Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple observations in the laboratory and the clinical setting have linked expression of the enzyme cyclo-oxygenase-2 (COX-2) to carcinogenesis. The frequency and amount of COX-2 and Bcl-2 expression in primary lung and bladder cancer sites were detennined by immunoblot analysis of cell lysates prepared from frozen human tumor tissue and matched normal adjacent tissue. COX-2 protein was expressed statistically more frequently and at a higher level in primary adenocarcinomas and squamous cell carcinomas of the lung as well as transitional cell carcinomas of the bladder than in normal adjacent tissue. No correlation was observed between COX-2 and Bcl-2 expression in either the lung or bladder cancer specimens. Immunohistochemistry was also employed to localize COX-2 expression. In addition to expression in the malignant tissues, COX-2 was occasionally localized to the normal bronchial and transitional cell epithelia of the normal adjacent tissue. Detection of COX-2 in histologically normal appearing adjacent tissue suggests that COX-2 may be involved in early cellular changes leading to the development of lung and bladder cancer.
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PMID:Cyclo-oxygenase-2 expression in primary cancers of the lung and bladder compared to normal adjacent tissue. 1226 72

Vascular endothelial growth factor (VEGF) and its receptor Flk-1/KDR play an important role in vascular permeability and tumor angiogenesis. Prompted by the hypothesis that VEGF/Flk-1 system may have regulatory roles in breast carcinogenesis, we investigated the expression of Flk-1 in 141 invasive breast carcinomas in correlation with clinical and immunohistochemical prognostic parameters, including proliferation indices like Ki-67 and Topoisomerase IIalpha (Topo-IIalpha). The immunohistochemical avidin-biotin-peroxidase method was performed on paraffin sections for the detection of Flk-1, p53, Bcl-2, c-erbB-2, Ki-67, Topo-IIalpha, ER, and PR. Flk-1 was detected in 91 of 141 (64.5%) of invasive breast carcinomas showing a widespread cytoplasmic expression in most of the neoplastic cells. Flk-1 expression was correlated with the menopausal status (P = 0.051) of the patient and the nuclear grade of the invasive breast carcinoma (P = 0.003), but demonstrated no correlation with histologic grade, stage, and patient survival. It is interesting that Flk-1 expression demonstrated a significant correlation with 2 well-established proliferation indices, Ki-67 (P = 0.037) and topo-IIalpha (P = 0.009), whereas there was no correlation with the expression of ER, PR, p53, Bcl-2, and c-erbB-2. Moreover, Flk-1 expression showed an inverse correlation with TIMP-1 mRNA localization in intratumoral stromal cells (P = 0.013). In conclusion, the significant correlation of Flk-1 expression in invasive breast carcinomas with proliferation indices like Ki-67 and topo-IIalpha suggests that VEGF may exert a growth factor activity on mammary cancer cells through its receptor Flk-1. On the other hand, the inverse correlation of Flk-1 with TIMP-1 mRNA in intratumoral stromal cells supports the notion that TIMP-1 may have an inhibitory role on angiogenesis.
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PMID:Expression of the vascular endothelial growth factor receptor-2/Flk-1 in breast carcinomas: correlation with proliferation. 1245 8

Brn-3a, a member of the POU gene family (so-called because of the similarity with the group of transcription factors Pit, Oct, and Unc), was found in neuronal cells engaged in the transcription activity of the p1 and p2 promoters of the most powerful antiapoptotic gene, namely, Bcl-2. The alternative splicing of Brn-3a mRNA produces two molecular forms: a longer, Bcl-2 transactivating form, and a shorter inactive form, lacking 84 AA in the aminoterminus. In neuronal cells, following Brn-3a gene transfection and superexpression, an increase of 30 fold of the Bcl-2 protein occurs, leading to apoptosis protection. However, recent works demonstrate that Brn-3a expression is not restricted to neuronal cells, as its activity was detected also in cancer cells of non-neuronal nature. Looking for mechanisms linking Brn-3a to carcinogenesis, we discuss the role of this transcription factor in influencing Bcl-2/p53 antagonism and Bcl-2/VEGF induction of tumor angiogenesis, concluding this review with a proposal for the oncogenic nature of Brn-3a.
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PMID:Brn-3a, a neuronal transcription factor of the POU gene family: indications for its involvement in cancer and angiogenesis. 1240 60

