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)

The redox environment of the cell is currently thought to be extremely important to control either apoptosis or autophagy. This study reported that reactive oxygen species (ROS) and nitric oxide (NO) generations were induced by evodiamine time-dependently; while they acted in synergy to trigger mitochondria-dependent apoptosis by induction of mitochondrial membrane permeabilization (MMP) through increasing the Bax/Bcl-2 or Bcl-x(L) ratio. Autophagy was also stimulated by evodiamine, as demonstrated by the positive autophagosome-specific dye monodansylcadaverine (MDC) staining as well as the expressions of autophagy-related proteins, Beclin 1 and LC3. Pre-treatment with 3-MA, the specific inhibitor for autophagy, dose-dependently decreased cell viability, indicating a survival function of autophagy. Importantly, autophagy was found to be promoted or inhibited by ROS/NO in response to the severity of oxidative stress. These findings could help shed light on the complex regulation of intracellular redox status on the balance of autophagy and apoptosis in anti-cancer therapies.
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PMID:Reactive oxygen species and nitric oxide regulate mitochondria-dependent apoptosis and autophagy in evodiamine-treated human cervix carcinoma HeLa cells. 1848 13

The Bcl-2 family proteins are important regulators of type I programmed cell death apoptosis; however, their role in autophagic cell death (AuCD) or type II programmed cell death is still largely unknown. Here we report the cloning and characterization of a novel Bcl-2 homology domain 3 (BH3)-only protein, apolipoprotein L1 (apoL1), that, when overexpressed and accumulated intracellularly, induces AuCD in cells as characterized by the increasing formation of autophagic vacuoles and activating the translocation of LC3-II from the cytosol to the autophagic vacuoles. Wortmannin and 3-methyladenine, inhibitors of class III phosphatidylinostol 3-kinase and, subsequently, autophagy, blocked apoL1-induced AuCD. In addition, apoL1 failed to induce AuCD in autophagy-deficient ATG5(-/-) and ATG7(-/-) mouse embryonic fibroblast cells, suggesting that apoL1-induced cell death is indeed autophagy-dependent. Furthermore, a BH3 domain deletion construct of apoL1 failed to induce AuCD, demonstrating that apoL1 is a bona fide BH3-only pro-death protein. Moreover, we showed that apoL1 is inducible by p53 in p53-induced cell death and is a lipid-binding protein with high affinity for phosphatidic acid (PA) and cardiolipin (CL). Previously, it has been shown that PA directly interacted with mammalian target of rapamycin and positively regulated the ability of mammalian target of rapamycin to activate downstream effectors. In addition, CL has been shown to activate mitochondria-mediated apoptosis. Sequestering of PA and CL with apoL1 may alter the homeostasis between survival and death leading to AuCD. To our knowledge, this is the first BH3-only protein with lipid binding activity that, when overproduced intracellularly, induces AuCD.
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PMID:Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death. 1850 29

It has been reported that ischemic insult increases the formation of autophagosomes and activates autophagy. However, the role of autophagy in ischemic neuronal damage remains elusive. This study was taken to assess the role of autophagy in ischemic brain damage. Focal cerebral ischemia was introduced by permanent middle cerebral artery occlusion (pMCAO). Activation of autophagy was assessed by morphological and biochemical examinations. To determine the contribution of autophagy/lysosome to ischemic neuronal death, rats were pretreated with a single intracerebral ventricle injection of the autophagy inhibitors 3-methyl-adenine (3-MA) and bafliomycin A1 (BFA) or the cathepsin B inhibitor Z-FA-fmk after pMCAO. The effects of 3-MA and Z-FA-fmk on brain damage, expression of proteins involved in regulation of autophagy and apoptosis were assessed with 2,3,5-triphenyltetrazolium chloride (TTC) staining and immunoblotting. The results showed that pMACO increased the formation of autophagosomes and autolysosomes, the mRNA and protein levels of LC3-II and the protein levels of cathepsin B. 3-MA, BFA and Z-FA-fmk significantly reduced infarct volume, brain edema and motor deficits. The neuroprotective effects of 3-MA and Z-FA-fmk were associated with an inhibition on ischemia-induced upregulation of LC3-II and cathepsin B and a partial reversion of ischemia-induced downregulation of cytoprotective Bcl-2. These results demonstrate that ischemic insult activates autophagy and an autophagic mechanism may contribute to ischemic neuronal injury. Thus, autophagy may be a potential target for developing a novel therapy for stroke.
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PMID:Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. 1856 42

