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 mechanisms responsible for the emergence of clinically advanced prostate cancer (PC) are incompletely understood. Recent studies suggest that altered tumoral apoptosis with disordered cell proliferation sustains advanced disease and may account for the phenomena of anti-androgen therapeutic resistance. Previous inquiry has focused primarily on faulty intracellular mechanisms with limited scrutiny of the extracellular matrix including fibronectin and collagen type 4. We evaluated cell proliferation with Ki-67 immunoassay/image analysis and apoptosis by TUNEL staining and Bcl-2 immunoassay/image analysis in LNCaP and PC-3 human PC cell lines at baseline and following propagation on fibronectin and collagen type 4-coated coverslip substrate. Cell cultures showed differing proliferative and apoptosis characteristics at baseline, with the LNCaP cell line showing relatively higher proliferation and apoptosis rates than the PC-3 cell line. Cell proliferation and apoptosis were statistically significantly decreased in both cell lines following propagation on fibronectin. Bcl-2 expression was significantly increased among both cell lines following propagation on fibronectin. In contrast, cell proliferation, apoptosis, and Bcl-2 expression showed insignificant changes in both cell lines following uncoated coverslip and collagen type 4 matrix propagation. Our findings showed that fibronectin influences cell proliferation, apoptosis, and Bcl-2 expression similarly among LNCaP and PC-3 PC cell lines. It is likely that the altered rates are independent of the androgen status of the cell line and are mediated through a nonhormonal mechanism.
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PMID:Fibronectin influences cellular proliferation and apoptosis similarly in LNCaP and PC-3 prostate cancer cell lines. 1086 57

We have identified conditions for forming cultured human umbilical vein endothelial cells (HUVEC) into tubes within a three-dimensional gel that on implantation into immunoincompetent mice undergo remodeling into complex microvessels lined by human endothelium. HUVEC suspended in mixed collagen/fibronectin gels organize into cords with early lumena by 24 h and then apoptose. Twenty-hour constructs, s.c. implanted in immunodeficient mice, display HUVEC-lined thin-walled microvessels within the gel 31 days after implantation. Retroviral-mediated overexpression of a caspase-resistant Bcl-2 protein delays HUVEC apoptosis in vitro for over 7 days. Bcl-2-transduced HUVEC produce an increased density of HUVEC-lined perfused microvessels in vivo compared with untransduced or control-transduced HUVEC. Remarkably, Bcl-2- but not control-transduced HUVEC recruit an ingrowth of perivascular smooth-muscle alpha-actin-expressing mouse cells at 31 days, which organize by 60 days into HUVEC-lined multilayered structures resembling true microvessels. This system provides an in vivo model for dissecting mechanisms of microvascular remodeling by using genetically modified endothelium. Incorporation of such human endothelial-lined microvessels into engineered synthetic skin may improve graft viability, especially in recipients with impaired angiogenesis.
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PMID:In vivo formation of complex microvessels lined by human endothelial cells in an immunodeficient mouse. 1093 61

Primary biliary cirrhosis is characterized by the immune-mediated, progressive destruction of interlobular bile ducts. Lymphoid cells migrate into the biliary epithelial layer through integrin alpha(4)/fibronectin interaction and are responsible for chronic destructive cholangitis. The bile ducts express intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1), and infiltrating lymphocytes express LFA1 and VLA4, facilitating their interaction. Epithelioid granulomas contain foamy cells ingesting biliary lipids, and CD1d was detectable in epithelioid granulomas, suggesting that the biliary substance(s) which are leaked is a trigger for chronic destructive cholangitis. Apoptotic biliary destruction is brought about by antigen-specific and non-specific reactions. Shrunken biliary epithelial cells with pyknotic nuclei positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) may reflect apoptotic processes. Increased expression of caspase-3 and -8 with DNA fragmentation factor on the bile ducts may reflect molecular events during apoptosis, and down-regulation of Bcl-2 of biliary epithelial cells seems to facilitate apoptosis. Multiple factors, particularly the Fas system, are stimuli of apoptosis. Anoikis with decreased biliary expression of integrin 6, a ligand for laminin, may also be involved in biliary epithelial apoptosis.
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PMID:Destruction of bile ducts in primary biliary cirrhosis. 1097 14

