Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the cascade of proteolytic caspases has been identified as the final common pathway of apoptosis in diverse biological systems. We have isolated a gene, termed MRIT, that possesses overall sequence homology to FLICE (MACH), a large prodomain caspase that links the aggregated complex of the death domain receptors of the tumor necrosis factor receptor family to downstream caspases. However, unlike FLICE, the C-terminal domain of MRIT lacks the caspase catalytic consensus sequence QAC(R/Q)G. Nonetheless MRIT activates caspase-dependent death. Using yeast two-hybrid assays, we demonstrate that MRIT associates with caspases possessing large and small prodomains (FLICE, and CPP32/YAMA), as well as with the adaptor molecule FADD. In addition, MRIT simultaneously and independently interacts with BclXL and FLICE in mammalian cells. Thus, MRIT is a mammalian protein that interacts simultaneously with both caspases and a Bcl-2 family member.
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PMID:MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. 932 10

Kaposi's sarcoma-associated herpesvirus or human herpesvirus type 8 (HHV-8) is present in all forms of Kaposi's sarcoma (KS) as well as in primary effusion lymphomas and some cases of Castleman's disease. In KS tissues, HHV-8 is present in endothelial and spindle cells. Current serologic tests suggest that HHV-8 is predominantly found in those at risk of KS and is not as widespread as most other human herpesviruses. HHV-8 encodes various proteins that may play a role in promotion of cellular growth, including cyclin- and G-coupled protein receptor homologues, and anti-apoptotic proteins, including Bcl-2, IL-6 (i.e., interleukin 6), and FLIP (i.e., FLICE inhibitory protein) homologues. In addition, HHV-8 encodes two macrophage inflammatory-like proteins with anti-human immunodeficiency virus and angiogenic potential.
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PMID:Human herpesvirus type 8 and Kaposi's sarcoma. 970 3

The immune response in the central nervous system (CNS) involves microglial cells which represent intraparenchymal antigen-presenting cells (APC). To control immune effector mechanisms it may be required to induce apoptosis of APC and thereby limit reactivation of T cells that have invaded the CNS. In the present study we investigated the susceptibility of primary murine microglia and of the murine microglial cell line BV-2 to undergo Fas-mediated apoptosis. Whereas resting microglia are resistant to Fas ligand (FasL) treatment, induction of FasL-mediated apoptosis was achieved by treatment with TNF-alpha or IFN-gamma. The effect of these cytokines was paralleled by up-regulation of Fas expression and down-regulation of Bcl-2 and Bcl-xL but not Bax. Activation of microglia by TNF-alpha and IFN-gamma was also accompanied by increased amounts of mRNA for the apoptosis inhibitor FLIP, an effect which did not protect the cells from FasL-induced apoptosis. The FasL-induced cell death pathway in microglia involves reactive oxygen intermediates because the antioxidants N-acetylcysteine and glutathione interfere with induction of apoptosis. Surprisingly, microglia constitutively express FasL on the cell surface. However, blocking of endogenous Fas-FasL interaction with Fas-Fc fusion protein did not enhance the survival of microglia, excluding the possibility of suicide or fratricide mechanisms. By their expression of FasL and their TNF-alpha/IFN-gamma-dependent sensitivity to the pro-apoptotic effect of exogenous FasL, microglial cells may influence the course of T cell-mediated diseases of the CNS.
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PMID:TNF-alpha and IFN-gamma render microglia sensitive to Fas ligand-induced apoptosis by induction of Fas expression and down-regulation of Bcl-2 and Bcl-xL. 986 77

Apoptosis is a carefully regulated mechanism of cell death that differs from necrosis and plays an important role in normal tissue development and homeostasis, as well as disease processes. Apoptosis also plays an important role in autoimmunity. Defective apoptosis can cause systemic autoimmunity by allowing the survival of autoreactive lymphocytes. It may also be involved in the pathogenesis of organ-specific autoimmune diseases, such as Hashimoto's thyroiditis, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors. One of these pathways employs the death receptor Fas and its ligand (FasL). Fas expression and death pathway signaling have been demonstrated in the thyroid, but there is controversy surrounding the expression of FasL and its role in thyroid autoimmunity. A number of proteins, including FAP-1, Bcl-2 and I-FLICE may regulate the Fas pathway in the thyroid and provide potential mechanisms for modifying the pathogenesis of autoimmune thyroid disease.
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PMID:The role of Fas-mediated apoptosis in thyroid autoimmune disease. 1052 1

Caspases are the key effector molecules of the physiological death process known as apoptosis, although some are involved in activation of cytokines, rather than cell death. They exist in most of our cells as inactive precursors (zymogens) that kill the cell once activated. Caspases can be controlled in two ways. The processing and activation of a caspase can be regulated by molecules such as FADD, APAF-1, Bcl-2 family members, FLIP and IAPs. Active caspases can be controlled by a variety of inhibitors that directly interact with the protease. This review describes the later direct caspase inhibitors that have been identified, products of both viral and cellular genes, and artificial caspase inhibitors that have been developed both as research tools and as pharmaceutical agents to inhibit cell death in vivo.
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PMID:Caspase inhibitors. 1057 77

