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)

Apoptosis has been investigated in NB4, a t(15;17) human promyelocytic leukemia cell line susceptible to maturation by all-trans or 9-cis retinoic acid, and in NB4-R1, a subclone resistant to differentiation. Maturation resistant NB4-R1 cells exhibited an onset of cell death after RA-treatment (72 h), whereas maturation responsive NB4 cells showed no such apoptosis, cell death being considerably delayed after cell maturation. Only a few NB4-R1 cells underwent apoptosis in response to low doses of RA (below 0.1 microM), the surviving cells became refractory to higher doses of RA. While these cells became 'resistant' to apoptosis they became competent for maturation. Typically, these RA-'primed' cells responded to cAMP by maturation, then apoptosis followed rapidly. This model furnishes situations where cells are either resistant or susceptible to apoptosis, depending on whether they can or cannot undergo maturation. The potential role of the Bcl-2 protein in the regulation of apoptosis was analyzed. In NB4 and NB4-R1 cell lines, a high expression of the Bcl-2 protein was detected by immunocytology and Western blotting. NB4 cells treated with either all-trans or 9-cis retinoic acid (1 microM) were induced to differentiate and the level of Bcl-2 protein decreased to undetectable levels during terminal maturation when only a few apoptotic cells were detected. In NB4-R1 cells, while treatment with retinoids does not induce maturation, as much as 64% of cells became apoptotic, and immunocytological labelling of NB4-R1 showed a strong cytoplasmic labelling of Bcl-2. Although the expression of Bcl-2 remained high, cells were not protected from apoptosis. To assess whether Bcl-2 expression could be modulated as a consequence of differentiation, NB4-R1 cells previously 'primed' for maturation were triggered with cAMP. Downregulation of Bcl-2 protein occurred concomitant with maturation, followed by apoptosis. Clearly, NB4 and NB4-R1 cells show reciprocal behavior with regards to proliferation, maturation, Bcl-2 regulation and apoptosis in response to RA. Our results suggest, first, that the Bcl-2 downregulation in NB4 cells belongs to the maturation program rather than to apoptosis, and second, that neither a high Bcl-2 expression in NB4 cells is sufficient to protect cells from 9-cis RA induced apoptosis, nor is its full downregulation sufficient to produce apoptosis. Finally, this work suggests that apoptosis and maturation programs include events which cannot occur simultaneously.
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PMID:Distinct apoptotic responses in maturation sensitive and resistant t(15;17) acute promyelocytic leukemia NB4 cells. 9-cis retinoic acid induces apoptosis independent of maturation and Bcl-2 expression. 763 Jan 93

Mechanisms of etoposide (VP-16) resistance have been evaluated in a human promyelocytic leukemia HL60 cell line. HL60 resistant (HL60/AR) cells were selected for resistance with adriamycin and were 250-fold resistant to VP-16. We have found that while a significantly higher (10 to 15-fold more) dose of VP-16 was required to induce similar amounts of SDS-KCI-precipitable DNA-protein complex formation in the resistant cell line, there was no difference in the repair of VP-16-induced DNA damage, indicating that differential DNA repair was not involved in VP-16 resistance in HL60 cells. VP-16 treatment significantly inhibited c-myc expression and induced c-jun and c-fos expressions in sensitive cells. In contrast, VP-16 had no effect on c-myc, c-jun or c-fos expressions in resistant cells. The level of bcl2 oncogene was similar in both cell lines; however, treatment with VP-16 resulted in a time- and dose-dependent degradation of the genomic DNA into oligo-sized DNA only in the sensitive cells, indicating that differential expressions of oncogenes (c-myc, c-jun, and c-fos) and susceptibility to apoptosis may play important roles in the sensitivity and resistance to VP-16 in HL60 cells.
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PMID:Differential oncogene expression and susceptibility to apoptosis in the human leukemia HL60 cell lines: implications for etoposide resistance. 764 49

