and deaths from lung cancer and mesothelioma, respectively. The poor survival rates for small cell lung cancer and mesotheliomas argue powerfully for greater understanding of mechanisms of carcinogenesis, genetic abnormalities and the role of tumour suppressor genes and proteins in carcinomas of the lung and pleura. Despite progress in the development of newer cytotoxic drugs, lung cancer remains a lethal disease. Chemotherapy and radiotherapy produce only a modest improvement in survival of patients with advanced disease. Increased knowledge of molecular mechanisms of lung cancer and apoptosis are providing opportunities for treating lung cancer with new classes of molecularly targeted drugs. These novel therapies should target the abnormalities in lung cancer by maximizing the effects of anti-tumour molecules, with minimal side effects on normal tissues. Of the several molecular targets, those receiving attention are p53 gene replacement, Bcl-2 downregulation, apoptosis by induced by TNF, the FAS/CD95 receptor system and TRAIL, and inhibition of NF-kappaB. Although several studies have shown benefits, there is a need for well planned clinical trials of drugs that target the apoptotic cascade. Stem cell therapy and gene replacement offer the prospect of novel approaches that are likely in the near future to play a definitive role in the treatment of advanced lung cancer. Furthermore, with their apparent minimal toxicity to normal tissues, the newer molecular targets represent attractive investigational directions for innovative cancer therapies.
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PMID:Molecular genetics and mechanisms of apoptosis in carcinomas of the lung and pleura: therapeutic targets. 1803 30

Oral squamous cell carcinoma (OSCC) is a common cancer characterised by low survival rate and poor prognosis. The multistep process of oral carcinogenesis is affected by multiple genetic events such as alterations of oncogenes and tumour suppressor genes. The use of appropriate experimental animal models that accurately represent the cellular and molecular changes which are associated with the initiation and progression of human oral cancer is of crucial importance. The Syrian golden hamster cheek pouch oral carcinogenesis model is the best known animal system that closely correlates events involved in the development of premalignant and malignant human oral cancers. Therefore, we established an experimental system of chemically induced oral carcinogenesis in hamsters, in order to study different stages of tumour formation: normal mucosa, hyperkeratosis, hyperplasia, dysplasia, early invasion, well differentiated OSCC and moderately differentiated OSCC. We investigated the expression of oncogenes EGFR, erbB2, erbB3, FGFR-2, FGFR-3, c-myc, N-ras, ets-1, H-ras, c-fos and c-jun, apoptosis markers Bax and Bcl-2, tumour suppressor genes p53 and p16, and cell proliferation marker Ki-67 in the sequential stages of hamster oral oncogenesis. Here, we describe the findings of the experimental model in regard to the involvement of signal transduction pathways in every stage of cancer development. Increased apoptosis and cell proliferation were observed in early stages of oral oncogenesis. Furthermore, the increased expression of transmembrane receptors (EGFR, erbB2, FGFR-2 and FGFR-3) as well as the increased expression of nuclear transcriptional factors in early stages of oral cancer indicates that these molecules may be used as early prognostic factors for the progression of OSCC. Since the expression of both H-ras and N-ras do not seem to affect signal transduction during oral oncogenesis, it can be assumed that a different signalling pathway, such as the PI3K and/or PLCgamma pathway, may be implicated in the pathogenesis of OSCC.
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PMID:The hamster model of sequential oral oncogenesis. 1806 31

The ability of p53 to induce apoptosis in cells with damaged DNA is thought to contribute greatly to its tumour suppressor function. P53 has been proposed to induce apoptosis via numerous transcriptional targets or even by direct cytoplasmic action. Two transcriptional targets shown to mediate its apoptotic role in several cell types encode Noxa and Puma, BH3-only members of the Bcl-2 family. To test if their functions in p53-dependent apoptosis overlap, we generated mice lacking both. These mice develop normally and no tumours have yet arisen. In embryonic fibroblasts, the absence of both Noxa and Puma prevented induction of apoptosis by etoposide. Moreover, following whole body gamma-irradiation, the loss of both proteins protected thymocytes better than loss of Puma alone. Indeed, their combined deficiency protected thymocytes as strongly as loss of p53 itself. These results indicate that, at least in fibroblasts and thymocytes, p53-induced apoptosis proceeds principally via Noxa and Puma, with Puma having the predominant role in diverse cell types. The absence of tumours in the mice suggests that tumour suppression by p53 requires functions in addition to induction of apoptosis.
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PMID:In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. 1825 98

Tumour recurrence has a major impact on patients with non-invasive papillary urothelial tumours of the bladder. To explore the role of DBC1 (deleted in bladder cancer 1 locus), a candidate tumour suppressor gene located at 9q32-33, as prognostic marker we have performed loss of heterozygosity (LOH) testing in 49 patients with primary papillary urothelial tumours and associated normal urothelium. Data from the 38 tumours and 11 specimens of normal urothelium that were informative in the LOH study (D9S195 marker) showed that LOH in urothelium (45.4%) but not in non-invasive tumours (60.5%) was associated with tumour recurrence (p = 0.026) but not to grade or progression. Also, tumours whose normal urothelium had LOH were larger (p = 0.020) and showed cyclin D1 over-expression (p = 0.032). Non-significant increased expression of p53, p21Waf1, apoptotic index and tumour proliferation, and decreased expression of p27Kip1 or cyclin D3 also characterized tumours whose normal urothelium had LOH. The expression of these G1-S modulators, apoptotic index and tumour proliferation was more heterogeneous in papillary urothelial tumours, irrespective of having retained heterozygosity or LOH. Also, Bax expression decreased in papillary urothelial tumours having LOH (p = 0.0473), but Bcl-2 was unrelated to LOH status. In addition, FGFR3 protein expression decreased in LOH tumours (p = 0.036) and in those having LOH in their normal urothelium (p = 0.022). FGFR3 immunohistochemical expression was validated by western blot in selected cases. The survival analysis selected LOH in normal urothelium as a marker of disease-free survival (log-rank 5.32, p = 0.021), progression-free survival (log-rank 3.97, p = 0.046) and overall survival (log-rank 4.26, p = 0.038); LOH in tumours was significant in progression-free survival (log-rank 3.83, p = 0.042). It is concluded that LOH at the DBC1 locus in normal urothelium seems to be relevant in the prognosis of non-invasive papillary tumours of the bladder via selecting cases with increased proliferation, frequent alterations of the G1-S phase modulators, and decreased FGFR3 protein expression.
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PMID:Loss of heterozygosity at 9q32-33 (DBC1 locus) in primary non-invasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium. 1845 28


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