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)

In the previous study, we have shown that propentofylline (PPF) could induce the cellular differentiation and apoptosis-related growth regression in the human glioma cell lines. Its biological functions were partly due to the increasing endogeneous NGF and its high affinity receptor, trk A productions. Although little has been known about the precise machinary regulating the propentofylline induced apoptosis. Recently, we have found that propentofylline could modulate some apoptosis related genes products in the glioma cell lines, i.e. NGF, trk A mRNA levels and Fas protein expressions were increased, whereas bcl-2 mRNA level was decreased. In the present study, we examined the apoptotic signal cascade, especially focusing on the expressing pattern of Bcl-2/Bax gene products. In the normal human astrocyte cells, Bax-beta was markedly expressed, whereas Bcl-2 and Bax-alpha proteins and mRNA were weakly or even nondetectable. Accordingly, Bax beta might be a dominant variant in the normal glial cells, which could have the appropriate balance of proapoptotic (Bax beta) and anti-apoptotic proteins (Bcl-2). In the glioma cells, we showed the over-expressions of Bcl-2 and Bax alpha compared with the normal counterparts. According to Bax dominant theory, Bax, not Bcl-2 may have a major role in regulating apoptosis by means of homodimerization. In might be implied that in the glioma cells, excessive expressions of Bcl-2 and Bax alpha would favor the formation of the Bax alpha/Bax beta heterodimer or the Bax beta/Bcl-2 heterodimer rather than the Bax beta/Bax beta homodimer, which might be presumed to be functional proteins. And finally the increasing relative ratio of Bax alpha/ Bax beta or Bax beta/Bcl-2 to Bax beta/Bax beta could allow the tumor cells to survive. Thus over-expression of the bcl-2 and bax alpha gene renders the glioma cells resistant to apoptosis. In the present study, PPF could promote Bax beta over-expression and Bcl-2 retardative expression in the glioma cells, whereas had no effect on Bax alpha expression. Therefore, PPF might promote apoptotic cell death through the mechanism that restore the glioma cells to the appropriate balance of proapoptotic and anti-apoptotic proteins like as normal astrocytes. Our results indicated that propentofylline might have a potential role as apoptotic modulators in the human glioma cell lines, not only its protective activities against neuronal ischemic damages.
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PMID:[Neural protective agents, propentofylline (PPF) could induce apoptotic cell death in the human glioma cells: analysis of Bcl-2 and Bax alpha/Bax beta expressions]. 959 22

Propentofylline (PPF) is a xanthine derivative and it has been reported that PPF stimulated the synthesis/secretion of nerve growth factor (NGF) by cultured astroglial cells. We have reported that PPF induced apoptosis in human glioma cells and as its mechanism, up-regulation of NGF, Fas, Bax beta and down-regulation of Bcl-2 were assumed. Recent studies demonstrated the presence of apoptosis induced via NGF/p75NTR in developmental neuron, oligodendroglia. In the present study, to examine whether signal cascade via NGF/p75NTR participates the apoptosis in human glioma cells treated with PPF, we investigated the immunohistochemical study using anti-mouse monoclonal antibody, immunoprecipitation and northern blot analysis for p75NTR, NF-kappa B in human glioma cells (U251MG, T98G, U87) treated with PPF. We observed the up-regulation of p75NTR, translocation of NF-kappa B to the nucleus after treatment with PPF in these cell lines. According to above results, it is assumed that apoptosis in human glioma cells treated with PPF was induced via NGF/p75NTR.
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PMID:[Induction of apoptosis through NGF/p75NTR in human glioma cells treated with propentofylline]. 962 61