With the recent advances in molecular technology, diagnostic procedures of the diseases at a DNA level have been introduced in hematological fields. The diagnostic methods used are Southern blotting to detect gene rearrangements, Northern blotting to find gene expressions, RT-PCR (reverse transcriptase-polymerase chain reaction) to identify transcribed fusion messages, and PCR-SSCR (single strand conformation polymorphism) to detect mutated genes. Rearrangements within major Bcr (breakpoint cluster region) were observed in almost all cases in chronic myelogenous leukemia, and breakpoint were found within minor Bcr in Philadelphia-positive leukemia. The rearrangements within the second intron of the retinoic acid receptor-alpha and sixth intron (bcr 1), third intron (bcr 3) and sixth exon (bcr 2) of the PML gene were detected in all cases with acute promyelocytic leukemia. In malignant lymphoma, the rearrangements of immunoglobulin and T-cell receptor genes, and new genes such as Bcl-1, Bcl-2, Bcl-5, Tal-1, and Tal-2 were also reported and rearrangements of the Bcl-5 gene were found in this study using Bcl-5 specific probe which we have cloned. Point mutations and deletions of the genes involved in the coagulation and fibrinolysis system have been reported. One base insertion resulting in elongation of carboxy terminal region and one amino acid deletion in alpha 2-plasmin inhibitor gene were found in two cases of its deficiency. Further study revealed that mutated proteins were retained in the endoplasmic reticulum in the cells. With the development of the PCR method, identification of gene mutation is gradually carried out as a routine work.
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PMID:[Molecular study of hematological diseases]. 791 42

Human promyelocytic leukemia HL-60 cells treated with 8-chloroadenosine-3',5'-cyclic monophosphate (8-Cl-cAMP) undergo growth arrest and subsequently die by apoptosis. We describe here the isolation of a variant of HL-60 cells, HCW-2, which was resistant to the cytotoxic effects of 8-Cl-cAMP, but still underwent growth arrest. Thus, HCW-2 cells appeared to be altered in their ability to undergo apoptosis. HCW-2 cells were also completely refractory to the apoptotic action of cycloheximide and staurosporine, two compounds which were very potent inducers of apoptosis in the parental HL-60 cells, suggesting that the resistance to apoptosis was not unique to 8-Cl-cAMP. Western blot analysis demonstrated that the parental HL-60 cells expressed both Bcl-2 and Bax, two factors known to be intimately involved in the control of apoptosis. Surprisingly, HCW-2 cells no longer expressed Bcl-2 protein and paradoxically contained Bax protein at a level that was approximately 50-fold higher than in HL-60 cells. However, Northern and Western analyses indicated that the apoptotic suppressor gene, bcl-xL, which is not expressed in the parental HL-60 cells, was expressed in HCW-2 cells. Thus, the Bcl-2-independent resistance of HCW-2 cells to apoptotic induction is discussed in terms of the expression of bcl-xL.
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PMID:Isolation and characterization of an apoptosis-resistant variant of human leukemia HL-60 cells that has switched expression from Bcl-2 to Bcl-xL. 860 11

The induction of tumor cell differentiation represents an attractive strategy for the treatment of a wide range of malignancies. Differentiation of HL-60 promyelocytic leukemia cells towards neutrophils or monocytes has been shown to induce apoptotic cell death, which is inhibited by bcl-2 over-expression. However, the role of the bcl-2 gene family during erythroid differentiation of human leukemia cells remains unknown. We found that human erythroleukemia (HEL) and K562, two leukemia cell lines that undergo erythroid differentiation do not express Bcl-2, but express Bcl-XL, a related protein that functions as an inhibitor of apoptosis. Differentiation of HEL or K562 cells with inducers of erythroid differentiation (hemin, retinoic acid, or transforming growth factor-beta) was accompanied by progressive cell death and degradation of genomic DNA into oligonucleosomal fragments. The loss of cellular viability was associated with downregulation of bcl-xL mRNA and protein. In contrast, the levels of Bax, another Bcl-2 family member implicated in apoptosis remained unaltered. Constitutive expression of Bcl-XL by gene transfer inhibited apoptosis triggered by erythroid differentiation of HEL K562 cells. Yet, Bcl-XL did not alter the expression of epsilon-globin, which is induced during erythoid differentiation of HEL and K562 cells, arguing that apoptosis and differentiation can be uncoupled by Bcl-XL. These results indicate that Bcl-XL acts as an antiapoptosis protein in leukemia cells that undergo erythroid differentiation and that downregulation of bcl-x is a component of the apoptotic response that is coupled to differentiation in human leukemia cells.
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PMID:Apoptosis induced by erythroid differentiation of human leukemia cell lines is inhibited by Bcl-XL. 861 10

