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)

Overexpression of Bcl-2 can prevent or markedly delay cell death induced by a variety of apoptotic stimuli. Although Fas and Fas ligand (FasL) interactions play a major role in the elimination of self-reactive T cells in the periphery, inhibition of Fas-mediated killing by Bcl-2 has not been consistently observed. The mouse T hybridoma 2B4.11 (2B4) has been a useful model to study glucocorticoid- and activation-induced apoptosis, which is mediated through Fas and FasL. Using both stable transfectants and transient transfections, overexpression of Bcl-2 or Bcl-xL readily blocked glucocorticoid-induced but not activation-induced apoptosis of 2B4 cells. Bcl-2 expression did not inhibit Fas-mediated cytotoxicity triggered by cells expressing FasL or by the transient transfection of human Fas. Similarly, overexpression of Bcl-2 in the mouse T hybridoma A1.1 did not block activation-induced/Fas-mediated apoptosis. In Jurkat cells, however, expression of Bcl-2 partially inhibited anti-Fas-induced cell death. A Bcl-2-related protein that can interfere with anti-Fas killing, the adenoviral E1B 19K, also did not block activation-induced/Fas-mediated apoptosis in 2B4 cells. In contrast, expression of CrmA, a cowpox virus protein that inhibits ICE-like protease activity, blocked activation-induced apoptosis in 2B4 cells but had little effect on Dex-mediated cytotoxicity. These results show that: 1) Bcl-2 can have strikingly different anti-cell death activity in the same cell depending upon the apoptotic stimulus, 2) distinct apoptosis signaling pathways may exist with differential sensitivity to Bcl-2 and ICE-like protease inhibitors.
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PMID:Bcl-2 blocks glucocorticoid- but not Fas- or activation-induced apoptosis in a T cell hybridoma. 759 63

Apoptosis, or programmed cell death, is characterized by an active autodestruction of cells. Several proteins inducing (CED-3) or preventing (CED-9) neuronal death have been described in the nematode C. elegans. There is an homology between these proteins and Bcl-2 and ICE (Interleukin-1 beta-Converting Enzyme) in vertebrates. The cascade of biochemical events leading to this active neuronal "suicide" is triggered by initiating factors such as genotoxicity, growth factors deprivation, cytokines (TNF alpha). As the molecular mechanisms of nerve cell death start to be understood, clinicians and neurobiologists are confronted with the difficult problem of pathological aging and neuronal death in patients with neurodegenerative disorders compared to normal aging. In order to distinguish the biochemical abnormalities underlying dysfunction of neurons during aging, neuronal loss during neurodegeneration (Parkinson's disease) and nerve cell death, we searched for morphological and biochemical signs of apoptosis in dopaminergic neurons of the substantia nigra of parkinsonian patients and controls. We found characteristic histopathological features of apoptosis in about 5% of dopaminergic neurons in the brain of patients. In addition, the presence of TNF alpha receptors and the expression of the gene bcl-2 were observed in dopaminergic neurons. Thus, apoptosis could represent the ultimate step of dopaminergic neuronal degeneration in Parkinson's disease. Whether this is also the case in other neurodegenerative diseases still remains to be proven. In brief, neurons in the human brain could be classified into three categories: those which loose slowly part of their functions but are still spared by the process of neuronal death (senescence); those which are lost more rapidly than similar effects due to aging (neurodegeneration); a small number of neurons which die rapidly through apoptosis. The consequences of such observation may be important both for neurobiologists and pharmacologists as the basic mechanisms which result in senescence, disease and death of neurons could be different.
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PMID:[Aging, disease and nerve cell death]. 854 48

Genetic analyses of Caenorhabditis elegans has identified three genes that function in the regulation of nematode cell death. Mammalian homologs of two of these genes, ced-9 and ced-3, have been identified and comprise proteins belonging to the Bcl-2 and ICE families, respectively. To date, it is unclear where the negative regulators, ced-9 and bcl-2, function relative to the death effectors, ced-3 and the mammalian ced-3 homologs, respectively. Here, the molecular order of the cell death pathway is defined. Our results establish that Bcl-2 and Bcl-xL function upstream of two members of the ICE/CED-3 family of cysteine proteases, Yama (CPP32/apopain) and ICE-LAP3 (Mch3).
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PMID:Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases. 861 12

