UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin K2 is used for the treatment of osteoporosis, but the precise mode of action is still not clear. We investigated the effects of vitamin K2 on apoptosis of human osteoblasts. Human osteoblastic cell line MG63 cells and human primary osteoblast-like cells obtained from bone fragments in corrective surgery were used as human osteoblasts. Cells were cultured with or without various concentrations of vitamin K2 and tumor necrosis factor-alpha (TNF-alpha). We then determined the proliferative response, expression of Fas and Bcl-2-related proteins, and Fas-mediated apoptosis of these cells induced by anti-Fas immunoglobulin M (IgM). In addition, the effect of vitamin K2 in osteoblast apoptosis induced by Z-Leu-Leu-Leu-aldehyde (LLL-CHO), etoposide, or staurosporine was also examined. Human osteoblasts did not show spontaneous apoptosis in culture, even in the presence of vitamin K2 or TNF-alpha. Furthermore, proliferation of the cells was not influenced by vitamin K2 or TNF-alpha. Fas was functionally expressed on human osteoblasts, and the treatment with TNF-alpha significantly enhanced both Fas expression and Fas-mediated apoptosis of osteoblasts. The addition of vitamin K2 to the culture resulted in a dose-dependent inhibition of functional Fas expression on osteoblasts, in the presence or absence of TNF-alpha. Treatment of human osteoblasts with vitamin K2 clearly suppressed Bax expression of the cells, although the expression of Bcl-2 was not influenced by vitamin K2. Fas ligand (FasL) cDNA transformants were cytotoxic against osteoblasts, and the cytotoxicity was increased when osteoblasts were treated with TNF-alpha. The addition of vitamin K2 to osteoblasts significantly decreased the cytotoxic effects of FasL cDNA transformants. Furthermore, apoptosis of human osteoblasts induced by LLL-CHO, etoposide, or staurosporine was also clearly suppressed in vitamin K2-treated osteoblasts. Our results suggest that vitamin K2 inhibits apoptotic cell death of osteoblasts and maintains the number of osteoblasts. These actions may explain the therapeutic efficacy of vitamin K2 in osteoporosis.
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PMID:Effect of vitamin K2 on osteoblast apoptosis: vitamin K2 inhibits apoptotic cell death of human osteoblasts induced by Fas, proteasome inhibitor, etoposide, and staurosporine. 1098 96

LIGHT is a member of the tumor necrosis factor superfamily and is the ligand for LT-betaR, HVEM, and decoy receptor 3. LIGHT has a cytotoxic effect, which is further enhanced by the presence of interferon-gamma (IFN-gamma). Although LIGHT/IFN-gamma can activate caspase activity, neither benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone nor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone can completely inhibit LIGHT/IFN-gamma-mediated apoptosis. Moreover, overexpression of Bcl-2 further enhances LIGHT/IFN-gamma-mediated apoptosis. It appears that LIGHT and IFN-gamma act synergistically to activate caspase-3, with the resultant cleavage of Bcl-2, removal of the BH4 domain, leading to conversion of Bcl-2 from an antiapoptotic to a proapoptotic form in p53-deficient hepatocellular carcinoma Hep3BT2 cells. Thus, LIGHT seems to be able to override the protective effect of Bcl-2 and induce cell death. Although benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone can prevent the cleavage of Bcl-2 by LIGHT/IFN-gamma, they only partially inhibit apoptosis in Hep3BT2 cells that are overexpressing Bcl-2. In contrast, both LIGHT/IFN-gamma-mediated apoptosis and Bcl-2 cleavage are inhibited by free radical scavengers, indicating that free radicals may play an essential role in LIGHT/IFN-gamma-mediated apoptosis at a step upstream of caspase-3 activation. These results suggest that LIGHT signaling may diverge into multiple, separate processes.
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PMID:Overexpression of bcl-2 enhances LIGHT- and interferon-gamma -mediated apoptosis in Hep3BT2 cells. 1099 81

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
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PMID:Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. 1102 84

Seven pediatric rhabdomyosarcoma (RMS) cell lines were resistant to the induction of apoptosis via the Fas death receptor. In contrast, four of seven lines (RD, Rh1, Rh18, and Rh30) were highly sensitive to tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL). TRAIL induced apoptosis within 4 h and also reduced clonogenic survival, both reversible by caspase inhibitors. DR5 (but not DR4) was expressed at high level in all cell lines. Expression of the decoy receptors DcR1 and DcR2 did not correlate with TRAIL sensitivity. All RMS lines expressed the adapter molecule FADD, and six of seven expressed procaspase-8. Expression of the inhibitory proteins c-FLIPL and c-FLIPs was high in three TRAIL-sensitive (RD, Rh1, and Rh30) and two TRAIL-resistant (Rh28 and Rh41) lines. All RMS lines expressed Bid and procaspases-3, -6, -7, and -9. Procaspases-8 and -10 were highest in TRAIL-sensitive RMS (RD, Rh1, and Rh30), and procaspase-10 was not expressed in Rh18, Rh36, or Rh41. TRAIL induced loss of mitochondrial membrane potential in TRAIL-sensitive Rh1 but not in TRAIL-resistant Rh41 cells. There was no correlation between expression of members of the Bcl-2 family (Bcl-2, Bcl-xL, Bax, and Bak) and TRAIL sensitivity. TRAIL-sensitive Rh18 expressed procaspase-8 in the absence of procaspase-10 and c-FLIP, and procaspase-10 was not detected in TRAIL-resistant Rh41 in the presence of procaspase-8 and c-FLIP. Data suggest that caspase-8 may be sufficient to deliver the TRAIL-induced apoptotic signal in the absence of both caspase-10 and c-FLIP (Rh18) but not in the presence of c-FLIP (Rh41). In RD, Rh1, and Rh30, the presence of c-FLIP may require amplification of the apoptotic signal via caspase-10.
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PMID:Pediatric rhabdomyosarcoma cell lines are resistant to Fas-induced apoptosis and highly sensitive to TRAIL-induced apoptosis. 1105 Dec 65

