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)

Bcl-2 was the first recognized component of the physiological cell death mechanism. It belongs to an expanding family of proteins that regulate apoptosis during development and homeostasis. Experiments using transgenic and gene knockout mice have revealed much about the roles played by Bcl-2, Bcl-x and Bax in regulating apoptosis in the immune system. Genetic data from C. elegans have shown that Bcl-2 like proteins ultimately determine whether a set of apoptosis effector cysteine proteases becomes activated in response to a death signal. How Bcl-2 and its relatives achieve this regulation remains unknown.
 ...
PMID:The role of the Bcl-2 family of apoptosis regulatory proteins in the immune system. 910 5

CD6 and CD5 belong to a scavenger-receptor cysteine-rich (SRCR) super family of membrane glycoproteins that are expressed on chronic lymphocytic leukemia B (B-CLL) cells, normal T cells, and a small subset of normal B cells. CD6 configures in the membrane in relation to the cellular activation level and can act as a coreceptor for T-cell activation. We have examined a group of progressive and nonprogressive B-CLL cells. Most B-CLL cells were positive for CD6 and the expression of CD6 was increased after activation with Staphylococcus aureus Cowan I plus interleukin-2 or 12-O-tetradecanoylphorbol 13-acetate, although anti-CD6 antibodies did not increase proliferative responses to these stimuli. However, anti-CD6 stimulation was found to protect against anti-IgM-induced apoptosis in B-CLL. bax(alpha) upregulation and bcl-2 downregulation were found in anti-IgM- and glucocorticoid (GCC)-induced apoptotic cells, respectively. Furthermore, CD6 cross-linking downregulated bax(alpha) mRNA levels in anti-IgM-treated cells, resulting in an increased bcl-2/bax(alpha) ratio. CD6 activation also prevented bcl-2 mRNA downregulation and apoptosis induced by GCC in one of six GCC-sensitive patients. These data suggest that an interaction between CD6 and its ligand might contribute to B-CLL survival through the modulation of the Bcl-2/Bax ratio.
 ...
PMID:CD6 ligation modulates the Bcl-2/Bax ratio and protects chronic lymphocytic leukemia B cells from apoptosis induced by anti-IgM. 910 2

Emerging evidence suggests that multiple aspartate-specific cysteine proteases (caspases (CASPs)) play a crucial role in programmed cell death. Many cellular proteins have been identified as their substrates and serve as markers to assay the activation of CASPs during the death process. However, no substrate has yet been unambiguously identified as an effector molecule in apoptosis. PITSLRE kinases are a superfamily of Cdc2-like kinases that have been implicated in apoptotic signaling and tumorigenesis. In this paper we report that tumor necrosis factor (TNF)-mediated apoptosis is associated with a CrmA- and Bcl-2-inhibitable cleavage of PITSLRE kinases, indicating a role for CASPs. Testing of seven murine CASPs for their ability to cleave p110 PITSLRE kinase alpha2-1 in vitro revealed that only CASP-1 (ICE (interleukin-1beta-converting enzyme)) and CASP-3 (CPP32) were able to produce the same 43-kDa cleavage product as observed in cells undergoing TNF-induced apoptosis. Mutational analysis revealed that cleavage of p110 PITSLRE kinase alpha2-1 occurred at Asp393 within the sequence YVPDS, which is similar to that involved in the CASP-1-mediated cleavage of prointerleukin-1beta. TNF-induced proteolysis of PITSLRE kinases was still observed in fibroblasts from CASP-1(0/0) mice. These data implicate CASP-3 as a potentially important CASP family protease responsible for the cleavage of PITSLRE kinases during TNF-induced apoptosis.
 ...
PMID:Cleavage of PITSLRE kinases by ICE/CASP-1 and CPP32/CASP-3 during apoptosis induced by tumor necrosis factor. 911 19

c-Jun, a signal-transducing transcription factor of the AP-1 family, normally implicated in cell cycle progression, differentiation and cell transformation, recently has also been linked to apoptosis. To explore further the functional roles of c-Jun, a conditional allele was generated by fusion of c-Jun with the hormone-binding domain of the human estrogen receptor (ER). Here we demonstrate that increased c-Jun activity is sufficient to trigger apoptotic cell death in NIH 3T3 fibroblasts. c-Jun-induced apoptosis is evident at high serum levels, but is enhanced further in factor-deprived fibroblasts. Furthermore, apoptosis by c-Jun is not accompanied by an increase in DNA synthesis. Constitutive overexpression of the apoptosis inhibitor protein Bcl-2 delays the c-Jun-mediated cell death. The regions of c-Jun necessary for apoptosis induction include the amino-terminal transactivation and the carboxy-terminal leucine zipper domain, suggesting that c-Jun may activate cell death by acting as a transcriptional regulator. We further show that alpha-fodrin, a substrate of the interleukin 1beta-converting enzyme (ICE) and CED-3 family of cysteine proteases, becomes proteolytically cleaved in cells undergoing cell death by increased c-Jun activity. Moreover, cell-permeable irreversible peptide inhibitors of the ICE/CED-3 family of cysteine proteases prevented the cell death.
 ...
PMID:Induction of apoptosis by the transcription factor c-Jun. 913 Jul 14

