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)

Apoptosis is an active mechanism of cell death required for normal tissue homeostasis. Cells require survival signals to avoid the engagement of apoptosis. In the mammary gland, secretory epithelial cells are removed by apoptosis during involution. This cell loss coincides with matrix metalloproteinase activation and basement membrane degradation. In this paper we describe studies that confer a new role for basement membrane in the regulation of cell phenotype. We demonstrate that the first passage epithelial cells isolated from pregnant mouse mammary gland die by apoptosis in culture, but that cell death is suppressed by basement membrane. The correct type of extracellular matrix was required, since only a basement membrane, not plastic or a collagen I matrix, lowered the rate of apoptosis. Attachment to a matrix per se was not sufficient for survival, since apoptotic cells were observed when still attached to a collagen I substratum. Experiments with individually isolated cells confirmed the requirement of basement membrane for survival, and demonstrated that survival is enhanced by cell-cell contact. A function-blocking anti-beta1 integrin antibody doubled the rate of apoptosis in single cells cultured with basement membrane, indicating that integrin-mediated signals contributed to survival. We examined the cell death-associated genes bcl-2 and bax in mammary epithelia, and found that although the expression of Bcl-2 did not correlate with cell survival, increased levels of Bax were associated with apoptosis. We propose that basement membrane provides a survival stimulus for epithelial cells in vivo, and that loss of interaction with this type of matrix acts as a control point for cell deletions that occur at specific times during development, such as in mammary gland involution.
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PMID:Requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. 890 8

Breast cancer is the most common cancer and second leading cause of cancer related deaths in women in the United States. Genistein is a protein tyrosine kinase inhibitor and prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We have previously shown that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. In this study, we investigated these effects of genistein in the breast cancer cell line MDA-MB-435 and 435.eB cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. We also investigated the effect of genistein on matrix metalloproteinase (MMP) secretion previously shown to be effected by erbB-2 transfection. Genistein was found to inhibit MDA-MB-435 and 435.eB cell growth. Induction of apoptosis was also observed in these cell lines when treated with genistein, as measured by DNA laddering, poly(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. We also found an up-regulation of Bax and p21WAF1 expression and down-regulation of Bcl-2 and c-erbB-2 in genistein-treated cells. Gelatin zymography showed that genistein inhibits the secretion of MMP in the breast cancer cells. From these results, we conclude that genistein inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and may inhibit invasion and metastasis of breast cancer cells. These findings suggest that genistein may be a potentially effective chemopreventive or therapeutic agent against breast cancer.
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PMID:Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. 1042 35

Fas/Fas ligand (FasL) interaction has been suggested to play a role in the pathogenesis of Hashimoto's thyroiditis. This manuscript addressed a role for Fas/FasL interaction in the pathogenesis of Graves' disease (GD). Apoptosis was detected in 0.5-5.0% of GD thyrocytes, but not in normal thyrocytes from patients with adenoma (N). Fas was constitutively expressed on the basement membrane of both GD and N thyrocytes. Thyrocytes expressed Bcl-2 constitutively in both GD and N thyrocytes. FasL was detected at the messenger ribonucleic acid level in thyroid tissue and cultured thyroid cells by Northern blotting and RT-PCR. FasL protein was detected in the cytoplasm and basolateral surface of thyrocytes from GD, but not in N. Cell surface expression of FasL on cultured thyrocytes disappeared within 48 h after their isolation. However, it was retained by culturing the cells with a matrix metalloproteinase inhibitor. Coculture with thyrocytes induced apoptosis of Fas transfectants, which was blocked by an anti-FasL antibody. Although cultured thyrocytes expressed Fas on the surface, they were not killed by an agonistic anti-Fas antibody. Interferon-gamma-induced Fas up-regulation was suppressed by TSH. These results suggest that the increased expression of FasL in GD thyrocytes, the down-regulation of Fas expression by TSH or possibly by TSH receptor autoantibody, and the overexpression of Bcl-2, which could render thyrocytes resistant to FasL-mediated elimination, may thus be involved in the pathogenesis of GD.
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PMID:Functional Fas ligand expression in thyrocytes from patients with Graves' disease. 1044 44