Myeloid maturation appears to require exit from the cell cycle and leads to activation of apoptosis in the differentiated cells. The level of Bcl-2, which is known to promote cell survival, is shown here to influence both these critical steps. Bcl-2 function during myelomonocytic differentiation was investigated by introducing a deregulated bcl-2 gene into HL60 promyelocytic leukemia cells, which can be induced to exit the cell cycle and differentiate into granulocytes or monocytes. Deregulated Bcl-2 expression did not itself promote differentiation but extended the lifespan of mature cells elicited by granulocytic or monocytic inducers. Unexpectedly, in response to induction, Bcl-2 overexpression markedly potentiated and hastened cell cycle withdrawal into G(0). Enhanced survival cannot account for the elevated numbers of G(0) cells, because they arose under induction conditions that did not kill control cells. Since the cell cycle status and growth of uninduced cells was not affected by Bcl-2-overexpression, its cell cycle inhibitory activity must require an induction signal. While cell cycle withdrawal may be necessary for maturation, it was not sufficient, implicating a requirement for specific differentiative signals. These results identify, for the first time, a function for the bcl-2 proto-oncogene that is separable from its enhancement of cell survival.
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PMID:Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. 887 89

Curcumin, widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anti-tumor promoting activities. In the present study, curcumin was found to induce apoptotic cell death in promyelocytic leukemia HL-60 cells at concentrations as low as 3.5 micrograms/ml. The apoptosis-inducing activity of curcumin appeared in a dose- and time-dependent manner. Flow cytometric analysis showed that the hypodiploid DNA peak of propidium iodide-stained nuclei appeared at 4 h after 7 micrograms/ml curcumin treatment. The apoptosis-inducing activity of curcumin was not affected by cycloheximide, actinomycin D, EGTA, W7 (calmodulin inhibitor), sodium orthovanadate, or genistein. By contrast, an endonuclease inhibitor ZnSO4 and proteinase inhibitor N-tosyl-L-lysine chloro-methyl ketone (TLCK) could markedly abrogate apoptosis induced by curcumin, whereas 12-O-tetradecanoylphorbol-13-acetate (TPA) had a partial effect. The antioxidants, N-acetyl-L-cysteine (NAC), L-ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase, all effectively prevented curcumin-induced apoptosis. This result suggested that curcumin-induced cell death was mediated by reactive oxygen species. Immunoblot analysis showed that the level of the antiapoptotic protein Bcl-2 was decreased to 30% after 6 h treatment with curcumin, and was subsequently reduced to 20% by a further 6 h treatment. Furthermore, overexpression of bcl-2 in HL-60 cells resulted in a delay of curcumin-treated cells entering into apoptosis, suggesting that bcl-2 plays a crucial role in the early stage of curcumin-triggered apoptotic cell death.
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PMID:Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. 895 Jan 93