Glucocorticoid induces apoptosis in immature lymphocytes which is inhibitable by Bcl-2. Although glucocorticoid-mediated signal transduction is well understood, the mechanism of the induction of apoptosis by the activated glucocorticoid receptor as well as the inhibition of apoptosis by Bcl-2 remains enigmatic. Here we report that overexpressed Bcl-2 relieves the glucocorticoid receptor-mediated repressive function on the AP-1 activity and completely inhibits the activation of CPP32-like cysteine proteases. In contrast, glucocorticoid receptor-mediated transactivation was not affected by Bcl-2. This suggests that glucocorticoid may induce apoptosis by repressing transactivation by AP-1 which is relieved by Bcl-2. Furthermore, we report evidence that, in contrast with CPP32-like proteases, ICE-like proteases are not involved in this apoptotic pathway.
 ...
PMID:Bcl-2 relieves the trans-repressive function of the glucocorticoid receptor and inhibits the activation of CPP32-like cysteine proteases. 916 33

Bcl-2 overexpression in transfected PW cells is associated with inhibition of radiation-induced programmed cell death (PCD). We have previously reported that there is a relationship between inhibition of radiation-induced PCD and membrane hyperpolarization in these cells. In this article, we report that Na+/ K(+)-ATPase pump activity, as measured by the uptake of Rubidium-86 (86Rb+), is significantly higher in Bcl-2 overexpressing PW cells than in control PW cells, and that pump activity following irradiation with doses > or = 500 cGy was reduced to a lesser extent in the Bcl-2 transfectants than in the control cells. When PW-Bcl-2 cells were incubated with a dose of ouabain (1 microM) that decreased pump activity significantly, but did not induce PCD, the previously reported protection from radiation-induced PCD associated with overexpression of Bcl-2 no longer existed. In order to demonstrate that reactive oxygen species (ROS) affected Na+/ K(+)-ATPase pump activity, cells were incubated with N-acetyl cysteine (NAC) prior to irradiation, or treated with the ROS generating drug buthionine sulphoxamine (BSO). 86Rb+ uptake was significantly higher in irradiated cells incubated with NAC compared to cells irradiated in the absence of NAC, while BSO resulted in lower levels of 86Rb+ uptake, suggesting that the effects of radiation on the Na+/K(+)-ATPase pump were due to ROS. Furthermore, the resting cell membrane potential of cells exposed to NAC were slightly hyperpolarized compared to control PW cells, whereas cells exposed to BSO were depolarized in comparison to control PW cells. In summary, this data suggests that Bcl-2 affects Na+/K(+)-ATPase pump activity, which is associated with the resting membrane potential and the level of susceptibility to radiation-induced PCD.
 ...
PMID:Influence of Bcl-2 overexpression on Na+/K(+)-ATPase pump activity: correlation with radiation-induced programmed cell death. 918 Aug 99

Bax, a member of the Bcl-2 multigene family, is known to promote apoptosis. To investigate the role of Bax in an experimentally induced cell death of the murine dopaminergic neuronal cell line (MN9D), we established MN9D cells stably over-expressing murine Bax (MN9D/ Bax) or vector alone (MN9D/Neo). In MN9D/Neo cells treated with either 1 microM staurosporine or 0.1 microM nigericin, a ladder pattern of DNA fragmentation was induced. As expected, over-expression of Bax in MN9D cells accelerated staurosporine-induced cell death as measured by the MTT reduction assay (62.3% survival in MN9D/Neo vs 27.0% survival in MN9D/Bax). Surprizingly, both nigericin-induced cell death and its accompanying DNA fragmentation were largely attenuated in MN9D/Bax cells (22.0% survival in MN9D/Neo vs 86.7% survival in MN9D/Bax). Similar patterns were observed in two other MN9D/Bax cell lines. Cleavage of poly(ADP-ribose)polymerase caused by nigericin was greatly attenuated in MN9D/Bax cells suggesting that, like Bcl-2, Bax suppresses nigericin-induced cell death by inhibiting the activation of cysteine proteases. Thus, our data imply that Bax acts as a negative or positive regulator of cell death depending on the type of death stimulus applied to the cell.
 ...
PMID:Bax accelerates staurosporine-induced but suppresses nigericin-induced neuronal cell death. 922 64