Bile acids have been implicated in biliary tract carcinogenesis, in part, by activating the epidermal growth factor receptor (EGFR). Overexpression of Mcl-1, a potent antiapoptotic protein of the Bcl-2 family, has also been reported in cholangiocarcinomas. Because receptor tyrosine kinases like EGFR may modulate antiapoptotic protein expression, we examined the hypothesis that bile acids modulate Mcl-1 expression levels via EGFR. Deoxycholate increased cellular Mcl-1 protein in a concentration-dependent manner. The deoxycholate-mediated increase of cellular Mcl-1 protein was blocked equally by EGFR tyrosine kinase inhibitors or an EGFR-neutralizing antibody. Although inhibition of mitogen-activated protein kinases did not attenuate the deoxycholate-associated increase in Mcl-1 protein, the Raf-1 inhibitor, BAY 37-9751, effectively blocked the cellular increase of this protein. Neither Mcl-1 transcriptional activity nor its mRNA stability was altered by deoxycholate treatment. However, Mcl-1 protein stability was increased by bile acid treatment, an effect duplicated by proteasome inhibition. Deoxycholate prolongation of Mcl-1 turnover was blocked by either EGFR inhibitors or the Raf-1 inhibitor. Whereas the deoxycholate-induced increase in Mcl-1 reduced Fas-mediated apoptosis, the Raf-1 inhibitor potentiated Fas apoptosis. Our results demonstrate that bile acids block Mcl-1 protein degradation via activation of an EGFR/Raf-1 cascade resulting in its cellular accumulation. Raf-1 inhibitors block this increase of Mcl-1 and render the cells more susceptible to apoptosis, a potential therapeutic strategy for cholangiocarcinomas.
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PMID:Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism. 1243 43

Evidence from live cell bioassays shows that the flat mucosa from patients with colon cancer exhibits resistance to bile salt-induced apoptosis. Three independent cell lines derived from the colonic epithelial cell line HCT-116 were selected for resistance to bile salt-induced apoptosis. These cell lines were developed as tissue culture models of apoptosis resistance. Selection was carried out for resistance to apoptosis induced by sodium deoxycholate (NaDOC), the bile salt found in highest concentrations in human fecal water. Cultures of HCT-116 cells were serially passaged in the presence of increasing concentrations of NaDOC. The resulting apoptosis resistant cells were able to grow at concentrations of NaDOC (0.5 mM) that cause apoptosis in a few hours in unselected HCT-116 cells. These cells were then analyzed for changes in gene expression. Observations from cDNA microarray, 2-D gel electrophoresis/MALDI-mass spectroscopy, and confocal microscopy of immunofluorescently stained preparations indicated underexpression or overexpression of numerous genes at either the protein or mRNA level. Genes that may play a role in apoptosis and early stage carcinogenesis have been identified as upregulated in these cell lines, including Grp78, Bcl-2, NF-kappaB(p50), NF-kappaB(p65), thioredoxin peroxidase (peroxiredoxin) 2, peroxiredoxin 4, maspin, guanylate cyclase activating protein-1, PKCzeta, EGFR, Ras family members, PKA, PI(4,5)K, TRAF2 and BIRC1 (IAP protein). Under-expressed mRNAs included BNIP3, caspase-6, caspase-3 and serine protease 11. NF-kappaB was constitutively activated in all three resistant cell lines, and was responsible, in part, for the observed apoptosis resistance, determined using antisense oligonucleotide strategies. Molecular and cellular analyses of these resistant cell lines has suggested potential mechanisms by which apoptosis resistance may develop in the colonic epithelium in response to high concentrations of hydrophobic bile acids that are associated with a Western-style diet. These analyses provide the rationale for the development of hypothesis-driven intermediate biomarkers to assess colon cancer risk on an individual basis.
Carcinogenesis 2002 Dec
PMID:Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. 1250 30

