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 type I insulin-like growth factor receptor (IGF-IR) blocks osmotic mediated programmed cell death (PCD) in neurons. We speculated that IGF-IR activation could afford neuroprotection either by effecting the negative regulators of the death pathway, Bcl-2 and Bcl-xL, or by altering activity of the ced-3/ICE-like proteases. Here we report that osmotic stress decreases total neuronal Bcl-2 by 4-fold and that hyperosmotic PCD correlates with proteolytic processing of neuronal ced-3/ICE-like proteases. IGF-IR activation maintains normal Bcl-2 levels, and signaling via the IGF-IR:phosphatidylinositol 3-kinase pathway prevents ICE/LAP-3 and Yama/CPP32 processing. Finally, increased neuronal IGF-IR expression enhances the negative death regulator Bcl-xL. We suggest that IGF-IR signaling exerts its short-term inhibitory effects upon PCD "upstream" of both Bcl proteins and ced-3/ICE-like proteases, while chronic increased IGF-IR expression may modulate susceptibility to death signals by mediating the negative death regulator, Bcl-xL.
 ...
PMID:Type I insulin-like growth factor receptor activation regulates apoptotic proteins. 894 17

Mouse malignant T-lymphoma CS-21 cells grow in vitro in the presence of CA-12 lymph node stromal cells, but they undergo apoptotic cell death when separated from CA-12 stromal cells. In the course of examining the nursing effects of CA-12 stromal cells, we found that these cells provided some soluble factors that suppressed CS-21 cell apoptosis. We recently found that cysteine was an antiapoptotic soluble factor. In this report, we identify interleukin-7 (IL-7) as another antiapoptotic soluble factor secreted by CA-12 stromal cells. Although the activity of CPP32-like protease was increased in induction of CS-21 cell apoptosis, the addition of IL-7 suppressed the activity. The expression of Bcl-2 protein was down-regulated when CS-21 cells were cultured alone, but the addition of IL-7 recovered the expression of Bcl-2. These results indicate that CA-12 stromal cells inhibit CS-21 cell apoptosis by producing IL-7, which leads to the suppression of CPP32-like protease activation and the expression of Bcl-2 protein.
 ...
PMID:Interleukin-7 inhibits apoptosis of mouse malignant T-lymphoma cells by both suppressing the CPP32-like protease activation and inducing the Bcl-2 expression. 895 Sep 80

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

Although apoptosis and necrosis are morphologically distinct manifestations of cell death, apoptosis and some necroses share common features in the death signaling pathway involving functional steps of death-driving interleukin 1beta-converting enzyme family proteases and anti-cell death protein Bcl-2. One evident physiological difference in cells undergoing apoptosis versus necrosis is in intracellular levels of ATP. In this study, we specifically addressed the question of whether apoptosis depends on intracellular ATP levels, since longer incubation under ATP-depleting conditions results in necrotic cell death. Incubation of cells in glucose-free medium with an inhibitor of mitochondrial F0F1-ATPases reduces intracellular ATP levels and completely blocks Fas/Apo-1-stimulated apoptosis. ATP supplied through glycolysis or oxidative phosphorylation restores the apoptotic cell death pathway. ATP depletion also leads to a block in Fas-induced activation of CPP32/Yama(-like) proteases, and when ATP is depleted after the activation of the proteases, subsequent apoptosis is significantly blocked. Thus, ATP-dependent steps exist both upstream and downstream of CPP32/Yama(-like) protease activation in apoptotic signal transduction. Treatment with the calcium ionophore induces apoptosis under ATP-supplying conditions but induces necrotic cell death under ATP-depleting conditions, indicating that ATP levels are a determinant of manifestation of cell death.
 ...
PMID:Intracellular ATP levels determine cell death fate by apoptosis or necrosis. 915 70