To determine how hyaluronidase increases certain cancer cell sensitivity to tumor necrosis factor (TNF) cytotoxicity, we report here the isolation and characterization of a hyaluronidase-induced murine WW domain-containing oxidoreductase (WOX1). WOX1 is composed of two N-terminal WW domains, a nuclear localization sequence, and a C-terminal alcohol dehydrogenase (ADH) domain. WOX1 is mainly located in the mitochondria, and the mitochondrial targeting sequence was mapped within the ADH domain. Induction of mitochondrial permeability transition by TNF, staurosporine, and atractyloside resulted in WOX1 release from mitochondria and subsequent nuclear translocation. TNF-mediated WOX1 nuclear translocation occurred shortly after that of nuclear factor-kappaB nuclear translocation, whereas both were independent events. WOX1 enhanced TNF cytotoxicity in L929 cells via its WW and ADH domains as determined using stable cell transfectants. In parallel with this observation, WOX1 also enhanced TRADD (TNF receptor-associated death domain protein)-mediated cell death in transient expression experiments. Antisense expression of WOX1 raised TNF resistance in L929 cells. Enhancement of TNF cytotoxicity by WOX1 is due, in part, to its significant down-regulation of the apoptosis inhibitors Bcl-2 and Bcl-x(L) (>85%), but up-regulation of pro-apoptotic p53 ( approximately 200%) by the ADH domain. When overexpressed, the ADH domain mediated apoptosis, probably due to modulation of expression of these proteins. The WW domains failed to modulate the expression of these proteins, but sensitized COS-7 cells to TNF killing and mediated apoptosis in various cancer cells independently of caspases. Transient cotransfection of cells with both p53 and WOX1 induced apoptosis in a synergistic manner. WOX1 colocalizes with p53 in the cytosol and binds to the proline-rich region of p53 via its WW domains. Blocking of WOX1 expression by antisense mRNA abolished p53 apoptosis. Thus, WOX1 is a mitochondrial apoptogenic protein and an essential partner of p53 in cell death.
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PMID:Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity. 1105 90

Humoral factors produced by activated T cells are thought to be important in the development of bone loss in patients with rheumatoid arthritis (RA). We investigated the inhibitory effect of etidronate disodium (EHDP) on apoptosis of human osteoblasts induced by supernatants from in vitro activated T cell cultures. Human osteoblastic cell line MG63 cells and human primary osteoblast-like cells were used in the present study as human osteoblasts. T cells were incubated with interleukin-2 and further activated with 1 2-o-tetradecanoyl-phorbol 13-acetate and ionomycin, either in the presence or absence of EHDP. After we carried out the cultivation, we examined the cytotoxicity of cultured T cell supernatants toward MG63 cells and human primary osteoblast-like cells. Supernatants from activated but not resting T cell cultures efficiently induced apoptosis of MG63 cells and primary osteoblast-like cells. Supernatants from activated T cell cultures, incubated with EHDP, exhibited significantly less cytotoxicity than did supernatants incubated in the absence of EHDP. In contrast, the cytotoxicity of activated T cell culture supernatants was not affected by direct treatment of human osteoblasts with EHDP. The concentration of soluble Fas ligand in activated T cell culture supernatants was actually increased by EHDP. However, EHDP did not influence soluble Fas and tumor necrosis factor-alpha concentrations in the supernatant. Furthermore, treatment of human osteoblasts with EHDP did not alter their expression of Bcl-2/Bcl-xL or their sensitivity to anti-Fas immunoglobulin M-induced apoptosis. Our results suggest that EHDP inhibits the production of soluble factor that induces apoptosis of human osteoblasts and thus exhibits a protective action toward human osteoblast apoptosis induced by activated T cell culture supernatants. Although the exact EHDP-regulated molecule that induces apoptosis of human osteoblasts is unknown at present, our study may explain part of the therapeutic action of bisphosphonates in RA complicated by bone loss.
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PMID:Etidronate inhibits human osteoblast apoptosis by inhibition of pro-apoptotic factor(s) produced by activated T cells. 1107 61