Susceptibility of a tumor cell to undergo chemotherapy-induced apoptosis appears to be dependent upon the balance of proapoptotic and survival factors that are expressed within any given cell. We have chosen to evaluate how expression of several of these proteins influences chemosensitivity of a panel of 10 pediatric tumor cell lines chosen from three tumor histiotypes: neuroblastoma, rhabdomyosarcoma, and pediatric glial tumors. The proteins evaluated were p53 and six members of the Bax/Bcl-2 family: three proapoptotic proteins (Bax, Bak, and Bcl-xS) and three survival factors (Bcl-2, Bcl-xL, and Mcl-1). We investigated whether there was any relationship between endogenous expression of these proteins and chemosensitivity (or resistance) to three chemotherapeutic agents that directly damage DNA (doxorubicin, actinomycin D, and topotecan) and a mitotic spindle poison (vincristine). Even though exogenous overexpression of wild-type p53 has been associated with a chemosensitive phenotype in several model systems we demonstrated no such relationship in these studies. In addition, expression levels of Bcl-2, Bcl-xL, Bcl-xS, Bak, or Mcl-1 did not correlate with sensitivity or resistance to the four drugs. However, there was a statistically significant correlation between endogenous levels of Bax protein and sensitivity to both doxorubicin and actinomycin D. We conclude that even though many proteins such as p53 and Bcl-2 have been shown to influence drug response when exogenously overexpressed in model systems, in unmodified cell lines endogenous protein levels may not generate the same results. We have demonstrated that endogenous Bax expression was the only protein found to be associated with chemosensitivity across the three different tumor histiotypes and propose that analysis of Bax may be a more useful prognostic indicator for tumor response to therapy than either p53 or Bcl-2.
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PMID:Bax is an important determinant of chemosensitivity in pediatric tumor cell lines independent of Bcl-2 expression and p53 status. 980 58

The proteasome inhibitors lactacystin and AcLLNal induced p53-independent apoptosis in two human glioma cell lines, and the apoptosis was accompanied by up-regulation of immunoreactive wild-type p53, p21Waf1, Mdm2, and p27Kip1. Pretreatment with cycloheximide decreased the induction of cell death independently of p53 protein status, suggesting that the up-regulation of short-lived proteins is associated with proteasome inhibitor-induced apoptosis. Caspase-3-like proteases were activated in the proteasome inhibitor-mediated apoptosis, and the induction of cell death was inhibited more effectively in the presence of z-VAD.fmk than in the presence of Ac-DEVD.fmk, suggesting that caspases other than caspase-3 are involved. Nonetheless, there were no significant alterations in levels of immunoreactive Bcl-2, Bcl-X(L), Bax, Bad, and Bak, nor any evidence of cytochrome c release into cytosol and dissipation of delta(psi)m. Thus, the proteasome inhibitor-induced apoptosis is mediated by a mitochondria-independent mechanism, and the once activated caspase-3 does not cause the cytochrome c release and the delta(psi)m disruption.
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PMID:Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells. 998 1

The effectiveness of chemotherapy for human cancers is limited by pharmacokinetic parameters such as variation in metabolism and is determined by the cellular response. In this work, we aimed to gain a more holistic understanding of the molecular basis of glioma response to the DNA-alkylating agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by using a systematic approach: we investigated the expression of 588 genes with various cellular functions in a BCNU-resistant glioblastoma cell line and a BCNU-sensitive subline before and after treatment with BCNU. Our gene expression profiling revealed major differences in gene expression between these two cell lines, especially after treatment with BCNU. One striking example was that BCNU decreased the expression of six DNA-repair genes in sensitive but not in resistant cells. In sensitive cells, BCNU treatment resulted in the induction of two MAP kinase genes; this finding suggests that the specific response to BCNU in sensitive cells may involve the Jun kinase signal transduction pathway. After BCNU treatment, marked induction of tumor necrosis factor was detected only in sensitive cells, suggesting that tumor necrosis factor is a mediator of BCNU-induced cell death. Bcl-2 family members were not altered by BCNU in sensitive cells, suggesting that BCNU-induced cell death may be independent of the bcl-2 pathway. Results of the present study demonstrate that gene expression profiling may facilitate identification of cellular pathways associated with specific responses to chemotherapeutic agents and contribute to an understanding of the molecular basis of drug action.
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PMID:Characterization of cellular pathways involved in glioblastoma response to the chemotherapeutic agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by gene expression profiling. 1002 10