Apoptosis is a morphologically and biochemically distinct form of cell death which can be triggered by a variety of extracellular agents during both normal development as well as in adult pathological states. Much progress has recently been made in understanding the molecular pathways which regulate this process as well as new intersections between these. A direct interaction between components of the 'executioner'--the ICE-family of cysteine proteases--and the Bcl-2 family of proteins, which modulate a cell's propensity to undergo apoptosis, has recently been demonstrated. New pathways to cell survival, like the PI3-K/Akt signal transduction pathway, are also providing new clues as to the regulation of cell death by growth factors and extracellular matrix for example. The links which exist between apoptosis and cancer research are several. Genetic alterations in components of the apoptosis pathway occur during tumorigenesis and confer resistance to a variety of physiological (oncogene-induced cell death, loss of adhesion, growth under hypoxia) as well as therapeutic (chemotherapy and radiation) death triggers. Similarly, antineoplastic therapies are thought to induce tumor cell apoptosis, and consequently, common mutations in apoptosis-regulatory genes carry a poor prognosis for the patient. A more detailed understanding of the biochemistry of apoptosis and the ways in which it is disabled in tumors will likely reveal new transformation selective death triggers which stimulate cell death in ways independent of components like p53 and increase the therapeutic window of these drugs in the clinics.
 ...
PMID:Apoptosis in tumorigenesis and cancer therapy. 923 63

Programmed cell death, or apoptosis, is inhibited by the antiapoptotic oncogene, Bcl-2, and is mediated by a cascade of aspartate-specific cysteine proteases, or caspases, related to interleukin 1-beta converting enzyme. Depending on cell type, apoptosis can be induced by treatment with thapsigargin (TG); a selective inhibitor of the endoplasmic reticulum-associated calcium-ATPase. The role of caspases in mediating TG-induced apoptosis was investigated in the Bcl-2-negative human breast cancer cell line, MDA-MB-468. Apoptosis developed in MDA-MB-468 cells over a period of 24-72 h following treatment with 100 nM TG, and was prevented by Bcl-2 overexpression. TG-induced apoptosis was associated with activation of caspase-3 and was inhibited by stable expression of the baculovirus p35 protein, an inhibitor of caspase activity. Also, TG-induced apoptosis was inhibited by treating cells with Z-VAD-fmk, a cell-permeable fluoromethylketone inhibitor of caspases. These findings indicate that TG-induced apoptosis of MDA-MB-468 breast cancer cells is subject to inhibition by Bcl-2 and is mediated by caspase activity. This model system should be useful for further investigation directed toward understanding the role of calcium in signaling apoptosis, and its relationship to Bcl-2 and the caspase proteolytic cascade.
 ...
PMID:Baculovirus p35 and Z-VAD-fmk inhibit thapsigargin-induced apoptosis of breast cancer cells. 929 14

In the A20 cell line, we examined the mechanisms that modulate the Fas-mediated apoptotic pathway through the B cell receptor. As in other systems, Fas signaling activates cysteine proteases, leading to specific proteolysis of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. We describe that PKC-epsilon and PKC-zeta proteins are two new IL-1 beta-converting enzyme (ICE) substrates; we found that ICE activation and its proteolytic effects are inhibited by surface IgG (sIgG) cross-linking. Apoptosis induced by Fas ligation is consequently abrogated after sIgG engagement, and sIgG signaling therefore interferes with the apoptotic signal upstream of ICE protease activation. Since the PKC inhibitor bisindolylmaleimide I completely abolishes the protective effect of the sIgG signal, a member of the PKC family is probably responsible for the prevention of ICE cascade activation. Direct activation of PKC by PMA partially mimics the protective effect of sIgG cross-linking against Fas-mediated death in A20 cells. Nevertheless, PMA inhibits neither ICE activation nor the subsequent proteolysis of ICE substrates, suggesting that the PKC responsible for ICE inactivation is a non-PMA-sensitive PKC. In this system, Fas ligation also triggers Bcl-2/Bcl-x down-regulation, an effect inhibited by sIgG cross-linking, the cysteine protease inhibitor acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone, and PMA treatment. In A20 cells, Fas signaling may thus trigger both ICE activation and Bcl-x and Bcl-2 down-regulation. These results indicate that sIgG signaling gives rise to two pathways after PKC activation, one presumably promoted by non-PMA-sensitive PKC, which inactivates the ICE cascade, and another produced by PMA-sensitive PKC, which maintains normal Bcl-2/Bcl-x levels.
 ...
PMID:B cell receptor cross-linking prevents Fas-induced cell death by inactivating the IL-1 beta-converting enzyme protease and regulating Bcl-2/Bcl-x expression. 931 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>