UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Release of mitochondrial cytochrome c has been recently linked to the activation of the "executioner" phase of the cellular programs for death by apoptosis. This release is known to be negatively regulated by Bcl-2 and Bcl-XL proteins. We show here that treatment of human leukemia cells HL60 with 1,25-dihydroxyvitamin D3 (1,25D3) results in progressive increases in the levels of cellular antiapoptotic protein Mcl-1, a transient increase in Al protein level, but no increases in Bcl-2 or Bcl-XL proteins. The increase in Mcl-1 protein levels correlates with a reduced extent of apoptotic cell death induced by etoposide or the calcium ionophore A23187. The Mcl-1 protein is primarily localized in the mitochondria, and etoposide- or A23187-induced cytochrome c release is reduced in cells in which the mitochondria contain the Mcl-1 protein demonstrable by immunoblots. Raf-1 protein can also be detected in the mitochondrial fractions that contain Mcl-1 protein but not in the Mcl-1-negative fractions. These findings suggest that in these promyelocytic leukemia cells Mcl-1 has a function analogous to that of Bcl-2 in other cells, i.e., to target Raf-1 to mitochondria and to reduce cell damage-induced release of mitochondrial cytochrome c. Our findings provide a potential mechanism for the antiapoptotic action of 1,25D3 and show that differentiation and apoptosis signaling pathways not only interact but involve a proliferation-associated gene, Raf-1.
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PMID:Antiapoptotic action of 1,25-dihydroxyvitamin D3 is associated with increased mitochondrial MCL-1 and RAF-1 proteins and reduced release of cytochrome c. 928 70

Treatment of human promyelocytic leukemia HL-60 cells with phorbol esters ultimately induces the differentiation of these cells along the monocyte/macrophage lineage, whereas treatment with retinoic acid or DMSO induces granulocytic/neutrophillic differentiation. In this study, we demonstrate the disparate fates of HL-60 cells treated with the phorbol ester 12,13-phorbol dibutyric acid (PDBu) or DMSO. After DMSO treatment, HL-60 cells eventually died via apoptosis, whereas the viability of PDBu-treated cells was not affected during the same interval. The levels of the apoptosis effector proteins Bak and Bad were enhanced, whereas there was a slight down-regulation of the apoptosis suppressor protein Bcl-2 after treatment of the cells with PDBu and DMSO. Treatment with DMSO resulted in the elevation of the apoptosis effector Bax, whereas treatment with PDBu did not significantly alter the levels of this protein. However, treatment of HL-60 cells with PDBu induced the rapid expression of the apoptosis suppressor protein Bcl-xL, whereas the expression of this protein remained unaltered in DMSO-treated cells. The generality of this finding was confirmed by the induction of Bcl-xL in human myeloid U-937 cells, human peripheral blood monocytes exposed to phorbol ester, and mouse thioglycollate-activated and resident peritoneal macrophages. PDBu-treated HL-60 cells remained viable for 7 days and thereafter began to die via apoptosis, with a concomitant down-regulation of Bcl-xL. In conclusion, we propose that Bcl-xL expression is associated with differentiation and survival of hematopoietic cells along the monocyte/macrophage lineage.
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PMID:Monocytic differentiation of HL-60 promyelocytic leukemia cells correlates with the induction of Bcl-xL. 934 86

Nitric oxide (NO) generated from 1-hydroxy-2-oxo-3, 3-bis(2-aminoethyl)-1-triazene (NOC 18), an NO-releasing compound, induced monocytic differentiation of human promyelocytic leukemia HL-60 cells as assessed by expression of nonspecific esterases and morphologic maturation. Simultaneously, DNA fragmentation and morphological alterations typical of apoptosis were also induced. To investigate the mechanisms of apoptosis during differentiation of HL-60 cells induced by NO, the endogenous levels of Bcl-2 and Bax were assessed by immunoblotting. Treatment of cells with NOC 18 slightly reduced the level of Bcl-2 followed by Bax. These changes might be involved in the induction of apoptosis. The involvement of the activation of the interleukin-1 beta converting enzyme (ICE) family of proteases (caspases), such as ICE and CPP32, in the pathways was also investigated. CPP32, but not ICE, was strongly activated in response to NOC 18 stimulation, thereby implicating CPP32-like activity in the induction of apoptosis. Moreover, the possible involvement of tyrosine phosphorylation in apoptosis was investigated. Pretreatment of cells with herbimycin A, an inhibitor of tyrosine kinases, suppressed DNA fragmentation and CPP32-like activity, whereas pretreatment with vanadate, an inhibitor of tyrosine phosphatases, enhanced both parameters, suggesting that tyrosine phosphorylation might be involved in the pathways of apoptosis in HL-60 cells induced by NO.
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PMID:Molecular mechanisms of apoptosis in HL-60 cells induced by a nitric oxide-releasing compound. 935 Apr 36