Flavopiridol is a flavone that inhibits several cyclin-dependent kinases and exhibits potent growth-inhibitory activity against a number of human tumor cell lines, both in vitro and when grown as xenografts in mice. It is presently being investigated as a novel antineoplastic agent in the primary screen conducted by the Developmental Therapeutics Program, National Cancer Institute. Because breast cancer is the most common cancer and second leading cause of cancer-related deaths in women in the United States, we investigated whether flavopiridol could be an effective agent against a series of isogenic breast- cancer cell lines having different levels of erbB-2 expression and differential invasion and metastatic characteristics. Flavopiridol was found to inhibit the growth of MDA-MB-435 (parental) and 435.eB (stable transfectants) cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. Induction of apoptosis was also observed in these cell lines when treated with flavopiridol, as measured by DNA laddering, PARP, and CPP32 cleavages. We also found modest up-regulation of Bax and down-regulation of Bcl-2, but there was a significant down-regulation of c-erbB-2 in flavopiridol-treated cells. Gelatin zymography showed that flavopiridol inhibits the secretion of matrix metalloproteinase (MMP; MMPs 2 and 9) in the breast cancer cells and that the inhibition of c-erbB-2 and MMPs may be responsible for the inhibition of cell invasion observed in flavopiridol-treated cells. Collectively, these molecular effects of flavopiridol, however, were found to be independent of c-erbB-2 overexpression, suggesting that flavopiridol may be effective in all breast cancer. From these results, we conclude that flavopiridol inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and inhibits invasion and, thus, may inhibit metastasis of breast cancer cells. These findings suggest that flavopiridol may be an effective chemotherapeutic or preventive agent against breast cancer.
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PMID:Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by flavopiridol. 1065 53

Tissue inhibitors of matrix metalloproteinase (TIMPs) are multifunctional proteins with both matrix metalloproteinase (MMP) inhibitory effects and growth-regulatory activity. TIMPs inhibit MMP activity, suggesting a use for cancer gene therapy. However, here we report that systemic administration of human TIMP-4 by electroporation-mediated i.m. injection of naked TIMP-4 DNA stimulates tumorigenesis of human breast cancer cells in nude mice. Consistent with tumor stimulation, TIMP-4 up-regulates Bcl-2 and Bcl-X(L) protein. TIMP-4 also inhibits apoptosis in human breast cancer cells in vitro and mammary tumors in vivo. A synthetic MMP inhibitor BB-94 did not have such antiapoptotic effect. Analysis of TIMP-4 expression in human mammary specimens indicates that TIMP-4 protein is increased in mammary carcinoma cells compared with normal mammary epithelial cells. These data indicate an antiapoptotic activity in breast cancer cells and a tumor-stimulating effect of TIMP-4 when administrated systemically.
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PMID:Stimulation of mammary tumorigenesis by systemic tissue inhibitor of matrix metalloproteinase 4 gene delivery. 1128 97

Clear cell adenocarcinomas (CA), unlike serous adenocarcinomas (SA) of the ovary, are often at stage I, are resistant to platinum-based drugs and have a poor prognosis. The causes of these differences are unclear. In this study, the differences in progression between CA and SA were examined in terms of apoptosis-related and tumor invasion-related factors. The 16 cases of CA and the 16 cases of SA were reviewed. Excised tissues were classified into primary or metastatic loci, and the expressions of survivin, Bcl-2 and matrix metalloproteinase-2 (MMP-2) in each locus immunohistochemically assayed. Whether the expression of each protein was correlated to prognosis was investigated and additionally the invasion ability of cell strains established from CA and SA were examined using in vitro invasion assay. CA at stage I showed significantly higher survivin expression than SA (p<0.05). In CA, survivin tended to be expressed higher in primary locus than in metastatic locus (p=0.068), however, Bcl-2 was expressed relatively higher in the latter (p=0.087). SA did not have these tendencies. While MMP-2 was expressed significantly higher in SA than in CA (p<0.05), and more so in metastatic locus than in primary locus of SA (p<0.05). Invasion assay showed that the invasion of cells derived from SA was significantly inhibited by tissue inhibitors of metalloproteinase-2, an MMP inhibitor. The disease-free interval was significantly shorter when survivin expression was observed in the nucleus. These results suggest that the expression of apoptosis inhibiting factors and enhanced invasion ability affect progression of CA and SA, respectively.
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PMID:Survivin, bcl-2 and matrix metalloproteinase-2 enhance progression of clear cell- and serous-type ovarian carcinomas. 1149 33

Mammary cell apoptosis and proliferation were assessed after injection of Escherichia coli into the left mammary quarters of six cows. Bacteriological analysis of foremilk samples revealed coliform infection in the injected quarters of four cows. Milk somatic cell counts increased in these quarters and peaked at 24 h after bacterial injection. Body temperature also increased, peaking at 12 h postinjection. The number of apoptotic cells was significantly higher in the mastitic tissue than in the uninfected control. Expression of Bax and interleukin-1beta converting enzyme increased in the mastitic tissue at 24 h and 72 h postinfection, whereas Bcl-2 expression decreased at 24 h but did not differ significantly from the control at 72 h postinfection. Induction of matrix metalloproteinase-9, stromelysin-1 and urokinase-type plasminogen activator was also observed in the mastitic tissue. Moreover, cell proliferation increased in the infected tissue. These results demonstrate that Escherichia coli-induced mastitis promotes apoptosis and cell proliferation.
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PMID:Escherichia coli induces apoptosis and proliferation of mammary cells. 1152 34