Pseudolaric acid B (PAB) exerted cytostatic activity on murine fibrosarcoma L929 cells. The cytostatic mechanism of PAB on L929 cells was investigated in this paper. At 36 h, after 80 microM PAB treatment, the inhibitory ratio was 65.37 +/- 4.12%, and the MDC staining ratio was strongest in L929 cells. 3-Methyladenine (3-MA), an inhibitor of autophagy, inhibited the generation of autolysosomes induced by PAB. The expression of autophagy-associated Beclin 1 protein was up-regulated, and microtubule-associated protein light chain 3 I (LC3 I) was cleaved into LC3 II after 80 microM PAB treatment from 12 h. Therefore, it was concluded that PAB exerted a cytostatic effect on L929 cells through autophagy. However, 80 microM PAB treatment did not induce apoptotic body formation, but 3 mM 3-MA promoted apoptosis, so autophagy might inhibit apoptosis. PAB had no effect on mitochondrial membrane potential (MMP), but up-regulated the expressions of Bax and Bcl-2. Immunoprecipitation analysis showed that PAB inhibited Bcl-2 binding with Beclin 1. Additionally, PAB inhibited the localization of Bax in mitochondria, but Bcl-2 still was in the mitochondria to sustain MMP. Meanwhile PAB promoted the phosphorylation of cytoplasmic Bcl-2. Therefore the phosphorylation of Bcl-2 in the cytoplasm and the mitochondrial location of Bcl-2 might be the reasons why PAB inhibited the binding of Bcl-2 and Beclin 1.
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PMID:Bcl-2 family proteins were involved in pseudolaric acid B-induced autophagy in murine fibrosarcoma L929 cells. 1863 20

Anthocyanins extracted from the berries of Phillyrea latifolia L., Pistacia lentiscus L., and Rubia peregrina L., three evergreen shrubs widely distributed in the Mediterranean area, were examined for their antioxidant and anticancer activity. The P. lentiscus anthocyanins showed the highest H(2)O(2) and 1,1-diphenyl-2-picryl-hydrazil radical scavenging effects, indicating that these compounds can be considered as an alternative source of natural antioxidants for food and pharmaceutical products. Here, we also report a novel function of anthocyanins: the induction of autophagy, a process of subcellular turnover involved in carcinogenesis. Autophagy was characterized by the up-regulation of eIF2alpha, an autophagy inducer, and down-regulation of mTOR and Bcl-2, two autophagy inhibitors. This led to the enhanced expression of LC3-II, an autophagosome marker in mammals, and monodansylcadaverine incorporation into autolysosomes. Anthocyanin-induced autophagy switched to apoptosis, as shown by the activation of Bax, cytochrome c and caspase 3, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-positive fragmented nuclei, and cells with sub-G(1) DNA content, which were prevented by z-VAD. Inhibition of autophagy by either 3-methyladenine or Atg5 small interfering RNA enhanced anthocyanin-triggered apoptosis. This provided evidence that autophagy functions as a survival mechanism in liver cancer cells against anthocyanin-induced apoptosis and a rationale for the use of autophagy inhibitors in combination with dietary chemopreventive agents.
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PMID:Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma. 1872 93

Macroautophagy, a tightly orchestrated intracellular process for bulk degradation of cytoplasmic proteins or organelles, is believed to be essential for cell survival or death in response to stress conditions. Recent observations indicate that autophagy is an adaptive response in cells subjected to prolonged hypoxia. However, the signaling mechanisms that activate autophagy under acute hypoxic stress are not clearly understood. In this study, we show that acute hypoxic stress by treatment with 1% O(2) or desferroxamine, a hypoxia-mimetic agent, of cells renders a rapid induction of LC3-II level changes and green fluorescent protein-LC3 puncta accumulation, hallmarks of autophagic processing, and that this process involves protein kinase Cdelta (PKCdelta), and occurs prior to the induction of BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3). Interestingly, hypoxic stress leads to a rapid and transient activation of JNK in Pa-4 or mouse embryo fibroblast cells. Acute hypoxic stress-induced changes in LC3-II level and JNK activation are attenuated in Pa-4 cells by dominant negative PKCdeltaKD or in mouse embryo fibroblast/PKCdelta-null cells. Intriguingly, the requirement of PKCdelta is not apparent for starvation-induced autophagy. The importance of PKCdelta in hypoxic stress-induced adaptive responses is further supported by our findings that inhibition of PKCdelta-facilitated autophagy by 3-methyladenine or Atg5 knock-out renders a greater prevalence of cell death following prolonged desferroxamine treatment, whereas PKCdelta- or JNK1-deficient cells exhibit resistance to extended hypoxic exposure. These results uncover dual roles of PKCdelta-dependent signaling in the cell fate determination upon hypoxic exposure.
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PMID:Novel roles for protein kinase Cdelta-dependent signaling pathways in acute hypoxic stress-induced autophagy. 1883 80

The Bcl-2 associated athanogene (BAG) family of proteins function as cochaperones by bridging molecules that recruit molecular chaperones to target proteins. BAG-1 provides a physical link between the heat shock proteins Hsc70/Hsp70 and the proteasome to facilitate ubiquitin-proteasome-mediated protein degradation. In addition to the proteasome, protein degradation via autophagy is responsible for maintaining cellular metabolism, organelle homeostasis and redox equilibrium. Our recent report shows that autophagy plays an important role in cardiac adaptation-induced cell survival against ischemia-reperfusion injury in association with the BAG-1 protein. BAG-1 is associated with the autophagosomal membrane protein LC3-II and it may participate in the induction of autophagy via Hsc70. Moreover, another BAG family member, BAG-3, is responsible for the induction of macroautophagy in association with HspB8. These results show the involvement of BAG family members in the induction of autophagy for the degradation of damaged or oxidized proteins to promote cell survival.
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PMID:BAG-1 induces autophagy for cardiac cell survival. 1900 66