The effects of an acidic environment on the induction of apoptosis by 42 degrees C hyperthermia were investigated. An acidic environment (pH 6.6) enhanced the hyperthermia-induced apoptosis in HL-60 human promyelocytic leukemia cells as judged by the DNA fragmentation, flow cytometric analysis of DNA content, and cleavage of poly(ADP-ribose) polymerase. Hyperthermia exerted no effect on the expression of Bcl-2 and Bax, regardless of the environmental acidity during heating. The time of increase in apoptosis after heating coincided with the time of decrease in the G1-phase cell population. It seemed that the increase in heat-induced apoptosis in HL-60 cells in an acidic environment was due to a direct increase in the proteolytic cleavage of poly(ADP-ribose) polymerase by acidic caspases without the involvement of Bcl-2 and Bax, and that heat-induced apoptosis occurred during G1 phase in HL-60 cells.
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PMID:Apoptosis and perturbation of cell cycle progression in an acidic environment after hyperthermia. 963 68

Recent reports have implicated a possible role of reactive oxygen species (ROS) in the induction and mediation of apoptosis and DNA damage. Oxidative DNA base modification induced by cupric nitrilotriacetate (Cu-NTA) and the following apoptosis were observed in human promyelocytic leukemia HL-60 cells. We measured the level of ROS in the cells by using a fluorescence probe, 2',7'-dichlorofluorescein diacetate (DCFH-DA), and the amount of a modified DNA base, 8-hydroxydeoxyguanosine (8-OHdG) by HPLC-ECD. It was found that Cu-NTA exposure significantly enhanced ROS and 8-OHdG formation in the cells. Meanwhile, we observed both DNA fragmentation and morphological changes characteristic of apoptosis, which was also determined quantitatively by flow cytometry and showed dose- and time-dependent manners. Furthermore, several antioxidants such as dimethyl sulfoxide (DMSO), superoxide dismutase (SOD), and catalase were used to detect whether the apoptosis could be blocked. Only DMSO protected against this form of cell death. To elucidate molecular events in the apoptosis, expressions of Bcl-2 protein family members, such as Bcl-2, Bcl-X and Bax, and heat shock protein 70 (HSP-70) were measured by western blotting using specific antibodies. The levels of Bax and Bcl-Xs remained largely unchanged, but the Bcl-2 and Bcl-XL expression showed down-regulation. After 24 h incubation in the presence of copper, the levels of Bcl-2 and Bcl-XL reduced about 33.8% and 51.1% compared with untreated cells, respectively. Furthermore, after 16 h incubation, the level of HSP-70 expression was about 3.4-fold greater than that in untreated cells, suggesting that HSP-70 is important in increasing resistance to oxidative stress induced by Cu-NTA. But overexpression of HSP-70 failed to protect HL-60 cells from apoptosis induced by Cu-NTA. We inferred that Cu-NTA may induce oxidative DNA damage through free radical injuries, which may turn on the apoptosis in HL-60 cells.
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PMID:Cupric nitrilotriacetate induces oxidative DNA damage and apoptosis in human leukemia HL-60 cells. 974 94

Arsenic trioxide (As2O3) has been demonstrated to be effective for the treatment of acute promyelocytic leukemia (APL) and to inhibit proliferation and produce apoptosis in the APL cell line NB4. To determine if As2O3 might be useful for the treatment of other lineages, we investigated the effects of As2O3 on viability, proliferation, and induction of apoptosis in the megakaryocytic leukemia cell lines HEL, Meg-01, UT7, and M07e. Our results showed that As2O3, at concentrations of 0.1-2.0 microM, causes a dose- and time-dependent inhibition of survival and growth in all four megakaryocytic leukemia cell lines studied. In contrast, As2O3 at similar concentrations had no effects on either viability or growth of the nonmegakaryocytic leukemia cell line HL60 and two human breast cancer cell lines, ZR75 and MCF7. In situ end-labeling of DNA fragments (TUNEL assay) indicated that As2O3, at concentrations of 0.5-2 microM, could significantly induce apoptosis in the aforementioned four megakaryocytic leukemia cell lines, but not in the nonmegakaryocytic HL60, ZR75, and MCF7 cell lines. These results were confirmed using conventional morphologic assessment and the DNA ladder assay. Induction of apoptosis in arsenic-treated Meg-01 and UT7 cells was accompanied by a dose-response decrease of Bcl-2 protein, whereas As2O3 had no effect on this measurement in HL60, ZR75, and MCF7 cell lines. Pertinently, these concentrations of As2O3 produced identical changes in the characteristics of the APL cell line NB4. Collectively, these data demonstrate that As2O3 can selectively inhibit growth and induce apoptosis in megakaryocytic leukemia cell lines. The use of As2O3 for the treatment of malignant megakaryocytic disorders should be considered.
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PMID:Effect of arsenic trioxide on viability, proliferation, and apoptosis in human megakaryocytic leukemia cell lines. 1034 Apr

