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)

The present report is of immunohistochemical and cell biological studies on cyclooxygenase(COX)-2, Bcl-2 and Ki-67 in pleomorphic adenoma (n = 35). Pleomorphic adenomas from oral minor glands (n = 15), parotid gland (n = 11), Submandibular gland (n = 8) were studied and sublingual gland (n = 1). Expression of COX-2, Bcl-2 and Ki-67 was examined immunohistologically. Immunostaining intensity of COX-2 and Bcl-2 was classified into expression levels from +3 to 0. The positivity to Ki-67 was evaluated by counting the number of positive cells per 1000 cells, and the values were expressed in as percentage. Apoptotic cells were detected using the modified TUNEL method. Expression of COX-2 mRNA was analyzed by real time PCR using fresh tissues of 4 cases. The relationship between morphological findings and the level of COX-2 mRNA expression was analyzed using a laser capture microdissection (LCM). The results of immunohistochemistry and gene analysis using LCM revealed expression of COX-2 mainly in luminar tumor cells. Expression of COX-2 in pleomorphic adenoma was correlated with expression of Bcl-2 statistically (p = 0.044 < 0.05, r = 0.342). There was only a small number of apoptotic cells cells, and intensity of expression of TUNEL was not correlated with the expression of COX-2 (p = 0.463 > 0.05, r = -0.128). There was no statistical correlation between COX-2 and Ki-67 (p = 0.97 > 0.05, r = -0.07). It is suggested that COX-2 may inhibit apoptosis mediating Bcl-2 expression in pleomorphic adenoma, rather than playing a role in cell proliferation.
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PMID:Expression of cyclooxygenase-2, Bcl-2 and Ki-67 in pleomorphic adenoma with special reference to tumor proliferation and apoptosis. 1538 Jan 75

Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27(kip1)) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas.
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PMID:Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population. 1550 20

PRIMA-1 (p53 reactivation and induction of massive apoptosis) is a chemical compound that was originally identified as a selective mutant p53-dependent growth suppressor by screening a library of low-molecular-weight compounds. However, its mechanism of action is unknown. In this study, we examined toxicity of PRIMA-1 to three premalignant human colorectal adenoma cell lines (RG/C2, BR/C1, and AA/C1) and four colorectal carcinoma cell lines (DLD-1, SW480, LOVO, and HCT116) and its mechanism of action. It selectively induced apoptosis only in the mutant p53 premalignant and malignant colon cell lines, but was not toxic to the wild-type p53 premalignant and malignant colon cell lines. Using stable transfectants of temperature-sensitive p53 mutant Ala(143) in null p53 H1299 lung cancer cells, we found that PRIMA-1 induced significantly more apoptosis in cells with mutant p53 conformation (37 degrees C) than the wild-type p53 conformation (32.5 degrees C). Cell cycle analysis indicated that its inhibition of cell growth was correlated with induction of G(2) arrest. Western blot analysis showed PRIMA-1 increased p21 and GADD45 expression selectively in the mutant p53 cells. However, Fas, Bcl-2 family proteins, and caspases were not involved in PRIMA-1-induced cell death. The c-Jun-NH(2)-kinase (JNK) inhibitor SP 600125, but not p38 mitogen-activated protein kinase inhibitor SB 203580 or extracellular signal-regulated kinase inhibitor PD 98059, blocked PRIMA-1-induced apoptosis. Transfection with a dominant-negative phosphorylation mutant JNK, but not a dominant-negative p38 or wild-type JNK, inhibited PRIMA-1-induced cell death, suggesting that the JNK pathway plays an important role in PRIMA-1-induced apoptosis. PRIMA-1 is a highly selective small molecule toxic to p53 mutant cells and may serve as a prototype for the development of new p53-targeting agents for therapy of premalignant and malignant cells.
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PMID:Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway. 1595 47

Although the retinoblastoma susceptibility gene RB1 is inactivated in a wide variety of human cancers, the retinoblastoma protein (Rb) has been shown to be overexpressed in colon cancers, which is linked to the anti-apoptotic function of the protein. However, the mechanisms by which Rb regulates apoptosis are yet to be fully elucidated. We have established that Rb interacts with the anti-apoptotic BAG-1 (Bcl-2 associated athanogene-1) protein, and that a decrease in nuclear localization of BAG-1 is detectable when the interaction between Rb and BAG-1 is disrupted by expression of the E7 viral oncoprotein. Interestingly, although reported as deregulated in colorectal cancers, we have found that BAG-1 expression is also altered in small adenomas, where its localization was found to be predominantly nuclear. In addition, we have established that maintenance of high nuclear BAG-1 in vitro increases the resistance of adenoma-derived cells to gamma-radiation-induced apoptosis. Our work suggests a novel function for Rb, involving modulation of the subcellular localization of BAG-1. We have found predominant nuclear BAG-1 localization in small adenomas, and suggest that BAG-1 may promote colorectal tumour cell survival by making colonic epithelial cells less sensitive to DNA damage.
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PMID:The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival. 1604 72

