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)

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
 ...
PMID:Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. 1102 84

UVC-induced apoptotic symptoms such as morphological changes, DNA fragmentation, Bcl-2 and Bax protein expression were examined in primary splenocyte cultures from young (3 months) and old (24 months) rats. The activities of AP-1 and CRE transcription factors in UVC-irradiated splenocytes were also assessed. At 24 h after UVC irradiation 40% of cells derived from young rats were found to be apoptotic, which was twice as much as in splenocytes from old rats. Apoptosis in cells from old rats did not give typical symptoms like a "DNA ladder" and Bcl-2 protein downregulation, in contrast to splenocytes from young rats. No AP-1 transcription factor activity was found in UVC-irradiated splenocytes from old animals and only a trace activity in splenocytes from young animals. This indicates that, UVC-induced apoptosis in rat splenocytes is practically AP-1 independent and that cells from old rats are less sensitive to UVC irradiation than splenocytes from young rats.
 ...
PMID:Effect of aging on UVC-induced apoptosis of rat splenocytes. 1105 Nov 98

Reperfusion of ischemic myocardium results in apoptotic cell death and DNA fragmentation. Several transcription factors are known to regulate the apoptotic cell death. This study sought to examine the regulation of cardiomyocyte apoptosis by these transcription factors. Isolated working rat hearts were divided into six groups: control, 15 min ischemia, 60 min ischemia, 15 min ischemia followed by 2 h reperfusion, ischemic stress adaptation by subjecting the hearts to four cyclic episodes to 5 min ischemia, each followed by 10 min of reperfusion, and adaptation followed by 15 min ischemia and 2 h reperfusion. Redox-regulated transcription factors, NF kappa B and AP-1 and the expression of two anti- and pro-apoptotic genes, Bcl-2 and p53 were determined. The results demonstrated NF kappa B and AP-1 progressively and steadily increased as a function of the duration of ischemia. In the adapted heart, NF kappa B binding remained high while AP-1 binding was lowered to almost baseline value. The anti-oxidant gene, Bcl-2 was downregulated in the ischemic/reperfused heart, but upregulated in the preconditioned myocardium. Significant induction of the expression of p53 occurred after ischemia and reperfusion. Apoptotic cells were barely detected in the adapted myocardium which was subjected to the same ischemia/reperfusion protocol. The results demonstrate for the first time differential regulation of cardiomyocyte apoptosis by pro- and anti-apoptotic transcription factors and genes as a function of different durations of ischemia and reperfusion.
 ...
PMID:Regulation of cardiomyocyte apoptosis by redox-sensitive transcription factors. 1108 56

Two redox-sensitive transcription factors, AP-1 and NF-kappaB, have been implicated in the regulation of apoptosis induced by myocardial ischemia and reperfusion. Hearts adapted to ischemic stress by cyclic episodes of short durations of ischemia and reperfusion attenuate apoptotic cell death. This study was designed to examine the pattern of expression of these transcription factors and the redox sensitive transacting molecule, AP-1, NF-kappaB, and- Bcl-2, during ischemia/ reperfusion and myocardial adaptation to ischemia. NF-kappaB binding activity was low in nonischemic control heart. Fifteen minutes of ischemia resulted in translocation of NF-kappaB from cytosol to nucleus followed by activation. The binding activity of NF-kappaB was further enhanced after 60 min of ischemia. An even higher degree of NF-kappaB binding was noticed in the ischemically adapted myocardium. In contrast, AP-1 binding activity was highest for the hearts subjected to 15 min of ischemia followed by 2 hr of reperfusion. AP-1 binding was higher in the ischemically adapted heart as compared to the control. The Bcl-2 gene, which was found to be present in the control hearts, had lowered expression after 15 min of ischemia and 2 hr of reperfusion. Significant upregulation of Bcl-2 mRNA was noticed in the ischemically adapted hearts. Apoptotic cardiomyocytes were found only in the hearts that were reperfused for at least 90 min. No apoptosis occurred in hearts subjected up to 1 hr of ischemia or ischemic adaptation. Prolonged reperfusion, and not ischemia up to 1 hr, can induce cardiomyocyte apoptosis. In concert, ischemic/reperfusion increases the nuclear binding of both AP-1 and NF-kappaB, but downregulates Bcl-2 gene. Ischemic adaptation attenuates apoptotic cell death, further increases NF-kappaB binding activity and Bcl-2 gene induction, but reduces AP-1 binding activity. These results suggest that AP-1, NF-kappaB, and Bcl-2 are differentially regulated by ischemia/reperfusion and ischemic adaptation.
 ...
PMID:Redox regulation of NF-kappaB and AP-1 in ischemic reperfused heart. 1122 43

