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)

Mammary epithelial cells (MEC) undergo programmed cell death (PCD) when deprived of serum and growth factors at high cell density but not at low density. The addition of epidermal growth factor and insulin to serum-free medium (SFM) completely restores cell survival. In this report, we examine the role of cell-cell and cell-matrix interaction. When cell attachment is prevented, PCD is markedly accelerated. This effect is observed in cells collected at low or high density and is unaffected by calcium depletion. Cells plated in SFM on purified laminin, tenascin C, or collagen IV-coated dishes, as well as on dishes coated with endogenous extracellular matrix deposited by HC11 mammary cells, show reduced PCD. The addition of soluble laminin or tenascin C to suspension cultures of MECs also partially inhibits PCD. In contrast, no effect is seen with fibronectin or collagen I. These results indicate that reduced contact with a solid substrate contributes to the induction of PCD, which might partially explain the fact that it is only observed in confluent cultures. Ectopic Bcl-2 expression in MCF-10-A and HC11 mammary cells results in a complete suppression of PCD. In MCF-10-A cells, the level of endogenous Bcl-2 increases when the survival factors epidermal growth factor and insulin are added to the SFM but is unaffected by cell density. On the contrary, Bax protein expression increases sharply with cell density but does not change upon addition of epidermal growth factor and insulin. When compared to lactating tissue, Bcl-2 protein levels decrease during mammary gland involution. Bax protein levels increase during lactation and remain high during involution. These data suggest that Bcl-2 and Bax might be intracellular mediators of signals that influence MEC apoptosis.
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PMID:Apoptosis is accompanied by changes in Bcl-2 and Bax expression, induced by loss of attachment, and inhibited by specific extracellular matrix proteins in mammary epithelial cells. 904 Sep 47

The effect of TGF-beta1, an auto/paracrine antiproliferative and apoptogenic factor on Bax transcript level (RT-PCR), subcellular distribution of Bax protein (immunoelectron microscopy), Bcl-2 protein level and apoptotic cell number (flow cytometry with FITC-conjugated monoclonal anti-Bcl-2 antibody and DNA stained with DAPI) in HC11 mouse mammary epithelial cells was examined. TGF-beta1 increased Bax transcript level (evaluated by Bax mRNA/GAPDH mRNA ratio) and stimulated Bax protein movement from cytosol to organellar membranes, mainly mitochondrial, during 60 min. The new observation is the presence of Bax on channel membranes of Golgi apparatus and translocation of Bax from cytosol to the fibrous nucleoplasm via nuclear envelope pores (especially after 120 min. of cell exposure to TGF-beta1). Prolactin protected HC11 cells against TGF-beta1-induced PCD, which could occur at two levels: 1) TGF-beta1 expression, through the decrease of TGF-beta1 transcript content, and 2) Bax/Bcl-2 checkpoint, through down-regulation of Bax and up-regulation of Bcl-2. In conclusion, Bax and Bcl-2 proteins are implicated in the mechanism of TGF-beta1-induced PCD and antiapoptotic action of prolactin in HC11 mouse mammary epithelial cells. The activation of transcription and redistribution of Bax from cytosol to organellar membranes and nucleus constitute the early events in the cellular response to TGF-beta1.
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PMID:Expression and subcellular redistribution of Bax during TGF-beta1-induced programmed cell death of HC11 mouse mammary epithelial cells. 1072 83

The effect of a-difluoromethylornithine (DFMO) on the apoptosis of HC11 mouse mammary epithelial cells was investigated. The involvement of reactive oxygen species (ROS) and Bcl-2 protein in the mechanism of apoptosis induced by ornithine decarboxylase (ODC) inhibition was also assessed. DFMO (0.1, 1 and 5mM) induced apoptosis of HC11 cells in dose- and time-dependent manner. Apoptosis manifests itself with morphological features like: cell shrinkage, condensation of chromatin, pyknosis and fragmentation of nucleus, followed by secondary necrosis (putrosis). The decrease in the nuclear DNA contents appearing as the hypodiploidal peak sub-G1 in the DNA histogram was not dependent on the presence of prolactin (5 microg/ml) in DFMO-treated cultures. Apoptosis induced by ODC inhibition was associated with a rapid increase in ROS concentration in HC11 cells observed within 1 h after DFMO treatment. The down-regulation of Bcl-2 as a decrease in cell number expressing bcl-2 and a lowered Bcl-2 protein content in cells expressing this protooncogene was also noted. The administration of putrescine (50 microM) lowered the number of early-apoptotic, late-apoptotic and necrotic cells. Moreover, it increased the number of cells expressing bcl-2. In conclusion, the disturbance of cellular polyamine homeostasis by inhibition of their synthesis enhances mammary epithelial cell susceptibility to apoptosis. It may occur in the mammary gland at the end of lactation, when the depletion of circulating lactogenic hormones and activation of intra-mammary apoptogenic factors expression take place.
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PMID:Inhibition of ornithine decarboxylase by alpha-difluoromethylornithine induces apoptosis of HC11 mouse mammary epithelial cells. 1112 55