To investigate the expression of apoptosis-related protein (Fas, FasL, and Bcl-2) in the pathogenesis of autoimmune thyroid disorders (ATDs), immunohistochemical staining was performed on 20 Hashimoto's thyroiditis (HT), 20 Graves' disease (GD), and 20 thyroid follicular adenoma (TFA, as control). All the cases expressed Fas, mainly on the cell surface and cytoplasm. FasL was found in 17 cases of the TFA. Bcl-2 was detected in 15 cases of HT, 19 of GD and 17 of TFA. In TFA, a moderate Fas expression and a minimal or no FasL expression was detected on follicular cells. In HT, the follicles adjacent to infiltrating lymphocytes showed increased levels of Fas and FasL expression. A weaker staining of Fas and FasL was exhibited on infiltrating lymphocytes than on thyrocytes. In a comparison of GD with HT, thyrocytes and lymphocytes showed similar Fas staining, but for FasL the staining was rather weaker in HT. The expression of Bcl-2 was nearly identical in GD and TFA, but much weaker on the follicular cells in vicinity of lymphocytes and on the lymphocytes located in germinal centers of HT tissues. The expression of Fas, FasL, Bcl-2 in Hashimoto's thyroiditis and Graves' disease were almost same. FasL strong expression and Bcl-2 weak expression on the follicles in HT may induce apoptosis. These results provided evidence for expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disease. The lymphocytes seem not to be directly engaged in the process via their own FasL, but they may provide some cytokines that, in turn, upregulate Fas and/or FasL expression to induce apoptosis.
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PMID:Analysis of the expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disorders. 1621 72

Diagnostic criteria for intracapsular carcinoma ex pleomorphic adenoma (CXPA) are subjective and vary among authors. Biomarker analysis, which could provide more objective evaluation of these tumors, has rarely been studied in intracapsular CXPA. Immunohistochemical evaluation of c-erbB-2, p53 protein, bcl-2, and Ki-67 was performed in 8 cases of CXPA at an early phase of malignant transformation (4 intracapsular and 4 minimally invasive) and in 17 pleomorphic adenomas (PA). In all cases of CXPA, p53 and Ki-67 were demonstrated predominantly in luminal cells of benign and malignant areas, significantly more in the latter. Few benign myoepithelial cells were p53 positive. c-erbB-2 reactivity was strongly associated with atypical luminal cells. Bcl-2 expression was weak and focal in malignant areas from 2 cases. In conclusion, both p53 and c-erbB-2 proteins appear to be involved at an early stage of malignization of PA. In PA with atypical cells, evaluation of the expression of these 2 markers provides more objective criteria for the diagnosis of intracapsular CXPA.
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PMID:Biomarker analysis in carcinoma ex pleomorphic adenoma at an early phase of carcinomatous transformation. 1627 89

Overexpression of cyclooxygenase-2 (COX-2) is observed early in colon cancer. Treatments with COX-2-specific NSAIDs have been shown to reduce polyp size and polyp number in FAP patients with a predisposition to colorectal adenoma and cancer. However, the use of COX-2-specific NSAIDs in colon cancer patients has recently revealed increased cardiovascular risks. These harmful side effects may be the result of COX-dependent and/or COX-independent mechanisms. RNA interference (RNAi) is a method of post-transcriptional gene silencing intrinsic to cells. This study employed RNAi to specifically knockdown endogenous COX-2 expression in the HT-29 colon cancer cell line, and to observe the apoptotic response as well as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression levels. Following treatment with a COX-2 siRNA, we demonstrated a significant knockdown at the protein level of 57% as compared to a non-silencing siRNA control. Protein results were corroborated by concurrent decrease in COX-2 mRNA levels following the same treatment regimen. Despite previous studies using NSAID treatment to implicate COX-2 involvement in apoptosis, we did not observe any alteration in Bcl-2 expression and Caspase-3 activation following COX-2 knockdown in these cells. 15-PGDH, a physiological antagonist of COX-2 in its catabolism of PGE2, showed a modest but significant induction in response to COX-2 knockdown. The precise role of COX-2 in apoptosis and PGE2 regulation remains unclear; however, having shown that down-regulation of endogenous levels of COX-2 can be achieved in colon cancer by RNAi, this strategy should prove to be a valuable tool in revealing the specific function of COX-2 in tumourigenesis.
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PMID:Cyclooxygenase-2 knockdown by RNA interference in colon cancer. 1639 11

