Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of bcl-2 in the signal transduction pathway was assessed by studying the inositol phospholipid metabolism in fibroblasts transfected by this oncogene. The rate of accumulation of water soluble inositol phosphates in response to several growth factors was much higher in bcl-2 transfected NIH3T3 clones than in untransfected control. Moreover, bcl-2 transfected clones express elevated levels of phosphatidic acid, a phospholipid produced during receptor stimulated breakdown of phosphoinositides. Our findings suggest that the expression of bcl-2 in NIH3T3 fibroblasts leads to the coupling of growth factor receptors to stimulate inositol phosphate production, henceforth establishing its role in the growth factor receptor mediated signal transduction pathway.
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PMID:Role of bcl-2 in growth factor triggered signal transduction. 212 38

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.
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PMID:In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells. 774 43

A commercial monoclonal antibody to bcl-2 protein (bcl-2, 124) is useful in immunohistochemical detection of this 25 kDa oncogene product in frozen sections. In order to overcome the difficulty in identifying bcl-2 protein in formalin-fixed, paraffin-embedded sections, its antigenicity was retrieved by a variety of pretreatments. The heating pretreatment by hydrated autoclaving was the best method for retrieving the antigenicity, and deionized water was the most adequate solution for soaking sections. This antigen retrieval sequence was helpful to examine the localization of bcl-2 protein in archival sections of normal lymphoid and nonlymphoid tissues and follicular lymphomas.
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PMID:Antigen retrieval for bcl-2 protein in formalin-fixed, paraffin-embedded sections. 774 22

Recent reports have demonstrated that prostaglandin F2alpha-induced generation of reactive oxygen species or their intermediates inhibits progesterone synthesis and may also serve as a trigger for apoptosis in the corpus luteum (CL). BCL-2, an inhibitor of apoptosis in a wide variety of cell types, has been reported to prevent oxidative stress-induced cell death. Thus, the present studies were conducted to determine whether levels of mRNA encoding BCL-2 and related members of this gene family (BAX and BCL-Xshort, which induce apoptosis; BCL-Xlong, a BCL-2 homologue that prevents apoptosis) differed in functional (Day 21 of pregnancy) versus regressed (Day 21 of the estrous cycle) CL in the bovine ovary. Levels of mRNAs encoding p53, a transcriptional regulator of the bcl-2 and bax genes, and interleukin-1beta-converting enzyme (ICE), a protein recently implicated in the induction of apoptosis whose expression may be enhanced by oxidative stress, were also assessed. Partial cDNA clones encoding bovine bax, bcl-x, p53, and Ice were isolated using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique with total RNA prepared from functional or regressed CL. A bovine bcl-2 cDNA could not be isolated from luteal tissue RNA despite the use of several primer pairs for amplification. Total RNA was then extracted from functional or regressed CL and analyzed by Northern blot analysis. The occurrence of apoptosis in regressed CL, as evidenced by the presence of internucleosomal DNA cleavage, was associated with a significant increase in both bax and Ice mRNA levels as compared with levels of bax and Ice expression in functional CL (p < 0.05, n = 3). There were no significant differences in bcl-x or p53 mRNA levels in functional versus regressed CL. Analysis of bcl-x mRNA by RT-PCR revealed that the long form was the primary, if not only, mRNA expressed in functional and regressed bovine luteal tissue. On the basis of data that increased expression of bax is associated with, and may be required for, apoptosis in ovarian granulosa cells and germ cells, we propose that BAX may play a similar role in apoptosis induction during luteal regression. Moreover, the increased Ice mRNA levels in regressed CL provides the first evidence that the ICE family of death proteases may be involved in luteolysis.
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PMID:Increased bax and interleukin-1beta-converting enzyme messenger ribonucleic acid levels coincide with apoptosis in the bovine corpus luteum during structural regression. 900 48

The flux of calcium forms an important intracellular messenger system. The bcl-2 oncoprotein is thought to make cells resistant to a variety of insults, including cytotoxic drugs, by the suppression of apoptosis, which appears to involve the repartitioning of intracellular calcium. Three drugs that affect calcium pathways and may influence this repartitioning, i.e. dantrolene, azumolene (a water-soluble dantrolene analogue) and nimodipine, were studied in cell culture, using both a transformed follicle centre lymphoma cell line and primary culture of lymphoma cells in vitro in a manner that resulted in a growth pattern closely resembling that of the malignancy in vivo. Dantrolene and azumolene were potent inducers of cell death in both systems reducing the viable cell count by 70-90% in comparison with normal controls. Nimodipine, in comparison, appeared to have no significant effect. These results obtained in an in vitro setting suggest that further evaluation of dantrolene and azumolene for the treatment of low-grade non-Hodgkin's lymphoma is warranted.
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PMID:In vitro testing of calcium channel blockers and cytotoxic chemotherapy in B-cell low-grade non-Hodgkin's lymphoma. 963 34