COS cells are resistant to cell death induced either by interleukin-1beta-converting enzyme (*ICE) and ICE homolog (ICH-1L) overexpression or by serum deprivation. COS cells deprived of serum undergo apoptosis after transfection with an ICE expression construct, but not an ICH-1L construct. ICE-mediated apoptosis of COS cells in serum-free medium is suppressed by insulin-like growth factor (IGF)-1 and insulin. Viability of Rat-1 cell line (Rat-1/ICE) expressing low levels of ICE-LacZ fusion protein is lower than those of cell lines expressing either both Bcl-2 and ICE or mutant ICEGly-->Ser during serum deprivation. Enzymatic activation and processing of ICE are observed in cells induced to die by serum deprivation, which are suppressed by IGF-1. IGF-1 or insulin suppresses ICE-mediated cell death without affecting the expression levels of Bcl-2, Bcl-x, or Bax. Taken together, these results indicate that ICE is activated by growth factor deprivation, and IGF-1 is able to suppress ICE-mediated cell death through a mechanism independent of the expression of Bcl-2, Bcl-x, or Bax.
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PMID:Suppression of interleukin-1 beta-converting enzyme-mediated cell death by insulin-like growth factor. 861 90

The E1A oncoproteins of adenovirus type 5 are potent inducers of apoptotic cell death. To manifest growth promoting and transforming properties, therefore, E1A requires the co-expression of a suppressor of apoptosis. During normal viral infection, this function is provided by the E1B 19 kDa protein. However, the cellular suppressor Bcl-2 can substitute for 19K during infection, and both proteins can effectively cooperate with E1A to facilitate transformation of primary cells in culture. How E1A induces apoptosis and at what point(s) on this pathway Bcl-2 and E1B 19K act are not presently known. Here, we demonstrate that E1A-induced apoptosis is accompanied by specific endo-proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), an event that is linked to the Ced-3/ICE apoptotic pathway in other systems. PARP cleavage was also observed in p53-null cells infected with 19K- virus expressing 13S E1A. In addition to PARP cleavage, expression of E1A caused processing of the zymogen form of CPP32, a Ced-3/ICE protease that cleaves PARP and is required for apoptosis in mammalian cells. These events were prevented when E1A was co-expressed with E1B 19K or BCL-2, which places these suppressors of apoptosis either at or upstream of processing of pro-CPP32.
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PMID:Bcl-2 and adenovirus E1B 19 kDA protein prevent E1A-induced processing of CPP32 and cleavage of poly(ADP-ribose) polymerase. 863 9

The Bcl-2 family and the ICE family of cysteine proteases play important roles in regulating cell death. We show here that induction of cell death by a Ca2+ ionophore or hypoxia results in increased levels and activity of active ICE(-like) proteases and the subsequent activation of CPP32/Yama(-like) proteases, and that inhibition of these protease activities reduces the extent of cell death. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-xL inhibits the cell death and the activation of ICE(-like) and CPP32/Yama(-like) proteases, indicating that Bcl-2 and Bcl-xL act upstream of these proteases. We also show that specific inhibition of ICE(-like) proteases in vivo prevents activation of CPP32/Yama(-like) proteases, whereas inhibition of CPP32/Yama(-like) proteases does not prevent activation of ICE(-like) proteases, suggesting the existence of a protease cascade in vivo that requires ICE(-like) proteases for activation of CPP32/Yama(-like) proteases. Induction of necrotic cell death by KCN also induces activation of ICE(-like) proteases but not of CPP32/Yama(-like) proteases, and Bcl-2 and Bcl-xL inhibit the activation and the cell death, suggesting that the functional site of Bcl-2 and Bcl-xL is also upstream of ICE(-like) proteases in at least some forms of necrosis.
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PMID:Bcl-2 expression prevents activation of the ICE protease cascade. 864 64