Apoptosis was induced in human glioma cell lines by exposure to 100 nM calphostin C, a specific inhibitor of protein kinase C. Calphostin C-induced apoptosis was associated with synchronous down-regulation of Bcl-2 and Bcl-xL as well as activation of caspase-3 but not caspase-1. The exposure to calphostin C led to activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) and p38 kinase and concurrent inhibition of extracellular signal-regulated kinase (ERK). Upstream of ERK, Shc was shown to be activated, but its downstream Raf1 and ERK were inhibited. The pretreatment with acetyl-Tyr-Val-Ala-Asp-aldehyde, a relatively selective inhibitor of caspase-3, or benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.fmk), a broad spectrum caspase inhibitor, similarly inhibited calphostin C-induced activation of SAPK/JNK and p38 kinase as well as apoptotic nuclear damages (chromatin condensation and DNA fragmentation) and cell shrinkage, suggesting that caspase-3 functions upstream of SAPK/JNK and p38 kinase, but did not block calphostin C-induced surface blebbing and cell death. On the other hand, the inhibition of SAPK/JNK by transfection of dominant negative SAPK/JNK and that of p38 kinase by SB203580 induced similar effects on the calphostin C-induced apoptotic phenotypes and cell death as did z-VAD.fmk and acetyl-Tyr-Val-Ala-Asp-aldehyde, but the calphostin C-induced PARP cleavage was not changed, suggesting that SAPK/JNK and p38 kinase are involved in the DNA fragmentation pathway downstream of caspase-3. The present findings suggest, therefore, that the activation of SAPK/JNK and p38 kinase is dispensable for calphostin C-mediated and z-VAD.fmk-resistant cell death.
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PMID:Activation of stress-activated protein kinase/c-Jun NH2-terminal kinase and p38 kinase in calphostin C-induced apoptosis requires caspase-3-like proteases but is dispensable for cell death. 1002 38

Gap junctions are conductive channels that connect the interiors of coupled cells. We determined whether gap junctions propagate transcellular signals during metabolic stress and whether such signaling exacerbates cell injury. Although overexpression of the human proto-oncogene bcl2 in C6 glioma cells normally increased their resistance to injury, the relative resistance of bcl2+ cells to calcium overload, oxidative stress and metabolic inhibition was compromised when they formed gap junctions with more vulnerable cells. The likelihood of death was in direct proportion to the number and density of gap junctions with their less resistant neighbors. Thus, dying glia killed neighboring cells that would otherwise have escaped injury. This process of glial 'fratricide' may provide a basis for the secondary propagation of brain injury in cerebral ischemia.
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PMID:Gap-junction-mediated propagation and amplification of cell injury. 1019 36

To prevent neoplasia, cells of multicellular organisms activate cellular disposal programs such as apoptosis in response to deregulated oncogene expression, making the suppression of such programs an essential step for potentially neoplastic cells to become established as clinically relevant tumors. Since the mutation of ras proto-oncogenes, the most frequently mutated proto-oncogenes in human tumors, is very rare in some tumor types such as glioblastomas and gastric cancers, we hypothesized that mutated ras genes might activate a cell death program that cannot be overcome by these tumor types. Here we show that the expression of oncogenically mutated ras gene induces cellular degeneration accompanied by cytoplasmic vacuoles in human glioma and gastric cancer cell lines. Cells dying as a result of oncogenic Ras expression had relatively well-preserved nuclei that were negative for TUNEL staining. An immunocytochemical analysis demonstrated that the cytoplasmic vacuoles are derived mainly from lysosomes. This oncogenic Ras-induced cell death occurred in the absence of caspase activation, and was not inhibited by the overexpression of anti-apoptotic Bcl-2 protein. These observations suggested that oncogenic Ras-induced cell death is most consistent with a type of programmed cell death designated 'type 2 physiological cell death' or 'autophagic degeneration', and that this cell death is regulated by a molecular mechanism distinct from that of apoptosis. Our findings suggest a possible role for this non-apoptotic cell death in the prevention of neoplasia, and the activation of the non-apoptotic cell death program may become a potential cancer therapy complementing apoptosis-based therapies. In addition, the approach used in this study may be a valuable way to find genetically-regulated cell suicide programs that cannot be overcome by particular tumor types.
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PMID:Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells. 1032 74