We have begun to explore the mechanisms of apoptosis using a cell-free system based on extracts from Xenopus eggs. Nuclei assembled or placed in these extracts undergo the morphological changes typical of apoptosis and eventually disintegrate. We used this system to investigate the potential involvement in apoptosis of proteins containing Src homology 2 (SH2) domains, which are known to interact with specific tyrosine-phosphorylated ligands. SH2 domains from a number of signaling proteins, including Lck, Src, and Abl, inhibited apoptosis when present at concentrations of 10-100 nM. The inhibition was dependent on specific interaction with endogenous tyrosine-phosphorylated ligands. A synthetic peptide ligand for Src family SH2 domains also inhibited apoptosis in a phosphotyrosine-dependent manner. Kinetic analysis defined three phases in the apoptotic process occurring in this cell-free system. SH2 domains and ceramide act throughout the first 60-90 min of the process (the "initiation" phase). Next, Bcl-2, interleukin-1beta converting enzyme family(CPP32-like) proteases, and the heavy membrane fraction act in a period occurring approximately 90-120 min after the start of incubation (the "sentencing" phase). In the final phase ("execution"), the process of active nuclear destruction ensues.
 ...
PMID:Temporal phases in apoptosis defined by the actions of Src homology 2 domains, ceramide, Bcl-2, interleukin-1beta converting enzyme family proteases, and a dense membrane fraction. 916 11

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

In the granule exocytosis pathway of cell-mediated cytotoxicity, rapid apoptotic nuclear damage in target cells has been unequivocally linked to granzyme B activity. Direct cleavage and activation of caspase-3 and related proteases by granzyme B have been identified as a central event in apoptosis induction by cytotoxic granules. The Bcl-2 oncoprotein has been recently shown to act at the level or upstream of caspase-3 family activation to inhibit apoptosis induced by various stimuli including Fas ligation, an alternative cell-mediated lytic pathway. In this study, we have investigated whether activation of this caspase family by granzyme B, during human NK and lymphokine-activated killer cell granule-mediated apoptosis, could be influenced by Bcl-2 expression. Bcl-2-overexpressing clones were generated from parental K562 and U937 cell lines (K6 and U4 clones, respectively). Bcl-2 expression abrogated early 125I-DNA release and DNA fragmentation, these defects being compensated for by extended incubation times. Cleavage of poly(ADP-ribose) polymerase, a specific caspase-3 family substrate, was detected in parental K562 cells exposed to lymphokine-activated killer effectors but not in K6 targets, indicating that caspase-3 and related proteases function was inhibited by Bcl-2. Functional inhibition of caspase-3 family with benzyloxycarbonyl-Asp-Glu-Val-Asp(OMe) fluoromethylketone led to similar consequences on apoptotic nuclear events as for Bcl-2 expression. Thus, Bcl-2 antagonizes granzyme B-mediated apoptosis by a mechanism that interferes with caspase-3 activity. Finally, Bcl-2 expression or the Asp-Glu-Val-Asp peptide was much less efficient in preventing phosphatidylserine externalization, suggesting that despite impaired nuclear apoptosis, immediate recognition and elimination of Bcl-2-expressing cells by tissue phagocytes should remain partly unaffected.
 ...
PMID:Bcl-2 expression in target cells leads to functional inhibition of caspase-3 protease family in human NK and lymphokine-activated killer cell granule-mediated apoptosis. 920 Apr 47

According to current understanding, cytoplasmic events including activation of protease cascades and mitochondrial permeability transition (PT) participate in the control of nuclear apoptosis. However, the relationship between protease activation and PT has remained elusive. When apoptosis is induced by cross-linking of the Fas/APO-1/CD95 receptor, activation of interleukin-1beta converting enzyme (ICE; caspase 1) or ICE-like enzymes precedes the disruption of the mitochondrial inner transmembrane potential (DeltaPsim). In contrast, cytosolic CPP32/ Yama/Apopain/caspase 3 activation, plasma membrane phosphatidyl serine exposure, and nuclear apoptosis only occur in cells in which the DeltaPsim is fully disrupted. Transfection with the cowpox protease inhibitor crmA or culture in the presence of the synthetic ICE-specific inhibitor Ac-YVAD.cmk both prevent the DeltaPsim collapse and subsequent apoptosis. Cytosols from anti-Fas-treated human lymphoma cells accumulate an activity that induces PT in isolated mitochondria in vitro and that is neutralized by crmA or Ac-YVAD.cmk. Recombinant purified ICE suffices to cause isolated mitochondria to undergo PT-like large amplitude swelling and to disrupt their DeltaPsim. In addition, ICE-treated mitochondria release an apoptosis-inducing factor (AIF) that induces apoptotic changes (chromatin condensation and oligonucleosomal DNA fragmentation) in isolated nuclei in vitro. AIF is a protease (or protease activator) that can be inhibited by the broad spectrum apoptosis inhibitor Z-VAD.fmk and that causes the proteolytical activation of CPP32. Although Bcl-2 is a highly efficient inhibitor of mitochondrial alterations (large amplitude swelling + DeltaPsim collapse + release of AIF) induced by prooxidants or cytosols from ceramide-treated cells, it has no effect on the ICE-induced mitochondrial PT and AIF release. These data connect a protease activation pathway with the mitochondrial phase of apoptosis regulation. In addition, they provide a plausible explanation of why Bcl-2 fails to interfere with Fas-triggered apoptosis in most cell types, yet prevents ceramide- and prooxidant-induced apoptosis.
 ...
PMID:The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. 920 94