Sustained, increased cell proliferation induced by dietary zinc deficiency in rats plays a critical role in esophageal carcinogenesis. It is the determining factor that converts an otherwise nontumorigenic dose of N-nitrosomethylbenzylamine (NMBA) into a highly tumorigenic one. We studied whether the increased esophageal cell proliferation and susceptibility to NMBA-induced carcinogenesis induced by zinc deficiency can be inhibited by alpha-difluoromethylornithine (DFMO), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (the first enzyme in polyamine synthesis). Weanling rats were divided into four groups: Zn+/DFMO-, Zn+/DFMO+, Zn-/DFMO-, and Zn-/DFMO+. They were fed ad libitum either a zinc-sufficient (Zn+, 75 ppm zinc) or a zinc-deficient (Zn-, 4 ppm zinc) diet and given either deionized water (DFMO-) or 1% DFMO in deionized water (DFMO+). After 5 weeks, 5-19 animals from each group were sacrificed after in vivo 5-bromo-2'-deoxyuridine labeling to detect cells in S phase. The remaining animals in each group were given a single intragastric dose of NMBA at 2 mg/kg and sacrificed 12 weeks later for tumor incidence analysis. At week 5, DFMO treatment greatly decreased (by 48-82%) the levels of putrescine and spermidine in rat esophagus, colon, and liver, irrespective of dietary zinc intake. The increased esophageal cell proliferation induced by dietary zinc deficiency, as measured by the labeling index, the number of labeled cells, and the total number of cells, was substantially reduced by DFMO. This was accompanied by an increase in the rate of apoptosis. In addition, the expression of bax protein, an apoptosis accelerator, was markedly stronger in esophagi from Zn-/DFMO+ animals that showed increased apoptosis, whereas increased expression of bcl-2, an inhibitor of apoptosis, was only seen in the highly proliferative, zinc-deficient esophagus (Zn-/DFMO-). At week 12 after NMBA dosing, DFMO reduced the incidence of esophageal tumors from 80 to 4% in zinc-deficient rats. Our data showed that DFMO effectively inhibited the increased esophageal cell proliferation induced by dietary zinc deficiency and reduced the incidence of esophageal tumors induced by a single dose of NMBA in zinc-deficient animals. Our results also indicate a role for increased apoptosis in the mechanism(s) whereby DFMO brings about the inhibition of cell proliferation and tumor induction. These findings support a role for DFMO as a chemopreventive agent.
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PMID:Alpha-difluoromethylornithine inhibits N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in zinc-deficient rats: effects on esophageal cell proliferation and apoptosis. 985 69

To investigate the potential use of a bcl-2 antisense oligonucleotide for therapy against hepatocellular carcinoma, we examined the effects of the electroporetic transfer of a bcl-2 antisense oligonucleotide on rat hepatocarcinogenesis induced by N-nitrosomorpholine (NNM). Sprague-Dawley rats were given water containing 175 mg/l NNM for 8 weeks and received intraperitoneal injections of a bcl-2 antisense phosphorothioate oligonucleotide, a sense oligonucleotide or a scrambled sequence oligonucleotide encapsulated in empty liposomes, at a dose of 150 microg oligonucleotide/kg body weight, every 4 weeks. One hour after injection, in vivo electroporation was performed on the liver to achieve selective transfer of the oligonucleotides. By week 16, the rats that had received the bcl-2 antisense oligonucleotide had significantly fewer and smaller precancerous liver lesions positive for glutathione-S-transferase (placental type), and a significantly lower incidence of hepatocellular carcinoma in the electroporation zone than rats that had received the sense or the scrambled oligonucleotides. Moreover, the bcl-2 antisense oligonucleotide significantly increased the apoptotic indices in foci, neoplastic nodules and in hepatocellular carcinomas. The expression of bcl-2 mRNA also decreased, and 3'-fragments of bcl-2mRNA produced by cleavage at the antisense target site were detected in rat liver. Mean cellular fluorescence in the liver increased with higher doses of fluorescein-isothiocyanate-labeled antisense or sense oligonucleotides. Our results show that the electroporetic transfer of bcl-2 antisense oligonucleotide can inhibit rat hepatocarcinogenesis.
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PMID:In vivo electroporetic transfer of bcl-2 antisense oligonucleotide inhibits the development of hepatocellular carcinoma in rats. 1062 87