There is growing evidence which suggests that dysregulation of apoptosis may lead to several disease states including cancer. To investigate the mechanism controlling the induction of cell death, apoptosis defective/resistant (Apt-) mutants were isolated and characterized in this study. FDC-P1, a mouse myeloid cell line that depends upon IL-3 for survival and growth but undergoes apoptosis when deprived of growth factor, was mutagenized by treatment with ethyl methane sulfonate. We selected cells that survived the growth factor deprivation but did not grow without the factor. Surviving cells were cloned by limiting dilution and four clones that showed the least morphological characteristics and biochemical changes of apoptosis were chosen. Unlike the parent FDC-P1, these mutants were cross resistant to apoptosis induced by a variety of antitumor drugs such as Adriamycin, Dexamethasone, VP-16, as well as reactive oxygen species (ROS) generated by xanthine/xanthine oxidase (X/XO). We used one of these Apt- mutant to test candidate death genes. Our findings suggest that the preferential increase in Bax/Bcl-2 ratio, p53, c-Myc, Caspase-3 and decrease in AP-1 on treatment with various anticancer drugs may contribute to the preferential apoptotic response in FDC-P1 cells but to varying degrees. Whereas, the higher constitutive level of antioxidant enzymes superoxide dismutase and catalase in the Apt- mutant may contribute at least in part to its resistance.
 ...
PMID:Differential sensitivity of murine myeloid FDC-P1 cells and apoptosis resistant mutant(s) to anticancer drugs. 1123 67

Nerve growth factor (NGF) binds to the TrkA tyrosine kinase and the p75 neurotrophin receptors. Depending upon which receptor is activated, NGF can induce differentiation or apoptosis. C6-2B glioma cells express the p75 receptor, but NGF decreases their growth only when TrkA is introduced (C6trk). It is unclear, however, whether TrkA reduces C6-2B cell growth by apoptosis or differentiation. To examine which mechanisms account for the anti-proliferative effect of NGF in these cells, we first analyzed whether NGF causes apoptosis by flow cytometry, two-site immunoassay and in situ TUNEL. None of these methods indicated that C6trk undergo apoptosis. Additional apoptotic markers, such as Bcl-2, Bax, Bad, p53, caspase 3, and NF-kappaB were also used. C6trk cells exhibited lower levels of Bcl-2 compared with the parental C6 mock cells, but no changes in the levels of other apoptotic proteins. Moreover, NGF increased AP-1 binding activity in C6trk cells, suggesting that NGF may induce differentiation. We then examined whether TrkA changes the glioma phenotype. In C6trk cells, but not in C6mock cells, NGF enhanced the levels of neuron-specific enolase as well as the levels of A2B5 and 2', 3'-cyclic nucleotide 3'-phosphodiesterase, markers for oligodendrocytes, without affecting the expression of other neuronal markers. Our data suggest that the antiproliferative properties of TrkA may rely on its ability to induce differentiation of C6 cells from undifferentiated glioma to oligodendrocytes.
 ...
PMID:TrkA induces differentiation but not apoptosis in C6-2B glioma cells. 1139 88

The mood-stabilizing agents lithium and valproic acid (VPA) increase DNA binding activity and transactivation activity of AP-1 transcription factors, as well as the expression of genes regulated by AP-1, in cultured cells and brain regions involved in mood regulation. In the present study, we found that VPA activated extracellular signal-regulated kinase (ERK), a kinase known to regulate AP-1 function and utilized by neurotrophins to mediate their diverse effects, including neuronal differentiation, neuronal survival, long term neuroplasticity, and potentially learning and memory. VPA-induced activation of ERK was blocked by the mitogen-activated protein kinase/ERK kinase inhibitor PD098059 and dominant-negative Ras and Raf mutants but not by dominant-negative stress-activated protein kinase/ERK kinase and mitogen-activated protein kinase kinase 6 mutants. VPA also increased the expression of genes regulated by the ERK pathway, including growth cone-associated protein 43 and Bcl-2, promoted neurite growth and cell survival, and enhanced norepinephrine uptake and release. These data demonstrate that VPA is an ERK pathway activator and produces neurotrophic effects.
 ...
PMID:The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. 1141 8