Erythropoietin (EP) is required by late-stage erythroid progenitor cells to prevent apoptosis. Several lines of evidence suggest that it is this action of EP that regulates erythrocyte production in vivo. To study the control of apoptosis in mouse and human erythroblasts, the expression of members of the Bcl-2 family of proteins and the expression and activation of the apoptosis-linked cysteine protease Yama/CPP32/apopain were examined. These proteins have been implicated as regulators of apoptosis in several cell models. The Bcl-2 family members analyzed were Bcl-2, Bcl-X, Bax, Bad, Bak, A1, and Mcl-1. Bcl-X expression in proerythroblasts was highly EP-dependent. Bcl-X was strongly increased during the terminal differentiation stages of human and mouse erythroblasts, reaching maximum transcript and protein levels at the time of maximum hemoglobin synthesis. This increase in Bcl-X expression led to an apparent level of approximately 50 times the level in proerythroblasts. In contrast, neither mouse nor human erythroblasts expressed Bcl-2 transcript or protein. Bax and Bad proteins remained relatively constant throughout differentiation, but diminished near the time of enucleation. Bak protein was present in early erythroblasts, but diminished progressively during differentiation. EP deprivation in both mouse and human erythroblasts led to activation of the cysteine protease, apopain, as was indicated by cleavage of the proenzyme into its proteolytically active fragments. Apopain activation was detectable within 2 hours of EP deprivation in mouse erythroblasts. These findings suggest an important role for Bcl-X in late erythroid differentiation and for apopain in apoptosis of erythroblasts caused by deprivation of EP.
 ...
PMID:The roles of Bcl-X(L) and apopain in the control of erythropoiesis by erythropoietin. 922 63

High-dose Ara-C (HIDAC) induces the cleavage and activity of caspase-3 (CPP32beta/Yama/apopain), resulting in the morphological and biochemical features of apoptosis. High levels of the antiapoptotic Bcl-x(L) or Bcl-2, relative to the proapoptotic Bax, have been shown to inhibit HIDAC-induced cleavage and activity of caspase-3 and apoptosis of the human acute myeloid leukemia HL-60 cells. In a previous report, we demonstrated this inhibition, using the control HL-60 (HL-60/neo) cells and their counterparts, HL-60/Bcl-x(L), which have enforced overexpression of Bcl-x(L) and a significantly lower ratio of free to bound Bax. Results of the present studies demonstrate that, in the initiation phase of apoptosis of HL-60/neo cells due to HIDAC (10 or 100 microM for 4 h), cytochrome c is released from the mitochondria to the cytosol, followed by the loss of mitochondrial membrane potential (deltapsi m) and an increase in the reactive oxygen species; these events precede and trigger the cleavage and activity of caspase-3. These HIDAC-induced early mitochondrial and cytosolic perturbations, which represent the initiation phase of HIDAC-induced apoptosis, were inhibited in HL-60/Bcl-x(L) cells. HIDAC treatment for 4 h also modestly increased the intracellular levels of free Bax relative to Bax bound to Bcl-2 and Bcl-x(L) in HL-60/neo but not in HL-60/Bcl-x(L) cells. In HL-60/neo cells, HIDAC-induced progressive accumulation of cytochrome c in the cytosol, the decrease in deltapsi m, and the increase in reactive oxygen species were not inhibited by coculture with the tetrapeptide inhibitors of caspases that have been previously shown to inhibit Ara-C-induced cleavage and activity of caspase-3 and apoptosis. These findings indicate that Bcl-x(L) inhibits HIDAC-induced preapoptotic mitochondrial perturbations, which prevent the accumulation of cytochrome c in the cytosol, thereby preserving caspase-3 in the inactive zymogen state and checking the molecular cascade of apoptosis.
 ...
PMID:Overexpression of Bcl-X(L) inhibits Ara-C-induced mitochondrial loss of cytochrome c and other perturbations that activate the molecular cascade of apoptosis. 924 35


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