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 products of a growing number of genes have been shown to display seemingly contradictory functions; namely, the induction of tumorigenesis and the induction of apoptosis. Heregulin's involvement in oncogenesis occurs through its interactions with members of the EGF receptor tyrosine kinase family. Recently one isoform of heregulin, beta2b, was isolated in an in vitro screen for dominant, apoptosis-inducing genes in kidney epithelial cells. Here we show that heregulin is also capable of mediating apoptosis in human and murine mammary tumor cell lines and murine tumors. Furthermore, through transfection of the human breast cancer cell line MCF-7 with the truncated transmembrane/cytoplasmic segment of the heregulin gene, we show that the intracellular region of the heregulin precursor is sufficient for induction of apoptosis. Through the use of DNA fragmentation assays we also show that apoptosis occurs in cell lines established from heregulin-induced mammary gland tumors. TdT addition of digoxigenin labeled nucleotides to 3' OH ends of DNA breaks recapitulated these results in the actual tumors. Finally, over-expression of heregulin is shown to lead to the down-regulation of Bcl-2, an inhibitor of apoptosis. Conversely, the transfection of Bcl-2 into MCF-7 cells inhibits heregulin-mediated programmed cell death.
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PMID:The oncogene heregulin induces apoptosis in breast epithelial cells and tumors. 979 82

Aberrant regulation of apoptosis may contribute to tumorigenesis. Relative levels of apoptosis regulatory proteins, such as Bcl-2 and Bax as well as interactions of these proteins with other gene products, may contribute to the rate of apoptosis in neoplasia. We examined Bcl-2 expression in 104 squamous cell carcinomas of the head and neck, as well as histologically normal mucosa several centimeters away from the tumor, and in control normal mucosa from patients without cancer. Immunohistochemistry and immunoblotting demonstrated Bcl-2 expression in 30% (31 of 104) of squamous cell carcinoma, with an increase in Bcl-2 protein levels compared with control normal mucosa from noncancer patients. Bcl-2-positive tumors demonstrated a 5-fold decrease in the number of apoptotic cells compared with Bcl-2-negative tumors. Bcl-2 protein expression was associated with poorly differentiated tumor grade but was not correlated with Bax expression or patient survival. These findings demonstrate that Bcl-2 contributes to apoptosis in normal and transformed squamous epithelium.
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PMID:Bcl-2 but not Bax expression is associated with apoptosis in normal and transformed squamous epithelium. 982 60

Deregulation of cell death pathways is an important feature of tumorigenesis. Fas, a member of the tumor necrosis factor receptor superfamily, is a transmembrane protein that can transduce cell death signals via a proteolytic cascade upon crosslinking or ligand binding. Fas has been implicated in the cell turnover of normal stratified squamous epithelia. To determine if altered Fas mediated cell death pathways participate in epithelial tumorigenesis, we examined squamous cell carcinoma (SCC) lines for sensitivity to Fas ligand (FasL) or an agonistic anti-Fas antibody. All cell lines examined were resistant to FasL mediated cell death. The carcinoma cell line SCC71 was also highly resistant to anti-Fas antibody. Another line, SCC9, underwent rapid cell death with characteristic features of apoptosis after exposure to anti-Fas antibody. However, binding of both FasL and anti-Fas antibody recruited downstream effector molecules to the Fas cytoplasmic domain in both SCC9 and SCC71 cells. Inhibition of the caspase 3- but not the ICE family of cell death proteases blocked apoptosis in SCC9 cells independently of expression of the anti-apoptotic protein bcl2. We concluded that Fas differentially mediates apoptosis in SCC lines by activation of caspase 3 family members but independent of bcl2 expression.
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PMID:Anti-Fas antibody differentially regulates apoptosis in Fas ligand resistant carcinoma lines via the caspase 3 family of cell death proteases but independently of bcl2 expression. 985 79