Curcumin, a dietary pigment in turmeric, posseses anti-carcinogenic and anti-metastatic properties. The present study was conducted to study in vitro chemopreventive effects of curcumin in transformed breast cells. Here, we show that curcumin inhibits H-ras-induced invasive phenotype in MCF10A human breast epithelial cells (H-ras MCF10A) and downregulates matrix metalloproteinase (MMP)-2 dose-dependently. Curcumin exerted cytotoxic effect on H-ras MCF10A cells in a concentration-dependent manner. Curcumin-induced cell death was mainly due to apoptosis in which a prominent downregulation of Bcl-2 and upregulation of Bax were involved. We also suggest a possible involvement of caspase-3 in curcumin-induced apoptosis. Curcumin treatment resulted in the production of reactive oxygen species (ROS) in H-ras MCF10A cells. Apoptotic event by curcumin was significantly inhibited by pretreatment of an antioxidant N-acetyl-L-cysteine (NAC), suggesting redox signaling as a mechanism responsible for curcumin-induced apoptosis in H-ras MCF10A cells. Taken together, our results demonstrate that curcumin inhibits invasion and induces apoptosis, proving the chemopreventive potential of curcumin.
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PMID:Inhibition of invasion and induction of apoptosis by curcumin in H-ras-transformed MCF10A human breast epithelial cells. 1153 70

High intakes of dietary fiber or resistant starches have been associated with a lower incidence of colon cancers. Because short-chain fatty acids (SCFA) such as butyrate are produced in the colonic lumen by the bacterial fermentation of dietary fibers and resistant starches, we hypothesized that SCFA may inhibit the development of invasive human colon cancers. To test this hypothesis, primary human invasive colonocytes were isolated from fresh surgical specimens and treated with 0.01 mol/L acetate, propionate or butyrate; cell invasion, cell adhesion, F-actin polymerization, urokinase plasminogen activator (uPA), tissue inhibitor matrix metalloproteinase (TIMP)-1, TIMP-2 and mutant p53, Bcl-2, Bax, p21 and proliferating cell nuclear antigen (PCNA) protein expression levels were examined. Although each of the SCFA tested significantly reduced primary cell invasion, butyrate was the most potent, inhibiting primary invasive human colon cancer invasion by 54% (P < 0.0001). The effects of SCFA on primary cell invasion appeared to be independent of cell adhesion and F-actin polymerization but dependent on the inhibition of uPA (P < 0.05) and the stimulation of TIMP-1 and TIMP-2 activities (P < 0.05). Protein expression levels of mutant p53, p21, Bax, Bcl-2 and PCNA were significantly altered by each of the SCFA tested (P < 0.05). These data indicate that SCFA inhibit invasive human colon cancer by modulating proteolytic uPA and antiproteolytic TIMP-1 and TIMP-2 activities, but their mechanisms of action on tumor suppression, apoptosis and growth arrest may differ.
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PMID:Short-chain fatty acids inhibit invasive human colon cancer by modulating uPA, TIMP-1, TIMP-2, mutant p53, Bcl-2, Bax, p21 and PCNA protein expression in an in vitro cell culture model. 1169 45

Tissue inhibitors of metalloproteinases (TIMPs) are important regulators of matrix metalloproteinase (MMP) and adamalysin metalloproteinase activity. We previously reported that overexpression of TIMP-3 inhibits MMPs and induces apoptotic cell death in a variety of cell types and demonstrated that apoptosis is mediated through the N terminus of TIMP-3, which harbors the MMP inhibitory domain. However, little is known about the mechanisms underlying TIMP-3-induced apoptosis. Here we demonstrate that overexpression of TIMP-3 induced activation of initiator caspase-8 and -9 and promoted caspase-mediated cleavage of the death substrates poly(ADP-ribose) polymerase and focal adhesion kinase. Furthermore, TIMP-3 induced mitochondrial activation as demonstrated by loss of mitochondrial membrane potential and release of cytochrome c. Intervention studies demonstrated that overexpression of Bcl-2, the anti-apoptotic mitochondrial membrane protein, or CrmA, a viral serpin inhibitor of caspase-8, completely inhibited TIMP-3-induced apoptosis. Furthermore, a dominant-negative Fas-associated death domain mutant inhibited TIMP-3-induced death substrate cleavage and apoptotic death. Taken together, these results indicate that TIMP-3 overexpression induces a type II apoptotic pathway initiated via a Fas-associated death domain-dependent mechanism.
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PMID:Tissue inhibitor of metalloproteinase-3 induces a Fas-associated death domain-dependent type II apoptotic pathway. 1182 69


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