Erythroid progenitor cells (EPCs) are deficient in mice lacking either the ligand stem cell factor (SCF), its receptor c-Kit, or beta(1)-integrins. In nonhematopoietic cells, integrins and receptor tyrosine kinases can collaborate to modulate cellular functions, providing evidence for cross-talk between signals emerging from these cell surface molecules. Using specific recombinant fibronectin peptides that contain the binding site for the integrin alpha(4)beta(1) (FN-H296) or alpha(5)beta(1) (FN-CH271) or both alpha(4)beta(1) and alpha(5)beta(1) (FN-CH296), this study investigated the effect of adhesion alone, or in combination with activation of c-Kit, on functional and biochemical outcomes in an EPC line, G1E-ER2, and primary EPCs. G1E-ER2 cells and primary EPCs cultured on FN-CH271 in the presence of c-Kit activation led to a significant increase in proliferation in comparison with cells grown on FN-H296 or FN-CH296. G1E-ER2 cells cultured on FN-H296 or FN-CH296 resulted in significant cell death in comparison to cells grown on FN-CH271. Activation of c-Kit enhanced the survival of G1E-ER2 cells grown on FN-H296 or FN-CH296; however, the rescue was only partial. The reduced survival of G1E-ER2 cells on FN-H296 correlated with reduced activation of Akt and expression of Bcl-2 and Bcl-x(L), whereas increase in proliferation on FN-CH271 correlated with significantly enhanced and sustained activation of focal adhesion kinase (FAK) and extracellular-regulated kinase (ERK) pathways. These data demonstrate that adhesion-induced signals emanating from ligation of alpha(4)beta(1) and alpha(5)beta(1) result in distinct biologic outcomes, including death via alpha(4)beta(1) and survival/proliferation via alpha(5)beta(1). (Blood. 2001;97:1975-1981)
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PMID:Cross-talk between alpha(4)beta(1)/alpha(5)beta(1) and c-Kit results in opposing effect on growth and survival of hematopoietic cells via the activation of focal adhesion kinase, mitogen-activated protein kinase, and Akt signaling pathways. 1126 61

Integrin-mediated cell adhesion is necessary for the survival of many cell types, and loss of adhesion causes apoptosis. We have previously shown that the alpha5beta1 integrin supports cell survival on fibronectin and increases Bcl-2 protein expression. Here we show that bcl-2 transcription is elevated in cells that attach to fibronectin through alpha(v)beta1 or to vitronectin through alpha(v)beta3 but is not elevated in cells attaching through the alpha(v)beta1 integrin. Bcl-2 protein expression and protection from apoptosis under serum-free conditions correlated with bcl-2 transcription. This integrin-mediated regulation of bcl-2 is Shc- and FAK-dependent, and activation of Ras by FAK is required. Furthermore, Ras mediates this up-regulation of bcl-2 by activating the phosphatidylinositol 3-kinase-AKT pathway. Mitogen-activated protein kinase did not appear to be necessary for the activation of bcl-2 transcription. Therefore, our work characterizes the pathway that mediates the effect of integrins on bcl-2 transcription and cell survival.
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PMID:A signaling pathway from the alpha5beta1 and alpha(v)beta3 integrins that elevates bcl-2 transcription. 1133 70

We describe two pathways by which the vesicating agent sulfur mustard (HD) may cause basal cell death and detachment: induction of terminal differentiation and apoptosis. Following treatment of normal human epidermal keratinocytes (NHEK) with 10 or 100 microM HD, the differentiation-specific keratin pair K1/K10 was induced and the cornified envelope precursor protein, involucrin, was cross-linked by epidermal transglutaminase. Fibronectin levels were reduced in a time- and dose-dependent manner. The rapid increase in p53 and decrease in Bcl-2 levels was consistent not only with epidermal differentiation but with apoptosis as well. Further examination of biochemical markers of apoptosis following treatment of either NHEK or human papillomavirus (HPV)-immortalized keratinocytes revealed a burst of poly(ADP-ribose) synthesis, specific cleavage of poly(ADP-ribose)polymerase (PARP) in vivo and in vitro into characteristic 89 and 24 kDa fragments, processing of caspase-3 into its active form and the formation of DNA ladders. The intracellular calcium chelator BAPTA suppressed the differentiation markers, whereas antisense oligonucleotides and chemical inhibitors specific for calmodulin blocked both markers of differentiation and apoptosis. Modulation of p53 levels utilizing retroviral constructs expressing the E6, E7 or E6 + E7 genes of HPV-16 revealed that HD-induced apoptosis was partially p53-dependent. Finally, immortalized fibroblasts derived from PARP -/- 'knockout mice' were exquisitely sensitive to HD-induced apoptosis. These cells became HD resistant when wild-type PARP was stably expressed in these cells. These results indicate that HD exerts its effects via calmodulin, 3 and PARP-sensitive pathways.
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PMID:Calmodulin, poly(ADP-ribose)polymerase and p53 are targets for modulating the effects of sulfur mustard. 1142 42

Quercetin has been known to have anti-tumor and anti-oxidation activities. In the present study, we have investigated its in vitro anti-metastatic activity. Quercetin inhibited the invasion and mobility of murine melanoma B16-BL6 cells in a dose-dependent manner but did not affect their adhesion to either laminin, fibronectin, or type VI collagen. Moreover, quercetin significantly inhibited the proliferation of B16-BL6 cells only in the case of time incubation longer than 48 h. Quercetin dose-dependently decreased the cell rates in S and G2-M phases of cell cycle. The effect of quercetin to cause a remarkable apoptosis of B16-BL6 cells was also demonstrated by flow cytometric assay as well as DNA fragmentation with a typical 180-bp ladder band in agarose electrophoresis and a quantitative analysis. Furthermore, quercetin markedly inhibited the expression of anti-apoptotic protein Bcl-2 but hardly influenced Bcl-XL. These results suggest that the inhibition of quercetin on invasiveness and migration of B16-BL6 cells are closely associated with the arrest of cell cycle as well as the induction of apoptosis by decreasing the Bcl-2 expression.
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PMID:Quercetin inhibits the invasion and mobility of murine melanoma B16-BL6 cells through inducing apoptosis via decreasing Bcl-2 expression. 1146 74