Malachite green (MG), consisting of green crystals with a metallic lustre, is very soluble in water and is highly cytotoxic to mammalian cells in culture and also acts as a liver tumour promoter. In view of its industrial importance and possible exposure to human beings, MG poses a potential environmental health hazard. Accordingly, we have studied the effect of MG on the formation of free radicals using Electron Spin Resonance (ESR) analysis with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping agent. ESR analysis showed formation of reactive free radicals during exposure of MG to Syrian hamster embryo (SHE) cells. As per mechanism-based toxicology in cancer risk assessment, the chemicals that have the potential to be metabolized to active free radical species could be human cancer hazards. So, we have investigated the effect of MG on the formation of Type II and Type III morphologically transformed foci using SHE cell transformation assay. MG induced dose related transformed foci. Some of these transformed foci were taken out using selective trypsinisation and established immortal cell lines. One of these immortal cell lines was characterized extensively. This immortal cell line showed enhanced DNA synthesis in the form of BrdU incorporation, increased presence of proliferating cell nuclear antigen (PCNA), bcl-2 and p53 proteins by immunohistochemistry. When these immortal cells were injected subcutaneously into nude mice, they developed tumors which were transplantable and histopathologically sarcomas. The present studies indicate that MG could be a potential candidate for two year chemical carcinogenesis rodent bioassays.
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PMID:Malignant transformation of Syrian hamster embryo (SHE) cells in culture by malachite green: an agent of environmental importance. 1068 87

Malachite green (MG) consisting of green crystals with a metallic lustre, is highly soluble in water, cytotoxic to various mammalian cells and also acts as a liver tumor promoter. In view of its industrial importance and possible exposure to human beings, MG poses a potential environmental health hazard. We have previously reported the malignant transformation of Syrian hamster embryo (SHE) cells by MG. In this study, we have made an attempt to study the effects of MG on the induction of apoptosis in normal and MG transformed Syrian hamster embryo cells and the expression of altered p53 and bcl-2 immunohistochemically. Induction of apoptosis was detected by flow cytometry on the basis of G0/G1 hypodiploid peak, Tunel assay and DNA ladder pattern. Flow cytometric analysis showed a dose and time dependent induction of apoptosis by MG in control cells whereas induction of apoptosis by MG was marginal in transformed cells. Tunel assay and DNA ladder pattern also showed decreased apoptosis in transformed cells by MG compared to controls. Immunostaining studies showed intense staining for p53 in transformed cells whereas no staining was observed in control cells. Also transformed cells showed overexpression of bcl-2 with exclusive nuclear localization compared to controls which did not show staining. The present study indicated that MG transformed Syrian hamster embryo cells have decreased sensitivity to apoptosis compared to normal cells and overexpression of altered p53 and bcl-2 seems to be conferring resistance to MG induced apoptosis.
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PMID:Malachite green induced malignant transformation of Syrian hamster embryo (SHE) cells in primary culture: transformation is associated with enhanced expression of altered p53, bcl-2 and decreased sensitivity to apoptosis. 1084 Sep 42

Carboxyfullerene, a water-soluble carboxylic acid derivative of a fullerene, which acts as a free-radical scavenger, was investigated as a protective agent against ultraviolet-light-induced damage in human keratinocytes. First, we demonstrate that carboxyfullerene is not cytotoxic for these cells. In addition, this compound significantly reduces the ultraviolet-B-induced inhibition of keratinocyte proliferation and protects keratinocytes from apoptosis caused by ultraviolet B irradiation in a time- and dose-dependent fashion. Furthermore, the percentage of cells with depolarized mitochondria is significantly lower in ultraviolet-B-irradiated keratinocytes pretreated with carboxyfullerene than in cells provided with diluent alone. Carboxyfullerene also protects human keratinocytes from apoptosis induced by exposure to deoxy-D-ribose, a sugar that causes cell death through a pathway involving oxidative stress. On the other hand, ultraviolet B downregulates bcl-2 levels in human keratinocytes, and carboxyfullerene fails to prevent this effect. These results suggest that carboxy- fullerene protects human keratinocytes from ultraviolet B damage possibly via a mechanism interfering with the generation of reactive oxygen species from depolarized mitochondria without the involvement of bcl-2.
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PMID:Carboxyfullerenes protect human keratinocytes from ultraviolet-B-induced apoptosis. 1106 21


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