Bcl-2 expression is able to confer drug resistance to chemotherapy-induced programmed cell death. Bax, a partner protein of bcl-2 with extensive aminoacid homology, is a promoter of apoptosis. Apparently the equilibrium of bcl-2 and bax hetero- and homodimers is important for the susceptibility of cells for stimuli inducing apoptosis. In this study we determined the role of bcl-2 to bax expression ratio, bcl-xL and ICE expression level for predicting clinical response to chemotherapy in acute myelold leukemia (AML). Bone marrow samples from 14 patients with AML were examined using an immunophosphatase staining method. Initial bone marrow blast portion was over 80% in all cases. Clinical response was defined by bone marrow aspiration 4 weeks after treatment initiation. There was a significant correlation between bcl-2 to bax expression ratio and clinical response (P < 0.005). No patients with a bcl-2/bax ratio >1.0 achieved complete remission after induction therapy. No significant correlation between bcl-2- and p-glycoprotein-expression was observed in this group. Conversely a high expression of ICE indicated a good clinical response (P < 0.01), whereas expression of bcl-xL had no influence on therapeutic success in this group.
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PMID:Association of bcl-2, bax, bcl-xL and interleukin-1 beta-converting enzyme expression with initial response to chemotherapy in acute myeloid leukemia. 865 95

Phylogenetic analysis of the CED-3/ICE family of cysteine proteases suggests the existence of a subfamily most related to the Caenorhabditis elegans death gene ced-3 and includes Yama (CPP32, apopain), LAP3 (Mch3, CMH1), and Mch2. Here, we show that Mch2 is processed from its zymogen form to a proteolytically active dimeric species during execution of the apoptotic program and by the cytotoxic T cell death protease granzyme B. Additionally, like Yama and LAP3, Mch2 functions downstream of the death inhibitors Bcl-2, Bcl-xL, and CrmA. Importantly, Mch2, but not Yama or LAP3, is capable of cleaving lamin A to its signature apoptotic fragment, indicating that Mch2 is an apoptotic laminase.
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PMID:The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A. 866 80

Bcl-2, Bcl-xL, CrmA and tetrapeptide ICE inhibitor reduce the extent of necrotic cell death induced by cyanide, which primarily damages mitochondria. Although none of them affects the drastic decrease in ATP levels induced by cyanide, Bcl-2 and Bcl-xL but not CrmA or ICE inhibitor inhibit the cyanide-induced decrease in mitochondrial membrane potential. A similar blocking effect is observed on necrotic cell death induced by other respiration inhibitors, rotenone and antimycin A, and on apoptotic cell death induced by etoposide or calcium ionophore. These results indicate that Bc1-2 and Bcl-xL protect mitochondria against the loss of function during both apoptosis and at least some forms of necrotic cell death. The ICE family proteases act at a different step other than the loss of mitochondrial membrane potential.
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PMID:Bcl-2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors. 870 May 49

In amniote vertebrates, the development of form and structure of the limb bud is accompanied by precise patterns of massive mesodermal cell death with morphological features of apoptosis. These areas of cell death appear to eliminate undifferentiated cells which are required only for a limited time period of limb development. Predictable skeletal and morphological anomalies of the limb occur when the pattern of cell death is modified in mutant species or under experimental conditions. Most evidence points to the occurrence of local triggering mechanisms to account for the establishment of the areas of cell death and the subsequent activation of cell death genes. Modifications of the extracellular matrix and diminution in the contribution of growth factors by neighbouring tissues appear as the most likely potential candidates for triggering the cell death program. Information on the genetical basis of cell death in the developing limb is very scarce. Among the increasing number of cell death genes identified in other cell death systems, such as p-53 and the ced-3/ICE and ced-9/ bcl-2 gene families, only bcl-2 has been studied in detail during limb development and yet, the information obtained is contradictory. Bcl-2 is not expressed in the areas of cell death of the developing limb, but normal limbs develop in mice with disruption of the bcl-2 gene. Obviously, the clarification of the role of the cell death genes constitute a major task in future studies of cell death in the developing limb.
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PMID:Cell death in the embryonic developing limb. 871 47


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