The phenotype of Bcr-Abl-transformed cells is characterized by a growth factor-independent survival and a reduced susceptibility to apoptosis. Furthermore, Bcr-Abl kinase alters adhesion features by phosphorylating cytoskeletal and/or signaling proteins important for integrin function. Integrin-mediated adhesion to extracellular matrix molecules is critical for the regulation of growth and apoptosis. However, effects of integrin signaling on regulation of apoptosis in cells expressing Bcr-Abl are largely unknown. The influence of adhesion on survival and apoptosis in Bcr-Abl+ and Bcr-Abl- BaF3 cells was investigated. p185bcr-abl-transfected BaF3 cells preadhered to immobilized fibronectin had a significant survival advantage and reduced susceptibility to apoptosis following gamma-irradiation when compared with the same cells grown on laminin, on polylysin, or in suspension. Both inhibition of Bcr-Abl kinase by STI571 and inhibition of specific adhesion reversed the fibronectin-mediated antiapoptotic effect in BaF3p185. The DNA damage response of Bcr-Abl- BaF3 cells was not affected by adhesion to fibronectin. In contrast to parental BaF3 cells, BaF3p185 adherent to fibronectin did not release cytochrome c to the cytosol following irradiation. The fibronectin-mediated antiapoptotic mechanism in Bcr-Abl-active cells was not mediated by overexpression of Bcl-XL or Bcl-2 but required an active phosphatidylinositol 3-kinase (PI-3K). Kinase-active Bcr-Abl in combination with fibronectin-induced integrin signaling led to a hyperphosphorylation of AKT. Thus, cooperative activation of PI-3K/AKT by Bcr-Abl and integrins causes synergistic protection of Bcr-Abl+ cells from DNA damage-induced apoptosis.
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PMID:Adhesion to fibronectin selectively protects Bcr-Abl+ cells from DNA damage-induced apoptosis. 1152 Aug 4

B-cell chronic lymphocytic leukemia is characterized by the accumulation of malignant B lymphocytes as a result of abnormal survival signals operating in vivo. Previously, we showed that adhesion of B-CLL cells to the fibronectin fragment H89, a ligand for alpha4beta1 integrin, prevents their spontaneous apoptosis in vitro. We have now studied whether alpha4beta1/H89 interaction affected the response of B-CLL cells to the therapeutic drug fludarabine. B-CLL cells cultured on H89 during treatment with fludarabine showed significantly higher mean viability (P<0.05) than cells cultured on the control polylysine for all doses of drug tested. Similar results were obtained with the EHEB cell line. Analysis of the expression of Bcl-2-family proteins after 48 h of fludarabine treatment revealed that Bcl-xL levels were significantly higher (P<0.05) for cells cultured on H89 than on polylysine and correlated (r=0.56, P<0.05) with the increased cell viability observed on H89 cultures. These results indicate that Bcl-xL is involved in the survival signals induced by alpha4beta1 ligation and may contribute to the progressive drug resistance observed in B-CLL.
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PMID:Engagement of alpha4beta1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine. 1186 87

We have studied the relevance of H-Ras and its downstream effectors to osteoblast functions. 1) Purified human osteoblasts highly expressed integrins beta1, alpha4, alpha5, alpha6 and the activation epitope of beta1. However, these molecules were markedly down-regulated on osteoblasts transfected with expression vector encoding fully activated H-Ras(V12), H-Ras(V12)T35S, activating Raf-1/mitogen-activated protein kinase (MAPK), or an active Raf-1 but not on cells having H-Ras(V12)Y40C, a phosphoinositide 3-kinase (PI3K)-binding mutant. 2) Although osteoblasts spontaneously adhered to fibronectin and laminin in beta1-dependent manner, the expression of H-Ras(V12) or H-Ras(V12)T35S, but not H-Ras(V12)Y40C, in osteoblasts reduced their adhesion. 3) Osteoblasts bearing H-Ras(V12), H-Ras(V12)T35S, or Raf-1 failed to proliferate, whereas those with H-Ras(V12)Y40C proliferated well. (4) The up-regulation of Fas and down-regulation of Bcl-2 were observed in osteoblasts expressing H-Ras(V12), H-Ras(V12)T35S, or Raf-1. (5) Most of the cells having H-Ras(V12), H-Ras(V12)T35S, or Raf-1 became annexin-V(high)/propidium iodide (PI)(high or low) and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL)(high)/PI(low) after 24 and 72 h incubation, respectively. Thus, we propose that H-Ras signals followed by Raf-1/MAPK pathway but not PI3K not only reduces beta(1)-mediated adhesion of osteoblasts to matrix proteins but induces apoptosis presumably via the Fas up-regulation and Bcl-2 down-regulation.
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PMID:H-Ras/mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts. 1193


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