The expression of apoptosis-related proteins: TGF-beta1 (auto/paracrine inducer) and its receptor (TGF-betaRIII), Bax (promoter), Bcl-2 (inhibitor) and CPP-32 (executor of apoptosis) as well as the apoptotic cell number in mammary glands of 11 Polish White Improved goats in the course of the lactation cycle (peak of lactation: days 40-70, late lactation: days 208-256, drying off: days 267-340) was investigated. The immunohistochemical study demonstrated a significant increase in TGF-beta1 and TGF-betaRIII expression in the lobuloalveolar tissue from the early lactation to the dry period. Our recent study on HC11 mouse mammary epithelial cells [Cell. Mol. Biol. 46 (2000) 175] has revealed an inhibitory effect of prolactin on TGF-beta1 transcription, which may explain the low TGF-beta1 synthesis during lactogenesis and galactopoiesis and the increase in TGF-beta1 and TGF-betaIIIR expression in late lactation and dry period. Bax expression was the lowest in the peak of lactation, significantly increased in late lactation and remained elevated during drying off. Bcl-2 content was lower than Bax in all examined periods, but it increased significantly at the end of lactation, which suggests the survival of cells with the highest resistance to apoptogenic stimuli. The increase in Bcl-2 level in remnant lobuloalveolar tissue is probably the molecular mechanism that limits the rate of secretory tissue involution. The induction of CPP-32 (caspase 3) from the peak of lactation to dry period was accompanied by a progressive loss of mammary epithelial cells and the increase in apoptotic cell numbers but only in the dry period. The increase in the expression of examined proteins in the late lactation and the dry period indicates their involvement in the induction (TGF-beta1 and TGF-betaRIII), regulation (Bax and Bcl-2) and execution (CPP-32) of programmed cell death in the course of mammary gland involution. The lack of an increase in apoptotic cell number in late lactation, in spite of the evident decrease in total cell number, suggests milk as an alternative route (apart from phagocytosis) of apoptotic cells elimination from the mammary gland. The presented results provide new insights into the molecular mechanism of mammary cell apoptosis in goat and for this reason may have practical implications for control and regulation of mammary gland remodelling, which is a prerequisite for subsequent successful lactation.
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PMID:Expression of apoptosis-related proteins in mammary gland of goat. 1132 13

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mammary gland carcinogen in cooked meat. Using the HC11 mouse mammary epithelial cell line, a well-characterized model for hormone-mediated differentiation, we examined whether PhIP altered the expression of genes regulated by lactogenic hormones dexamethasone, insulin, and prolactin (DIP). When HC11-Lux cells (stably transfected with a beta-casein promoter luciferase construct) were cultured in DIP-containing medium, PhIP (100 microM) enhanced luciferase activity 11-fold over that observed in DIP medium alone. The effect of PhIP on augmenting luciferase activity was observed only when lactogenic hormones were included in the medium. Expression of the endogenous beta-casein gene was also higher in HC11 cells treated with PhIP in hormone-enriched medium. With the increased expression of beta-casein gene, the level of phospho-signal transducer and activator of transcription 5A (phospho-STAT5A), the transcription factor regulating beta-casein gene expression, was elevated in PhIP-exposed HC11 cells. AG490, a Janus kinase 2 (JAK2)-specific inhibitor, blocked the effect of PhIP on beta-casein gene expression. PhIP-treated cells also showed higher expression of Bcl-2 and lower expression of Bax, consistent with a possible antiapoptotic action of PhIP. The findings indicate that PhIP modulates lactogenic hormone-mediated gene expression in mammary epithelial cells, apparently via enhanced phosphorylation of STAT5A. The findings have implications for a novel mechanism of action of the mammary gland carcinogen PhIP.
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PMID:2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) modulates lactogenic hormone-mediated differentiation and gene expression in HC11 mouse mammary epithelial cells. 1175 60

Epithelial cells within the mammary gland undergo apoptosis during weaning. To determine the expression of Bok mRNA (a member of the pro-apoptotic Bcl-2 family) in the mammary gland and its regulation, we examined the expression of the Bok transcript in the mouse mammary gland and HC11 mammary epithelial cells in culture through RT-PCR. The Bok mRNA expression was found in the mammary gland. The expression of the Bok mRNA level was induced through serum starvation and overexpression of Bok induced apoptosis in HC11 cells in culture. These results indicate that the expression of Bok mRNA in the mammary gland is regulated through serum starvation. It also may be related to the mammary involution.
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PMID:The expression of Bok is regulated by serum in HC11 mammary epithelial cells. 1180 37