In order to determine the mechanism of tumour destruction by tumour-infiltrating lymphocytes (TIL), we examined the ability of both CD4+ and CD8+ effector TIL, and TIL clones, to manifest granzyme-mediated and Fas-mediated destruction of tumour targets. In many in vitro studies TIL have been shown to manifest anti-tumour reactivity, yet many tumours escape immunological destruction. To investigate the role of Fas expression and the concomitant sensitivity to the inducibility of apoptotic death, we derived TIL from four melanomas and one glioma. The glioma, and all but one of the melanomas, expressed Fas, but Fas-mediated apoptosis could only be detected if the targets were treated with cyclohexamide. The melanomas and the glioma all expressed detectable cytoplasmic Bcl-2 protein, known to exert anti-apoptotic activity. Lysis of tumours by CD8-enriched cultures and CD8+ clones was Ca2+-dependent and could not be modified by an anti-Fas MoAb. In CD4-enriched cultures or CD4+ clones with cytotoxic potential against tumour cells, cytotoxicity was also Ca2+-dependent. As Ca2+-dependent cytotoxicity is usually the result of secretion of perforin/granzyme-B, we investigated the presence of perforin in cytotoxic CD4+ clones and demonstrated the presence of granular deposits of this enzyme in some of the CD4+ clones. Although an anti-Fas MoAb did not block the lysis of melanoma targets by CD4+ clones, the examination of Fas-dependent targets demonstrated that these clones also had the potential to kill by the Fas/Fas ligand system. These data suggest that the predominant mechanism in tumour killing by TIL appears to be perforin-granzyme-dependent, and that the solid tumour cell lines we studied are less susceptible to Fas-mediated apoptosis. As non-apoptotic pathways may enhance tumour immunogenicity, exploitation of the perforin-granzyme-dependent cytotoxic T lymphocyte (CTL) pathways may be important for achieving successful anti-tumour responses.
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PMID:Studies of the mechanism of cytolysis by tumour-infiltrating lymphocytes. 1036 Dec 24

Bcl-2 and bcl-xL are proteins known to inhibit cell death (apoptosis). Expression of these proteins in gangliogliomas has not been extensively examined. This study retrospectively evaluates bcl-2 and bcl-x immunostaining in paraffin-embedded materials in gangliogliomas. Twenty-nine gangliogliomas in 17 males and 12 females, age 2.5 to 47 years (mean, 20.7 years), were studied. Nineteen tumors were situated primarily in the temporal lobe. All but three patients presented with seizures ranging from 3 months to 28 years' duration (mean, 11.1 years) before surgery. All tumors histologically were comprised of an atypical neuronal component and a glioma component, which most frequently resembled a low-grade astrocytoma. Cortical dysplasia was observed adjacent to eight tumors. MIB-1 (marker of cell proliferation) labeling indices (percentage of positively staining tumor cell nuclei) ranged from 0 to 7.7 (mean, 0.8). bcl-2 staining was observed in 25 tumors (86%); neuronal staining was present in 24 cases (83%), and glial cell staining in 21 tumors (72%). Bcl-xL staining was only observed in eight gangliogliomas (28%); in all eight tumors (28%), neuronal staining was seen, and focal glial cell staining was present in two cases (7%). Four tumors (14%) did not stain with either bcl-2 or bcl-xL. There appeared to be no relationship between MIB-1 immunostaining and staining with bcl-2 or bcl-xL. bcl-2 expression by immunohistochemistry was observed more frequently than bcl-xL in gangliogliomas. Expression of these proteins may reflect abnormalities of apoptosis, which could play a role in the survival of cells that may be involved in the development of gangliogliomas.
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PMID:Bcl-2 and Bcl-X expression in gangliogliomas. 1037 80


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