The involvement of MAPK pathways in differentiation, proliferation and survival was investigated by comparing Epo and GM-CSF signalling in human factor-dependent myeloerythroid TF-1 cells with abnormal Epo-R. GM-CSF withdrawal induced cell-cycle arrest and apoptosis accompanied by increased caspase-3 activity, DNA degradation and reduced expression of the antiapoptotic Bcl-2 and Bcl-xl proteins. Readministration of GM-CSF but not Epo reversed these processes and induced proliferation. The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. In contrast, Epo failed to activate the Raf-1/ERK1/2 MAPK pathway or to induce Egr-1 and/or c-Fos expression, while it induced erythroid differentiation in GM-CSF-deprived cells. In addition, the Epo-induced haemoglobin production was inhibited in the presence of GM-CSF. These results demonstrate that the activation of MAPK cascade is not necessary for Epo-induced haemoglobin production in TF-1 cells and suggest a negative cross-talk between the signalling of GM-CSF-stimulated cell proliferation and Epo-induced erythroid differentiation.
 ...
PMID:Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells. 1160 85

Corpora amylacea (CAm) are regarded as a hallmark of brain ageing, but little is known about their role in normal and pathological circumstances. CAm contain, in addition to glucose polymers, ageing-, stress- and proinflammatory proteins. In view of their almost universal occurrence and their cumulation with time, formation of CAm may represent a basic mechanism for the management of metabolic degradation products. In this context, we studied samples from post-mortem cases with repetitive brain hypoxic episodes in the past history. We investigated, by immunohistochemistry, the presence of Bcl-2, c-jun and bax in CAm. CAm showed immunoreactivity for the mitochondrial membrane associated protein Bcl-2, and for the major component of activator protein 1 transcriptional factor c-Jun. We found higher numbers of CAm in the hippocampus and the dentate gyrus in cases with repetitive cerebral hypoxia than in controls. We conclude that: (1) the presence of C-Jun and Bcl-2 within the glucose polymer mass of CAm may be related to mitochondrial damage and/or a transient overload of proteolytic systems during cellular injury; and (2) repetitive cellular stress during life may cause the age-related increase of CAm in elderly subjects.
 ...
PMID:Immunoreactivity for Bcl-2 and C-Jun/AP1 in hippocampal corpora amylacea after ischaemia in humans. 1190 30

Although cytokine-induced nuclear factor kappaB (NF-kappaB) pathways are involved in muscle wasting subsequent to disease, their potential role in disuse muscle atrophy has not been characterized. Seven days of hind limb unloading led to a 10-fold activation of an NF-kappaB-dependent reporter in rat soleus muscle but not the atrophy-resistant extensor digitorum longus muscle. Nuclear levels of p50 were markedly up-regulated, c-Rel was moderately up-regulated, Rel B was down-regulated, and p52 and p65 were unchanged in unloaded solei. The nuclear IkappaB protein Bcl-3 was increased. There was increased binding to an NF-kappaB consensus oligonucleotide, and this complex bound antibodies to p50, c-Rel, and Bcl-3 but not other NF-kappaB family members. Tumor necrosis factor alpha (TNF-alpha) and TNF receptor-associated factor 2 protein were moderately down-regulated. There was no difference in p38, c-Jun NH(2)-terminal kinase or Akt activity, nor were activator protein 1 or nuclear factor of activated T cell-dependent reporters activated. Thus, whereas several NF-kappaB family members are up-regulated, the prototypical markers of cytokine-induced activation of NF-kappaB seen with disease-related wasting are not evident during disuse atrophy. Levels of an anti-apoptotic NF-kappaB target, Bcl-2, were increased fourfold whereas proapoptotic proteins Bax and Bak decreased. The evidence presented here suggests that disuse muscle atrophy is associated with activation of an alternative NF-kappaB pathway that involves the activation of p50 but not p65.
 ...
PMID:Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy. 1191 55


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