Although apoptosis (programmed cell death type I) is more frequently reported in the literature in imatinib-treated gastrointestinal stromal tumor (GIST) cell lines,morphological features consistent with autophagic changes aremore often encountered in surgical specimens of treated patients. Autophagy (programmed cell death type II) is highly regulated by a tumor-suppressor mechanism that mainly involves the genes beclin1, PI3KIII, and bcl2. Being our material not suitable for electron microscopy analysis (not paraformaldehyde-glutaraldehyde-fixed), we evaluated the morphological, biochemical, and immunophenotypical profiles expected to be related to autophagy and apoptosis in a series of surgically resected samples taken from 11 imatinib-treated patients with molecularly characterized GISTs. The samples were examined for imatinib-induced morphological changes, the presence/interactions of the autophagic-related proteins (beclin1, PI3KIII, bcl2, and LC3-II) and the presence of apoptosis-related proteins (caspase 3, caspase 7, and lamin A/C) by means ofWestern blot analysis and coimmunoprecipitation, complemented by immunohistochemistry. We also studied samples of two untreated GISTs used as controls. Sampling areas with different residual cellularity scores fromboth the imatinib-treated and untreated patients showed biochemical and immunohistochemical evidence of high levels of proautophagy beclin1/PI3KIII and low levels of antiautophagy beclin1/bcl2 complexes, together with the presence of LC3-II detected by Western blot analysis, thus supporting the presence of autophagy. There was no expression of cleaved/activated caspase 3 or 7 or cleaved lamin A/C. Our descriptive results support the idea that GISTs activate autophagy rather than apoptosis in response to imatinib treatment and that their molecular makeup includes fingerprints of autophagy.
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PMID:Is autophagy rather than apoptosis the regression driver in imatinib-treated gastrointestinal stromal tumors? 1904 28

The therapeutic usefulness of the quinoxaline derivatives XK469 (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid) has been attributed to their abilities to induce G(2)/M arrest and apoptotic or autophagic cell death. Concentrations of XK469 or SH80 > or = 5 microM were cytostatic to cultures of the normal murine melanocyte cell line Melan-a. Higher concentrations caused dose-dependent cytotoxicity. Concentrations > or =10 microM provoked dramatic morphological changes typified by marked increases in cell size and granularity. XK469/SH80-treated cultures accumulated tetraploid (4N) DNA-containing cells within 24 h of treatment, an 8N population within 3 days, and a 16N population within 5 days. Increases in ploidy correlated with the appearance of multinucleated cells. Under no circumstances did cells exhibit evidence of furrow formation. Both drugs suppressed cytokinesis in additional mammalian cell lines. Cytotoxic concentrations of XK469 elevated DEVDase activities (a measure of procaspase-3/7 activation) and enhanced cellular staining by a fluorescent analog of the pan caspase inhibitor valine-alanine-aspartic acid-fluoromethyl ketone within 48 to 96 h of treatment. Within 48 h of treatment, cytostatic and cytotoxic concentrations of XK469 elevated p21 contents, reduced Bcl-2 and Bcl-XL contents, and induced autophagy, as monitored by the accumulation of phosphatidylethanolamine-modified cleavage product of microtubule-associated protein light chain 3 (LC3-II). Cultures treated with > or =10 microM XK469 or SH80 for 5 days could not be induced to divide upon removal of drugs. Such cultures maintained high LC3-II contents, exhibited reduced cyclin E and D1 contents, and extensively expressed senescence-associated beta-galactosidase within 14 to 17 days of cessation of drug treatment. Hence, XK469 and SH80 inhibit cytokinesis, promote polyploidy, and induce senescence in Melan-a cells.
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PMID:The chemotherapeutic agents XK469 (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid) inhibit cytokinesis and promote polyploidy and induce senescence. 1906 41

Cell cycle arrest in G(0) and autophagy share features in common. The Bcl-2 family exerts cell cycle effects in addition to regulating apoptosis. Bcl-2 and Bcl-x(L) upregulate p27 and promote G(0) arrest. Recently, we asked whether autophagy was involved in Bcl-2 and Bcl-x(L)-mediated cell cycle arrest, and found that autophagy was activated, but not required, for G(0) arrest. We also discovered that the cell cycle function of Bcl-2 and Bcl-x(L) was dependent on Bax and Bak, and in bax(-/-) bak(-/-) double knockout cells, features of G(0) quiesecence were already present and p27 was constitutively elevated. Here, we queried the presence of autophagy in bax(-/-) bak(-/-) double knockout cells, and report the phosphorylation of p27 at Thr198, which is known to occur in autophagy, as well as constitutive Atg5 induction and LC3-I to -II conversion. These findings in bax(-/-) bak(-/-) cells suggest that a physiological role of Bax and Bak may be the suppression of autophagy.
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PMID:Bax-/- bak-/- cells exhibit p27 Thr198 phosphorylation and autophagy. 1913 29


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