We cloned mouse ING1 homologue (mINGh), an A1/Bfl-1-interacting protein, from mouse mammary glands using a yeast two-hybrid assay and unexpectedly found four splicing variants of mINGh by reverse transcription-PCR assay and sequence analysis. The alternative splicing variants were mINGh-S, mINGh-M, mINGh-L, and mINGh-L2 encoding 171, 248, 166, and 227 amino acids, respectively. Cell death of HC11 cells, induced by serum starvation, was enhanced by mINGhs, and the action of mINGhs was inhibited by A1 protein. These results indicate that A1 can inhibit cell death not only via the well known pathway related to the Bcl-2 family but also through direct interaction with mINGh in mammary epithelial cells.
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PMID:Mouse ING1 homologue, a protein interacting with A1, enhances cell death and is inhibited by A1 in mammary epithelial cells. 1188 90

The effect of prolactin on apoptosis and the expression of bcl-2 and bax in HC11 mouse mammary epithelial cells were investigated. Flow cytometric analysis of Bcl-2 level (FITC-conjugated monoclonal anti-Bcl-2 antibody and FITC-conjugated monoclonal anti-IgG1 antibody as a negative control), number of apoptotic cells and cell cycle phases (DNA stained with DAPI) was performed. Bax transcript was measured using the RT-PCR method with GAPDH serving as a reference gene. Administration of prolactin (5 microg/ml) in the presence of insulin stimulated differentiation of mammary epithelial cells, which manifested in stopping cells at G0/G1 phase, cell swelling and increase of cell number with enhanced protein content. Moreover, prolactin highly significantly reduced the extent of apoptosis of HC11 cells during 48 h of incubation. Nevertheless, the apoptotic cell number rose with increased time length of cell culture, probably due to the resulting high cell density and EGF withdrawal from t he incubation medium. The antiapoptotic effect of prolactin was associated with up-regulation of bcl-2 expression, shown as an increase in cell numbers expressing this protooncogene and elevated Bcl-2 content in these cells. A negative relationship (r=-0.87, p< or =0.001) between the number of apoptotic cells and those expressing bcl-2 was also found. Prolactin administration lowered Bax transcript by 68.8% and 70.7% after 3 and 6h, respectively. In conclusion, the results presented indicate that stimulation of bcl-2 expression with simultaneous suppression of bax may be key events in the mechanism of antiapoptotic action of prolactin in HC11 mammary epithelial cells.
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PMID:Antiapoptotic action of prolactin is associated with up-regulation of Bcl-2 and down-regulation of Bax in HC11 mouse mammary epithelial cells. 1464 94

Ceramide is a lipid mediator in cell proliferation, differentiation, and apoptosis in many cell lines. However, the molecular mechanisms for ceramide have not been clarified in HC11 mouse mammary epithelial cells. Under phase contrast microscope, C2-ceramide-treated cells clearly showed morphological changes, which were characteristic features of apoptosis. Treatment with C2-ceramide at 10 microM specifically resulted in the death of 50% of the cells after 48 h as assessed by MTT assay. To further investigate which genes contribute to cell death in C2-ceramide-treated cells, we used the reverse transcription-polymerase chain reaction to assess mRNA levels for five genes in the Bcl-2 family and five genes in the caspases family. The steady-state mRNA levels of Bax, Bad and Bak were not significantly changed for 48 h of C2-ceramide treatment. The increases of mRNA levels of Bcl-2 and Bcl-w were observed for the first 3 h of C2-ceramide treatment and the last 24 h between 24 and 48 h. We also found that in HC11 cells, C2-ceramide increased mRNA levels of the caspases family from 6 to 24 h. These results suggest that in the HC11 cells, C2-ceramide promote cell death by mediating the induction of caspases and that HC11 mouse mammary epithelial cells paradoxically up-regulate the expression of Bcl-2 and Bcl-w to prevent C2-ceramide-mediated cell death.
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PMID:C2-ceramide as a cell death inducer in HC11 mouse mammary epithelial cells. 1473 27

Chemokines, in addition to their chemotactic properties, act upon resident cells within a tissue and mediate other cellular functions. In a previous study, we demonstrated that CCL2 protects cultured mouse neonatal cardiac myocytes from hypoxia-induced cell death. Leukocyte chemotaxis has been shown to contribute to ischemic injury. While the chemoattractant properties of CCL2 have been established, the protective effects of this chemokine suggest a novel role for CCL2 in myocardial ischemia/reperfusion injury. The present study examined the cellular signaling pathways that promote this protection. Treatment of cardiac myocyte cultures with CCL2 protected them from hypoxia-induced apoptosis. This protection was not mediated through the activation of G(alphai) signaling that mediates monocyte chemotaxis. Inhibition of the ERK1/2 signaling pathway abrogated CCL2 protection. Caspase 3 activation and JNK/SAPK phosphorylation were decreased in hypoxic myocytes co-treated with CCL2 as compared to hypoxia only-treated cultures. Expression of the Bcl-2 family proteins, Bcl-xL and Bag-1, was increased in CCL2-treated myocytes subjected to hypoxia. There was also downregulation of Bax protein levels as a result of CCL2 co-treatment. These data suggest that CCL2 cytoprotection and chemotaxis may occur through distinct signaling mechanisms.
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PMID:MCP-1/CCL2 protects cardiac myocytes from hypoxia-induced apoptosis by a G(alphai)-independent pathway. 1610 24


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