Next to water, tea is the most ancient and widely consumed beverage in the world. Epidemiological studies have suggested a cancer protective effect, but the results obtained so far are not conclusive. In the current study, mechanisms of the apoptogenic effect of black tea extract were delineated. Black tea administration to Ehrlich's ascites carcinoma (EAC)-bearing Swiss albino mice caused a significant decrease in the tumor cell count in a dose-dependent manner. Flowcytometric analysis showed an increase in the number of cells in the sub-G(0)/G(1) population signifying tumor cell apoptosis by black tea. These results were further confirmed by nuclear staining that demonstrated distinct morphological features of apoptosis. Our data also revealed an increase in the expression of pro-apoptotic protein p53 in EAC. It is known that upon p53 induction, multiple downstream factors contribute to the decision making between growth arrest and apoptosis. Among those, pro-apoptotic gene Bax is up regulated during p53-mediated apoptosis. On the other hand, p53-mediated growth arrest involves p21 as a major effecter. In our system, increase in p53 expression was followed by moderate expression of p21/Waf-1 and high expression of Bax at protein levels. Interestingly, anti-apoptotic protein Bcl-2 was down regulated resulting in decrease in Bcl-2/Bax ratio. All these observations together signify that black tea-induced apoptogenic signals overrode the growth-arresting message of p21, thereby leading the tumor cells towards death.
Carcinogenesis 2003 Jan
PMID:Apoptogenic effects of black tea on Ehrlich's ascites carcinoma cell. 1253 51

BRCA1 is a tumor suppressor gene that is responsible for hereditary breast and ovarian cancer syndrome. Increased evidence suggests that BRCA1 protein is involved in mammary carcinogenesis in sporadic and hereditary forms. Recent experimental results suggest that BRCA1 plays a role in the regulation of apoptosis. In order to test whether the analysis of human tumors would provide data supporting this hypothesis in sporadic breast carcinomas, we have investigated the relationship between BRCA1 and apoptosis-related genes. Immunohistochemical analysis was performed to determine BRCA1 and the apoptosis-related proteins bcl-2, Bax and p53 in paraffin-embedded tissues of 156 sporadic invasive ductal carcinomas. BRCA1 expression was positively-correlated with Bcl-2 expression (p = 0.0008), but no relationship between BRCA1 expression and Bax or p53 expression could be established. In addition, loss of BRCA1 expression was also related to poor tumor differentiation and lymph node metastasis. Our study shows that bcl-2 might be one of the target genes involved in the oncogenesis related to BRCA1. Loss of BRCA1 may contribute to tumor development in breast carcinomas, which may be independent of the p53 tumor suppressor.
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PMID:Correlation between BRCA1 expression and apoptosis-related biological parameters in sporadic breast carcinomas. 1255 65

Early detection of lung cancer requires none or few invasive techniques. Distal lung cancer (40% of the cases in most European countries) can be sensitively detected by spiral computed tomography. Theoretically, in 60% of cases, the proximal lesions (main to segmental bronchi, accessible by bronchoscopy) should be able to be detected by sputum cytology. Unfortunately, this very specific technique has a low sensitivity and is time consuming. Fluorescent bronchoscopy increases the detection rate of early or micro-invasive lesions and may be proposed in highly selected populations, but not as a screening test. Biomarkers in blood and sputum have not yet been clinically validated. However, the amount of data generated from studies first on resected tumours, then on early bronchial lesions and more recently on blood and sputum offer a wide field for investigation. Lung carcinogenesis is a multistep process characterised by the accumulation of successive molecular genetic and epigenetic abnormalities, resulting in selection of clonal cells with uncontrolled growth capacities throughout the whole respiratory tract (field cancerisation). Molecular lesions far precede morphological transformation of preneoplastic bronchial lesions (dysplasia) or alveolar lesions (atypical alveolar hyperplasia). Genetic and epigenetic abnormalities in the genes involved in cell cycle, senescence, apoptosis, repair, differentiation and cell migration control may be detected on bronchial biopsies, on respiratory cells from the sputum and even in the circulating deoxyribonucleic acid (DNA). The key genes involved include those in the P53-retinoblastoma (Rb) pathways. The balance between cyclin-dependent kinases and their inhibitors regulates the level of Rb phosphorylation and its function at G1-S transition; P53 plays at least two functions (cell cycle and apoptosis control). The balance of bax-bcl2 is important in the control of apoptosis as well as loss of fragile histidine triad expression. O(6)-methylguanine-DNA methyltransferase seems to be important in DNA repair control, the RARbeta receptor in differentiation, and cadherin H and E and different metalloproteases genes in cell migration. The demonstration of hyperexpression or silencing of these genes needs different validated techniques: immunohistochemistry on biopsies or cytological preparations, molecular biology techniques for mutations, loss of heterozygosity and aberrant methylation abnormalities. Automation and miniaturisation of these techniques will allow early detection and may be widely applied once clinically validated.
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PMID:Early detection of lung cancer: role of biomarkers. 1257