All-trans retinoic acid (RA) induces granulocytic differentiation of acute promyelocytic leukemia cells both in vivo and in vitro. In the HL-60 wild-type (WT) early promyelocytic leukemia cell line, granulocytic differentiation appears to be directly mediated by the nuclear receptor RAR alpha. An HL-60 subline resistant to RA (HL-60 R) contains a point mutation which results in a truncation of 52 amino acids at the COOH end of RAR alpha. Cross-talk between differentiation, clonal inhibition of growth and apoptosis was studied using HL-60 WT, HL-60 R, and HL-60 R infected by a retroviral vector containing RAR alpha (LX) as targets, which were cultured with various retinoids, vitamin D3 analogs, HMBA, or DMSO. None of these compounds induced significant differentiation of HL-60 R and HL-60 LX, but they did induce differentiation of HL-60 WT. In contrast, retinoids inhibited the clonal proliferation of HL-60 WT, HL-60 R, and HL-60 LX. Vitamin D3 analogs including KH1060 stimulated the clonal growth of HL-60 R; but they inhibited clonal growth of HL-60 WT and LX. Levels of Bcl-2 strongly decreased in HL-60 WT and LX after treatment by retinoids, while no change in expression occurred in HL-60 R. Neither KH 1060 nor 9-cis RA induced apoptosis of HL-60 R, but these agents did induce apoptosis in HL-60 LX WT. Taken together, we showed that HL-60 R has a global defect in its ability to be induced to differentiate by a variety of pathways, not merely the retinoid pathway. Furthermore, our HL-60 models showed that inhibition of proliferation and induction of apoptosis and differentiation can be dissociated. Clinically, these results suggest that several putative differentiation agents may have anti-cancer (antiproliferative) activities, even though they do not induce differentiation of the cancer cells.
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PMID:Alterations of differentiation, clonal proliferation, cell cycle progression and bcl-2 expression in RAR alpha-altered sublines of HL-60. 906 79

In the acute promyelocytic leukemia cell line NB4, Bcl-2 downregulation occurred as a late event of retinoid-induced differentiation. In the maturation-resistant NB4-R1 subclone, retinoids failed to downregulate Bcl-2 even in the situation of apoptosis massively induced by pan-agonists and RXR-selective agonists. We observed that NB4 and NB4-R1 cells differed with respect to the intracellular localization of Bcl-2 which showed a perinuclear localization in NB4-R1 cells, while Bax was broadly expressed in the cytoplasm and to only a minor extent in the perinuclear area. Therefore, the distinct intracellular localization of Bcl-2 and Bax was in general nonoverlapping. Bcl-2 remained massively expressed until cell disruption. Bax was not significantly upregulated in cells committed to death. However, Bax localization changed from a diffuse pattern to concentrate in few specific cytoplasmic area at a stage preceding the formation of apoptotic bodies. A human Bcl-2 transgene was transiently overexpressed in NB4-R1 cells which showed increased resistance to apoptosis induced by retinoids. Stably transfected clones of NB4-R1 cells showed an increased expression of Bcl-2 and a marked resistance to apoptosis. Interestingly, the overexpression of Bcl-2 restored a pattern of uniform Bcl-2 labeling in the cytoplasm and, remarkably, the colocalization of Bcl-2 with Bax. This work demonstrates that the ability of retinoid-induced cells to undergo apoptosis depends on the level of expression and the functional interaction between Bcl-2 and Bax.
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PMID:Altered sensitivity to retinoid-induced apoptosis associated with changes in the subcellular distribution of Bcl-2. 919 90

We selected an apoptosis-resistant subline (VC-33) in a human promyelocytic leukemia cell line, HL-60, by alternating exposure to camptothecin (CPT) and etoposide (VP-16). When wild-type (WT) and VC-33 cells were incubated with various concentrations of either CPT or VP-16 for 4 h, VC-33 showed several-fold resistance to apoptosis induced by these agents in comparison with WT cells. VC-33 cells also exhibited cross-resistance to apoptosis induced by 1-beta-d-arabinofuranosylcytosine, hydroxyurea, a calcium ionophore (A23187), cycloheximide, or UV irradiation. The levels of protein-DNA cross-linking induced by CPT or VP-16, and the amounts of ara-CTP generation, tended to be smaller in VC-33 cells, but the difference was not sufficient to explain the difference in the sensitivity to apoptosis. The initial rise of intracellular calcium ions with A23187 and the expression of P-glycoprotein, Bcl-2, and Bcl-Xl were comparable between WT and VC-33 cells. This mutant may represent a new phenotype of resistance to apoptosis induced by a variety of agents, and may thus be useful in the study of the mechanisms of apoptosis.
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PMID:Apoptosis-resistant phenotype selected by alternating exposure to camptothecin and etoposide. 928 62


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