The present study investigated the effects of flupirtine (Katadolon) on tumor necrosis factor (TNF)-alpha-mediated cell death and Bcl-2 expression in the permanent rat oligodendrocyte cell line OLN-93 (OLN cells). TNF-alpha (500 U/ml) induced apoptosis of OLN cells, which was confirmed by DNA fragmentation using an in situ end-labeling technique and ultrastructural analysis. Flupirtine significantly reduced the rate of spontaneous cell death of OLN cells already at low concentrations; TNF-alpha-mediated apoptosis was suppressed only with higher concentrations of flupirtine (100 microM:). Expression of Bcl-2 protein and mRNA in OLN cells was detected by immunocytochemistry, western blot, and RT-PCR. Quantitative analysis of western blots revealed an approximately 2. 5-fold up-regulation of Bcl-2 protein during TNF-alpha treatment. Furthermore, addition of 10 or 100 microM: flupirtine before incubation with TNF-alpha led to an approximately threefold increase of Bcl-2 expression. Exposure of OLN cells to flupirtine alone moderately augmented the expression of Bcl-2 protein. Our data demonstrate that flupirtine up-regulates the expression of Bcl-2 protein in OLN cells; this Bcl-2 induction is associated with a reduced rate of TNF-alpha-induced cell death.
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PMID:Association of increased bcl-2 expression with rescue from tumor necrosis factor-alpha-induced cell death in the oligodendrocyte cell line OLN-93. 1108 Jan 78

In present studies, treatment with tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL, also known as Apo-2 ligand [Apo-2L]) is shown to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following treatment of Jurkat cells with 0.25 microg/mL of Apo-2L (95.0% +/- 3.5% of apoptotic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53(wt) function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibitors of apoptosis proteins (IAP) family. Apo-2L-induced apoptosis was associated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo-2L-induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-x(L). Cotreatment with either a caspase-8 or a caspase-9 inhibitor suppressed Apo-2L-induced apoptosis. Treatment of human leukemic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, Fas, DcR1, DcR2, Fas ligand, or Apo-2L levels. Importantly, sequential treatment of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide, doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileukemic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L-induced apoptosis. (Blood. 2000;96:3900-3906)
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PMID:Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells. 1109 76

Apoptotic proteases cleave and inactivate survival signaling molecules such as Akt/PKB, phospholipase C (PLC)-gamma1, and Bcl-2. We have found that treatment of A431 cells with tumor necrosis factor-alpha in the presence of cycloheximide resulted in the cleavage of epidermal growth factor receptor (EGFR) as well as the activation of caspase-3. Among various caspases, caspase-1, caspase-3 and caspase-7 were most potent in the cleavage of EGFR in vitro. Proteolytic cleavage of EGFR was inhibited by both YVAD-cmk and DEVD-fmk in vitro. We also investigated the effect of caspase-dependent cleavage of EGFR upon the mediation of signals to downstream signaling molecules such as PLC-gamma1. Cleavage of EGFR by caspase-3 significantly impaired the tyrosine phosphorylation of PLC-gamma1 in vitro. Given these results, we suggest that apoptotic protease specifically cleaves and inactivates EGFR, which plays crucial roles in anti-apoptotic signaling, to abrogate the activation of EGFR-dependent downstream survival signaling molecules.
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PMID:Proteolytic cleavage of epidermal growth factor receptor by caspases. 1122 7

Transforming growth factor beta (TGF-beta) is a multifunctional cytokine capable of regulating diverse cellular processes. In this study we investigated the effect of autocrine TGF-beta signaling on tumor necrosis factor (TNF) alpha-induced cell death. We abrogated the TGF-beta autocrine loop by overexpression of a truncated TGF-beta type II receptor in MCF-7 breast carcinoma cells and found that this generated resistance to TNF-alpha-induced cytotoxicity. To elucidate the molecular basis of the influence of TGF-beta on TNF-alpha-induced cytotoxicity, we evaluated the expression levels or activities of proteins involved in TNF-alpha signal transduction or the regulation of apoptosis in general in TGF-beta-responsive and TGF-beta-nonresponsive MCF-7 cells. We observed no significant difference in the expression of TNF-alpha receptors or the TNF receptor-associated death domain protein. In addition, downstream activation of nuclear factor kappaB by TNF-alpha was not altered in cells that had lost TGF-beta responsiveness. Analysis of members of the Bcl-2 family of apoptosis-regulatory proteins revealed that Bcl-X(L) and Bax expression levels were not changed by disruption of TGF-beta signaling. In contrast, the TGF-beta-nonresponsive cells expressed much higher levels of Bcl-2 protein and mRNA than did cells with an intact TGF-beta autocrine loop. Furthermore, restoration of a TGF-beta signal to MCF-7 cells that had spontaneously acquired resistance to TGF-beta caused a reduction in Bcl-2 protein expression. Taken together, our data indicate that loss of autocrine TGF-beta signaling results in enhanced resistance to TNF-alpha-mediated cell death and that this is likely to be mediated by derepression of Bcl-2 expression.
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PMID:Inhibition of transforming growth factor beta signaling in MCF-7 cells results in resistance to tumor necrosis factor alpha: a role for Bcl-2. 1124 65

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