Since the role of the Bcl-2 gene family has been only poorly investigated in colorectal cancer, we have examined the expression of the apoptosis blockers Bcl-xL and Bcl-2, as well as the proapoptotic factors Bax and Bak. Northern blot analysis and immunohistochemistry were performed on normal and cancerous colonic tissue from 12 patients. In colorectal cancer, Bcl-xL immunoreaction was stronger than in normal controls, and 83% of the cancers had increased Bcl-xL mRNA expression. The median densitometric Bcl-xL values were 3.4-fold higher in carcinomas (P<0.005). In contrast to the normal colon, colorectal carcinomas often lack any Bcl-2 immunostaining, and Bcl-2 mRNA was not detectable by Northern blots either. Bax was not obviously altered in colorectal cancer, either at the protein level or at the mRNA level compared to the normal control colon. Bak mRNA expression exhibited a wide variation in carcinomas, but was somewhat decreased in comparison to the controls. Of these members of the Bcl-2 gene family, Bcl-xL seems to play a major role in colorectal tumorigenesis and disease progression. An agonistic effect might have caused the tendency for reduced Bak expression. The Bcl-2/Bax regulation system of cell homeostasis seems to be of lesser importance.
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PMID:Apoptosis inhibiting factor Bcl-xL might be the crucial member of the Bcl-2 gene family in colorectal cancer. 988 95

The bcl-2 gene belongs to a class of oncogenes involved in the inhibition of apoptosis. Most follicular lymphomas are associated with the t(14;18) translocation that juxtaposes the bcl-2 gene located on chromosome 18 to the immunoglobulin gene locus located on chromosome 14. Consequently, the bcl-2 gene is overly expressed and leads to an accumulation of mature clonal B cells. Prolonged survival of the B cell clone appears to be the early event in tumorigenesis, creating an increased risk of cumulative mutations. Interestingly, bcl-2/Ig gene rearrangements may be identified in nearly 50% of normal individuals but the outcome of normal individuals carrying high levels of t(14;18) is not well defined. Persistent polyclonal B cell lymphocytosis (PPBL) is a unique polyclonal lymphoproliferative disorder mostly restricted to women. We have recently demonstrated that PPBL is also associated with multiple bcl-2/Ig gene rearrangements. In this report, we have extended our analysis to additional patients and demonstrated that all patients presented multiple detectable t(14;18) translocated clones. In addition, Bcl-2 protein expression was increased. Our findings, along with the clinical features of PPBL, make this disorder an exceptional model for the study of B-cell homeostasis.
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PMID:All patients with persistent polyclonal B cell lymphocytosis present Bcl-2/Ig gene rearrangements. 992 47

Apoptosis is a programmed cell death process in which cells commit suicide under certain environmental conditions. Recent studies suggest that apoptosis is controlled by a variety of cellular genes, and dysregulation of these genes plays an important role in the pathogenesis of human diseases, including cancer. BAG-1 is a novel anti-apoptotic protein isolated by its interaction with another anti-apoptotic protein, Bcl-2. It binds to several hormone receptors and growth factor receptors and modulates their function in apoptosis. However, the role of BAG-1 in the oncogenesis of human cervical cancer has yet to be illustrated. In this study, we examined the expression of BAG-1 in cervical normal and carcinoma cultured cells and tissues. BAG-1 was overexpressed in human cervical carcinoma cell lines and tissues. Overexpression was regulated at the transcriptional level. The increased expression of BAG-1 was correlated with enhanced resistance of cervical carcinoma cells to apoptosis induced by a DNA-damaging reagent. In addition, overexpression of BAG-1 enhanced the resistance of cervical cells to apoptosis. This study provided the first evidence that BAG-1 is upregulated in human cervical cancer and may play an important role in apoptosis and human cervical carcinogenesis.
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PMID:Overexpression of anti-apoptotic gene BAG-1 in human cervical cancer. 1004 62

Bcl-2-family proteins are key regulators of the apoptotic response. Here, we demonstrate that the pro-survival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB. We show that bfl-1 gene expression is dependent on NF-kappaB activity and that it can substitute for NF-kappaB to suppress TNFalpha-induced apoptosis. bfl-1 promoter analysis identified an NF-kappaB site responsible for its Rel/NF-kappaB-dependent induction. The expression of bfl-1 in immune tissues supports the protective role of NF-kappaB in the immune system. The activation of Bfl-1 may be the means by which NF-kappaB functions in oncogenesis and promotes cell resistance to anti-cancer therapy.
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PMID:The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. 1004 53