To study the molecular mechanisms by which drug resistance develops, we compared DU145 humanprostate cancer cells with a subline selected for resistance to camptothecin. Differences in gene expression level were assessed by hybridizing the two cell types against each other using quadruplicate "Oncochip" cDNA microarrays that included 1648 cancer-related genes. Expression levels differing by a factor of >1.5 were detected for 181 of the genes. These differences were judged statistically reliable on the basis of a stratum-adjusted Kruskal-Wallis test, after taking into account a dye-dependent variable. The 181 expression-altered genes included a larger than expected number of the "apoptosis-related" genes (P = 0.04). To assess whether this observation reflected a generalized resistance of RCO.1 to apoptosis, we exposed the cells to a range of stresses (cisplatin, staurosporine, UV, ionizing radiation, and serum starvation) and found greatly reduced apoptotic responses for RC0.1 (relative to DU145) using flow cytometric Annexin V and terminal deoxynucleotidyl transferase-mediated nick end labeling assays. We next examined the apoptosis-related genes in the context of a molecular interaction map and found expression differences in the direction "expected" on the basis of the apoptosis-resistance of RC0.1 for BAD, caspase-6, and genes that signal via the Akt pathway. Exposure of the cells to wortmannin, an inhibitor of the Akt effector phosphatidylinositol 3-kinase, provided functional support for involvement of the Akt pathway. However, closer examination of the molecular interaction map revealed a paradox: many of the expression differences observed for apoptosis-related genes were in the direction "contrary" to that expected given the resistance of RC0.1. The map indicated that most of these unexpected expression differences were associated with genes involved in the nuclear factor kappa B and transforming growth factor beta pathways. Overall, the patterns that emerged suggested a two-step model for the selection process that led to resistance in RC0.1 cells. The first hypothesized step would involve a decrease in apoptotic susceptibility through changes in the apoptosis-control machinery associated with the Bcl-2 and caspase gene families, and also in antiapoptotic pathways operating through Akt/PKB. The second step would involve changes in multifunctional upstream genes (including some genes in the nuclear factor kappa B and transforming growth factor beta pathways) that can facilitate apoptosis but that would also tend to contribute to cell proliferation in the presence of drug. Thus, we propose that a downstream blockade of apoptosis was "permissive" for the selection of upstream pathway changes that would otherwise have induced apoptosis. This model is analogous to one suggested previously for the relationship between oncogene function and apoptosis in carcinogenesis.
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PMID:Apoptotic susceptibility of cancer cells selected for camptothecin resistance: gene expression profiling, functional analysis, and molecular interaction mapping. 1261 15

Cancers may develop in the background of genomic instability with accumulated mutations. Helicobacter pylori gastritis is characterized by acute foveolitis of the proliferative zone, which is found in any stage of the gastritis as long as the infection persists. Because acute foveolitis targets specifically the proliferative zone of pits, the proliferating epithelial cells are under severe and persistent mutagenic pressure. In H. pylori gastritis, a characteristic morphological change of epithelial cells, the malgun (clear) cell change is frequently present in association with acute foveolitis. Malgun cells have enlarged euchromatic nuclei and abundant cytoplasm. The expression of proliferating cell nuclear antigen and cytokeratin 8 are typically up-regulated in them indicating that they are mitotically and metabolically active. Here, we report evidence for DNA damage and repair in malgun cells. Significant double-strand DNA breaks were shown by the consistent terminal dUTP nick-end labeling in the nuclei of malgun cells. Proteins related to DNA damage and repair, such as Ku, poly(ADP-ribosyl) polymerase, OGG1, and MSH2 were selectively up-regulated in malgun cells. Inducible nitric oxide synthase was also up-regulated. There were occasional bcl2- and p53-expressing cells suggesting that further steps of carcinogenesis took place at the single cell level. Our results suggest that the malgun cell change represents a characteristic morphological sign of cellular genomic damage and repair, and may be implicated in an early stage of carcinogenesis. It is suggested that acute foveolitis of the proliferative zone is a major pathogenetic step of gastric carcinogenesis in H. pylori gastritis.
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PMID:Malgun (clear) cell change in Helicobacter pylori gastritis reflects epithelial genomic damage and repair. 1265 12


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