Several endogenous or viral inhibitors of apoptosis, including Bcl-2, Bcl-xL, FLIP, p35, and CrmA, have been shown to be cleaved by caspases during apoptosis. In this study, we demonstrate that the endogenous inhibitor of apoptosis, hILP/XIAP, is also cleaved in apoptotic T lymphocytes, generating at least one prominent fragment of 29 kDa. This p29 cleaved fragment was detected in Jurkat cells induced to apoptose by anti-Fas antibody, staurosporin, or VP-16. The cleavage of hILP appears to be caspase mediated because the production of the p29 protein was inhibited by the pan-caspase peptide inhibitor, Z-VAD.FMK. In Jurkat cells engineered to overexpress CrmA, cleavage of hILP in response to anti-Fas antibody or staurosporin was inhibited, whereas overexpression of Bcl-2 abrogated the cleavage in response to VP-16. Cleavage of hILP was also observed in cell-free reactions using in vitro translated hILP and recombinant caspase-3 or -7. Moreover, we found that the p29 hILP fragment retained the ability to bind caspase-3 and -7, as shown previously for full-length or BIR-2 hILP. The p29 cleavage product was also detected during T-cell receptor-mediated apoptosis in peripheral blood lymphocytes from normal donors. Furthermore, tumor-associated T lymphocytes purified from ascites of patients with ovarian cancer expressed fragmented hILP, which was not detected in control T cells purified from peripheral blood of normal donors. Our results suggest that the cleavage of hILP represents an important event in apoptosis of T lymphocytes in both normal and pathological in vivo settings.
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PMID:Inhibitor of apoptosis protein hILP undergoes caspase-mediated cleavage during T lymphocyte apoptosis. 1076 65

The mechanism of injury and death of muscle cells in the inflammatory myopathies (dermatomyositis, polymyositis, and inclusion body myositis) remains obscure. We and others have not detected apoptosis in the muscle biopsies from patients with myositis despite clear evidence of cell damage and loss. We provide evidence in this study that Fas ligand (FasL) as well as Fas is present on muscle cells and inflammatory cells in myositis biopsies: Fas is present on most muscle cells and lymphocytes, and FasL is present on degenerating muscle cells and many infiltrating mononuclear cells. The expression of both Fas and FasL in the inflamed tissue makes the absence of apoptosis more striking. To address the mechanisms of this resistance to classical apoptosis in muscle cells, we have investigated the expression of the antiapoptotic molecule FLICE (Fas-associated death domain-like IL-1-converting enzyme)-inhibitory protein (FLIP) in muscle biopsies of myositis patients and in cultured human skeletal muscle cells. Using laser capture microscopy, we have shown that FLIP is expressed in the muscle fibers and on infiltrating lymphocytes of myositis biopsies. Furthermore, we have shown that FLIP, but not Bcl-2, is expressed in cultured human skeletal muscle cells stimulated with proinflammatory cytokines, and inhibition of FLIP with antisense oligonucleotides promotes significant cleavage of poly(ADP-ribose) polymerase autoantigen, a sensitive indicator of apoptosis. These studies strongly suggest that the resistance of muscle to Fas-mediated apoptosis is due to the expression of FLIP in muscle cells in the inflammatory environment in myositis.
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PMID:The inhibition of apoptosis in myositis and in normal muscle cells. 1079 13

To determine whether the apoptotic machinery of thyroid cancer cells is functional and could be activated for tumoricidal purposes, we examined the apoptosis induced by the cytokines TNF-alpha, Fas and TRAIL in thyroid cancer cell lines, NPA and SW579. Interestingly, out of these cytokines, only TRAIL was able to trigger significant apoptosis. The tumoricidal effect of TRAIL was further enhanced by CHX, suggesting the presence of CHX-sensitive inhibitor(s) of apoptosis in these thyroid cancer cell lines. The anti-apoptotic proteins like FLAME-1, Bcl-2 and Bcl-xL are believed to be such CHX-sensitive inhibitors in various types of cancer cells. We, however, provide the evidence using NPA and SW579 cell lines that these proteins were not affected by the CHX treatment in thyroid cancer cells. The apoptosis of thyroid cancer cells was mediated by the classical activation of caspases that in turn activated the DNA Fragmentation Factor (DFF-45). To elucidate the role of individual caspases in TRAIL-mediated apoptosis, the inhibitory effects of several general and specific tetrapeptide caspase inhibitors were studied. The inhibitors of caspase-1, -6, -8, and -9 as well as general upstream inhibitors of apoptosis could dramatically inhibit TRAIL-induced apoptosis in thyroid cancer cells. Caspase-2 and -3 inhibitors, on the other hand, had no significant effect. When the cells were treated with either agonistic Fas antibody (CH11) or TNF-alpha, no apoptotic changes were observed. The apoptosis induced by agonistic Fas Ab could be seen only after a prolonged exposure (24 h) to CHX, whereas TNF-alpha had no effect even in the presence of CHX. The efficacy of TRAIL was also tested on other types of thyroid cancer cells like ARO, FRO (anaplastic carcinoma) and TPC-1 (papillary carcinoma) and compared to that triggered by other death inducing cytokines FasL and TNF-alpha. Again TRAIL was more potent in triggering apoptosis than Fas and TNF-alpha. Since TRAIL is effective in selectively killing thyroid tumor cells without affecting normal thyrocytes and also does not cause organ toxicity and inflammation in vivo, its potential for the treatment of thyroid cancer seems very promising.
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PMID:TRAIL-induced apoptosis of thyroid cancer cells: potential for therapeutic intervention. 1091 93

Failure of Fas-mediated apoptosis of potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis. The intracellular protein FLIP, a naturally occurring caspase-antagonist, is a potent inhibitor of the Fas signalling pathway that may block Fas-mediated apoptosis of activated lymphocytes. This study reports specific overexpression of both long and short forms of FLIP in intrathecal lymphocytes from patients with multiple sclerosis. The overexpression of FLIP is independent of cellular expressions of Fas receptor or the anti-apoptotic protein Bcl-2. These results provide a better understanding of some of the intrinsic immunoregulatory mechanisms that are involved in multiple sclerosis.
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PMID:Increased cellular expression of the caspase inhibitor FLIP in intrathecal lymphocytes from patients with multiple sclerosis. 1106 39

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


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