Defects in apoptosis signaling pathways are common in cancer cells. Such defects may play an important role in tumor initiation because apoptosis normally eliminates cells with damaged DNA or dysregulated cell cycle, i.e., cells with increased malignant potential. Moreover, impaired apoptosis may enhance tumor progression and promote metastasis by enabling tumor cells to survive the transit in the bloodstream and to grow in ectopic tissue sites lacking the otherwise required survival factors. Finally, raised apoptosis threshold may have deleterious consequences by rendering cancer cells resistant to various forms of therapy. The intensive apoptosis research during the past decade has resulted in the identification of several proteins which may promote tumorigenesis by inhibiting apoptosis. Of special relevance in human cancer are those commonly expressed in primary tumors and functioning at the common part of the signaling pathway leading to apoptosis. Proteins fulfilling these criteria include antiapoptotic members of the Bcl-2 protein family, heat shock proteins, Hsp70 and Hsp27, as well as survivin, the novel cancer-associated member of the inhibitor of apoptosis protein family. Understanding the molecular mechanisms of action of these proteins may offer novel modes of rationally and selectively manipulating the sensitivity of cancer cells to therapy.
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PMID:Escaping cell death: survival proteins in cancer. 1009 11

Human chondrosarcomas (CS) are a frequent form of malignant bone tumors. The accurate distinction between benign solitary enchondroma and conventional CS of bones is a major diagnostic goal. Although the histological characteristics of chondrogenic tumors and the grading of CS (G1 to G3) have been defined by several authors, immunohistochemical markers for the different entities and grades are still missing and the mechanisms of tumorigenesis remain poorly understood. In addition to the emerging evidence that parathyroid hormone-related peptide (PTHrP) plays a critical role in endochondral bone formation we have recently reported that Bcl-2 lies downstream of PTHrP in the regulation of chondrocyte differentiation. To further characterize chondrogenic tumors and to determine whether PTHrP and the regulation of Bcl-2-expression is of relevance to tumorigenesis, we analyzed the expression of both PTHrP and Bcl-2 on a series of 23 cases of solitary enchondroma (9 cases) and primary CS (14 cases) using light and confocal microscopy. While all 9 enchondromas exhibited a detectable level of PTHrP-expression only, 2 showed low levels of immunoreactivity for Bcl-2. In sharp contrast, strong coexpression of Bcl-2 and PTHrP was found in 11 (composed of 3 CS G3, 7 CS G2, and one dedifferentiated CS) out of 14 CS, while the expression level of these proteins was below the detection limit in two CS G1 and one dedifferentiated CS. To verify this data 3 cases each of enchondroma, CS G2, and CS G3 respectively, were subjected to quantitative confocal analysis, after double labeling for PTHrP and Bcl-2. The results showed a significant increase in the expression of both PTHrP and Bcl-2, in malignant CS versus the benign enchondromas. Most interestingly, the levels of expression of both PTHrP and Bcl-2 correlated with the degree of malignancy of the chondrogenic tumors. These results therefore suggest that both PTHrP and Bcl-2 play a role in the tumorigenesis of chondrogenic tumors and further indicate that both proteins may participate in the same pathway regulating chondrocyte differentiation.
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PMID:PTHrP and Bcl-2: essential regulatory molecules in chondrocyte differentiation and chondrogenic tumors. 1009 28

Non-steroidal anti-inflammatory drugs (NSAIDs) can cause regression of early intestinal tumors and although this is believed to involve cyclooxygenase-2 and apoptosis, the molecular mechanisms remain unclear. Cytoplasmic and nuclear beta-catenin are overexpressed in many of these lesions and Bcl-2, which inhibits apoptosis, may also be elevated during the course of intestinal tumorigenesis. We recently showed that sulindac causes regression of 70-80% of small intestinal tumors in Min/+ mice within 4 days, but does not have the same impact on colonic lesions; after 20 days of treatment the tumor load stabilizes at 10-20% of that in untreated animals. The aim of this study was to determine if NSAID-induced regression of intestinal adenomas might be associated with changes in beta-catenin or Bcl-2 expression. Intestinal tumors from Min/+ mice were harvested after treatment with sulindac for 2, 4 or 20 days and evaluated for expression of beta-catenin and Bcl-2 using immunohistochemistry. There was a > or = 50% decrease in beta-catenin (P = 0.001) and diminishing Bcl-2 (P = 0.019) in small intestinal tumors harvested between 2 and 4 days of treatment when compared with untreated controls. In contrast, small intestinal tumors from animals treated for 20 days were not significantly different from untreated controls. Colonic tumors expressed higher levels of Bcl-2 than those from the small intestine and did not show any significant changes in either Bcl-2 or beta-catenin expression after treatment. Results suggest that modulation of aberrant beta-catenin expression occurs during NSAID-induced regression of intestinal adenomas and that Bcl-2 may confer resistance to these effects.
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PMID:Relationship of beta-catenin and Bcl-2 expression to sulindac-induced regression of intestinal tumors in Min mice. 1022 92


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