The aim of this study was to determine the expression of Bcl-2 gene and prognostic importance of Bcl-2 expression in paraffin embedded blocks of patients diagnosed with non-small cell lung cancer (NSCLC). This study included the retrospective analysis of overall 46 patients diagnosed with NSCLC in our clinic between 1996 and 1999. In 16 (34.8%) patients, the diagnosis was made on biopsy of bronchial mucosa and in 30 (65.2%) patients, on materials obtained by surgical resection (lobectomy and pneumonectomy). We reviewed the sections 4-6 microns in size and stained with Hemotoxylin-Eosine (HE) obtained from paraffin embedded blocks and fixed by 10% formalin. These sections are transferred on to slides covered with poly-L-lysine, then de-paraffinization was made. In all cases, immunohistochemical staining with Bcl-2 antibodies was performed. Positive staining was observed in 9 (19.6%) patients, but not in 37 (80.4%) patients. Out of 32 cases with squamous cell tumor, 8 (25%) were observed to have positive staining in their sections, but 24 (75%) were not so. No staining was observed in 11 cases whose cell type was adenoma and two cases whose cell type was adenosquamos (100%). Staining was present in the section of one case with large cell (100%). Median survival time was 36.6 months in cases in which staining was observed and 6.10 months in cases in which staining was not observed, with a significant difference (p< 0.05). In conclusion, the rate of survival was higher in cases in which staining was present.
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PMID:Distribution of Bcl-2 gene expression and its prognostic value in non-small cell lung cancer. 1645 30

Aims-To describe the expression of three genes involved in the regulation of cell proliferation and programmed cell death (apoptosis) in normal, dysplastic and malignant large bowel epithelium, and to relate any alterations to important biological and clinical variables.Methods-Immunohistochemistry was used to assess bcl-2, c-myc and p53 gene expression in 70 colorectal carcinomas, 36 adenomas and three samples of normal mucosa.Results-Bcl-2 and c-myc protein were detected in all samples of normal mucosa and most adenomas. P53 was never found in normal mucosa and was expressed in only 5% of adenomas. Sixty nine of 70 carcinomas expressed c-myc protein; p53 was found in 46% and bcl-2 was present in 35%. Bcl-2 expression correlated with a higher degree of tumour differentiation whereas the opposite was true for c-myc. Strong staining for c-myc protein predicted survival in univariate analysis. No correlation was found between p53 and bcl-2 expression.Conclusions-While c-myc and bcl-2 proteins are overexpressed at an early stage of the large bowel adenoma-carcinoma sequence, alterations to the p53 protein level only occur as a late event in large, highly dysplastic adenomas and carcinomas. Bcl-2 may therefore protect the growing adenoma against excessive programmed cell death and mutated p53 may play a similar role in carcinomas. In vitro there is a reciprocal relation between p53 and bcl-2 expression. This could not be confirmed in vivo. Similarly, there was no relation between bcl-2 and c-myc status, despite evidence that these proteins cooperate to cause neoplastic transformation. C-myc may be a prognostic indicator in large bowel cancer. There is no evidence in the present series that bcl-2 status will affect survival.
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PMID:Genes mediating programmed cell death: an immunohistochemical study of bcl-2, c-myc and p53 expression in colorectal neoplasia. 1669 64

Mitochondrial membrane permeabilization (MMP) is a rate-limiting step of apoptosis, including in anticancer chemotherapy. Adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP on the inner mitochondrial membrane in healthy cells. In addition, ANT can cooperate with Bax to form a lethal pore during apoptosis. Humans possess four distinct ANT isoforms, encoded by four genes, whose transcription depends on the cell type, developmental stage, cell proliferation, and hormone status. Here, we show that the ANT2 gene is up-regulated in several hormone-dependent cancers. Knockdown of ANT2 by RNA interference induced no major changes in the aspect of the mitochondrial network or cell cycle but provoked minor increase in mitochondrial transmembrane potential and reactive oxygen species level and reduced intracellular ATP concentration without affecting glycolysis. At expression and functional levels, ANT2 depletion was not compensated by other ANT isoforms. Most importantly, ANT2, but not ANT1, silencing facilitated MMP induction by lonidamine, a mitochondrion-targeted antitumor compound already used in clinical studies for breast, ovarian, glioma, and lung cancer as well as prostate adenoma. The combination of ANT2 knockdown with lonidamine induced apoptosis irrespective of the Bcl-2 status. These data identify ANT2 as an endogenous inhibitor of MMP and suggest that its selective inhibition could constitute a promising strategy of chemosensitization.
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PMID:Chemosensitization by knockdown of adenine nucleotide translocase-2. 1698 57


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