The molecular mode of action of arsenic, a therapeutic agent employed in the treatment of acute promyelocytic leukemia, has been elusive. Here we provide evidence that arsenic compounds may act on mitochondria to induce apoptosis. Arsenite induces apoptosis accompanied by a loss of the mitochondrial transmembrane potential (Delta Psim). Inhibition of caspases prevents the arsenite-induced nuclear DNA loss, but has no effect on the Delta Psim dissipation and cytolysis induced by arsenite. In contrast, Bcl-2 expression induced by gene transfer prevents all hallmarks of arsenite-induced cell death, including the Delta Psim collapse. PK11195, a ligand of the mitochondrial benzodiazepine receptor, neutralizes this Bcl-2 effect. Mitochondria are required in a cell-free system to mediate arsenite-induced nuclear apoptosis. Arsenite causes the release of an apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space. This effect is prevented by the permeability transition (PT) pore inhibitor cyclosporin A, as well as by Bcl-2, which is known to function as an endogenous PT pore antagonist. Arsenite also opens the purified, reconstituted PT pore in vitro in a cyclosporin A- and Bcl-2-inhibitible fashion. Altogether these data suggest that arsenite can induce apoptosis via a direct effect on the mitochondrial PT pore.
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PMID:Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. 1036 41

Resveratrol, a triphenolic stilbene present in grapes and other plants, has striking antioxidant and anti-inflammatory activities which have been considered to be responsible for the beneficial effects of red wine consumption on coronary heart disease. Recent studies reveal that resveratrol can inhibit each step of multistage carcinogenesis. However, the molecular mechanisms underlying anti-tumorigenic or chemopreventive activities of this phytochemical remain largely unknown. In the present work, we have found that resveratrol reduces viability and DNA synthesis capability of cultured human promyelocytic leukemia (HL-60) cells. The growth inhibitory and antiproliferative properties of resveratrol appear to be attributable to its induction of apoptotic cell death as determined by morphological and ultrastructural changes, internucleosomal DNA fragmentation, and increased proportion of the subdiploid cell population. Resveratrol treatment resulted in a gradual decrease in the expression of anti-apoptotic Bcl-2. These results, together with previous findings, suggest the cancer therapeutic as well as chemopreventive potential of resveratrol.
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PMID:Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells. 1040 35

Granulocyte colony-stimulating factor (G-CSF) is a cytokine that regulates the proliferation, differentiation and survival of cells in the granulocytic lineage. In this study, however, we found that G-CSF or interleukin-6 (IL-6) induced UF-1, a human acute promyelocytic leukemia cell line, into apoptosis that was confirmed by morphological features and DNA fragmentation. This rare response is demonstrated for the first time with human acute promyelocytic leukemia cell line. The apoptosis induced by G-CSF or IL-6 was not preceded by terminal differentiation characterized by morphological maturation, capability to reduce nitroblue tetrazolium, or surface CD11b expression. Interestingly, Western blot analysis revealed that the stimulation of UF-1 with either G-CSF or IL-6 resulted in excessive activation of both signal transducer and activator of transcription 3alpha (Stat3alpha) and Stat3beta. Furthermore, an additional 18 kDa Bax-related protein was expressed by the stimulation of G-CSF or IL-6, while Bcl-2 and Bcl-X proteins remained unchanged. These findings suggest that UF-1 may be a valuable tool in investigating the aberrant regulation of apoptosis, especially the Stat3 involvement in the mechanism of apoptosis induction.
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PMID:G-CSF induces apoptosis of a human acute promyelocytic leukemia cell line, UF-1: possible involvement of Stat3 activation and altered Bax expression. 1062 10

Apoptosis or programmed cell death is a highly organized physiologic process of not only maintaining homeostasis but also selectively eliminating damaged or abnormal cells. Apoptotic destruction of predisposed cells may reduce the proportion of cells available for malignant progression. Thus, pharmacologic manipulation of apoptotic pathway is regarded as a novel strategy in cancer chemoprevention as well as therapy. 2-(Allylthio)pyrazine (2-AP), a pyrazine derivative of allylsulfide synthesized for use as a chemoprotective agent, has been shown to protect against experimental carcinogenesis and mutagenesis. The present study examined the capability of 2-AP to induce apoptosis in cultured human promyelocytic leukemia (HL-60) cells. Treatment of HL-60 cells with 2-AP led to suppression of viability and proliferation in a concentration-dependent manner. Microscopic examination of the treated cells revealed typical morphological features of apoptosis, such as nuclear fragmentation and chromatin condensation. Furthermore, cells treated with 2-AP exhibited internucleosomal DNA fragmentation. Flow cytometric analysis of HL-60 cells exposed to 2-AP showed appearance of a distinct peak representing the subdiploid cell population. 2-AP treatment decreased the ratio of anti-apoptotic Bcl-2 to the death stimulating protein Bax, which may account for the molecular basis of apoptosis-inducing activity of this chemopreventive organosulfur derivative.
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PMID:2-(allylthio)pyrazine suppresses the growth and proliferation of human promyelocytic leukemia (HL-60) cells via induction of apoptosis. 1062 56

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