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Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential DeltaPsim. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2, 4-dinitrophenol (DNP) reduce DeltaPsim by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis.
Mol Cell Biol 1999 May
PMID:Uncouplers of oxidative phosphorylation can enhance a Fas death signal. 1020 55

Apoptosis plays a crucial role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Under that premise, the dysregulation of apoptosis may result in an inappropriate survival of mutated cells. This study demonstrates that ectopic expression of Bcl-2 effectively suppresses benzene-active metabolites, 1,4-hydroquinone- and 1, 4-benzoquinone-induced apoptosis in human leukemic HL-60 cells, as evidenced by morphological changes and DNA fragmentation. Although reactive oxygen species production largely contributes to the benzene metabolites-induced apoptotic cell death, Bcl-2 fails to attenuate the benzene metabolites-elicited increase of reactive oxygen species in HL-60 cells, as confirmed by flow cytometry analysis. These data suggest that Bcl-2 prevents benzene metabolites-induced apoptosis at the downstream of oxidative damage events. This study also determines the level of 8-hydroxydeoxyguanosine (8-OH-dGua), an indicator for oxidative DNA damage, in neo- and Bcl-2-overexpressing HL-60 cells after treating with 1,4-hydroquinone or 1,4-benzoquinone. Interestingly, our results indicate that a majority of the 8-OH-dGua is efficiently removed in neo control cells within 3 to 6 h, whereas only 25 to 35% of 8-OH-dGua is repaired in Bcl-2 transfectants even for 24 h. Similarly, another oxidative DNA base, thymine glycol, failed to repair and was retained in genomic DNA of Bcl-2 transfectants. The above findings suggest that Bcl-2 may retain benzene metabolites-induced oxidative DNA damage in surviving cells. Indeed, the failure of repairing 8-OH-dGua and thymine glycol in benzene metabolites-treated Bcl-2 survivors increases the number of mutation frequencies at the hprt locus. Results in this study thus provide a novel benzene-induced carcinogenesis mechanism by which up-regulation of Bcl-2 protein may promote the susceptibility to benzene metabolites-induced mutagenesis by overriding apoptosis and attenuating DNA repair capacity.
Mol Pharmacol 1999 May
PMID:Suppression of apoptosis by Bcl-2 to enhance benzene metabolites-induced oxidative DNA damage and mutagenesis: A possible mechanism of carcinogenesis. 1022 May 68

In this study, we investigate Fas ligand expression in the human endometrium during the menstrual cycle in relation to Fas antigen and Bcl-2 expression, using immunoelectron microscopy and Western blotting. Endometrial samples were obtained from 54 pre-menopausal non-pregnant women who underwent laparotomies for benign diseases. The Fas ligand, as well as the Fas antigen, were expressed on the surface of endometrial glandular cells throughout the menstrual cycle, whereas Bcl-2 showed a cyclic expression pattern, peaking during the late proliferative phase. A noteworthy finding was that both the Fas ligand and the Fas antigen were localized on Golgi apparatuses and vesicles, in addition to the cell membranes, during the late proliferative phase. These results indicate that the Fas ligand and Fas antigen which are localized on Golgi apparatus and vesicles during the late proliferative phase are incorporated into the cell membranes during the secretory phase, and are co-expressed on the cell membranes of endometrial glands throughout the menstrual cycle. The factors regulating Fas-mediated apoptosis in the human endometrium, including the level of expression of the Fas ligand and Bcl-2 are discussed.
Mol Hum Reprod 1999 Apr
PMID:Fas ligand, Fas antigen and Bcl-2 expression in human endometrium during the menstrual cycle. 1032 8

Sindbis virus has been recognized as a potentially useful virus vector for gene therapy. In an effort to improve its utility and provide cell-targeting capability to gene therapy vectors, we recently developed Sindbis virus vectors possessing chimeric envelopes with cell-specific targeting ability [K. Ohno et al. Nature Biotechnol 15:763-767, 1997; K. Sawai et al. Biochem Biophys Res Commun 248:315-323, 1998]. However, a residual problem associated with Sindbis virus vectors is the apoptotic effect of this virus on infected cells. To address this issue, we have studied the possible role of bcl-2 expression. Bcl-2 expression has been postulated to facilitate the establishment of persistent Sindbis viral infection by blocking virus-induced apoptosis. In this study we produced a Sindbis virus vector capable of expressing human bcl-2 and the reporter gene, lacZ. This chimeric virus (SinRep/lacZ/bcl-2/DH-BB) showed a marked reduction in induced apoptosis in infected cells. For example, after infection with this vector, cell proliferation of BHK cells was 55% of that of uninfected cells 2 days after infection and 40% 3 days after infection. While this reflected a significant degree of apoptosis, the effect was much less pronounced than that seen with wild-type Sindbis virus. Cell proliferation was reduced to 26% 2 days after wild-type virus infection of BHK cells and to only 7% 3 days after infection. Although additional work will be required to eliminate apoptosis induced by Sindbis virus vectors, the studies reported here suggest that such a goal may be achievable after additional modification of the vectors.
Mol Genet Metab 1999 May
PMID:Reducing cytotoxicity induced by Sindbis viral vectors. 1032 21

The adenovirus E1B 19,000-molecular-weight (19K) protein is a potent inhibitor of apoptosis and cooperates with E1A to transform primary rodent cells. E1B 19K shows sequence and functional homology to the mammalian antiapoptotic gene product, Bcl-2. Like Bcl-2, the biochemical mechanism of E1B 19K function includes binding to and antagonization of cellular proapoptotic proteins such as Bax, Bak, and Nbk/Bik. In addition, there is evidence that E1B 19K can affect gene expression, but whether this contributes to its antiapoptotic function has not been determined. In an effort to further understand the functions of E1B 19K, we screened for 19K-associated proteins by the yeast two-hybrid system. A novel protein, Btf (Bcl-2-associated transcription factor), that interacts with E1B 19K as well as with the antiapoptotic family members Bcl-2 and Bcl-xL but not with the proapoptotic protein Bax was identified. btf is a widely expressed gene that encodes a protein with homology to the basic zipper (bZip) and Myb DNA binding domains. Btf binds DNA in vitro and represses transcription in reporter assays. E1B 19K, Bcl-2, and Bcl-xL sequester Btf in the cytoplasm and block its transcriptional repression activity. Expression of Btf also inhibited transformation by E1A with either E1B 19K or mutant p53, suggesting a role in either promotion of apoptosis or cell cycle arrest. Indeed, the sustained overexpression of Btf in HeLa cells induced apoptosis, which was inhibited by E1B 19K. Furthermore, the chromosomal localization of btf (6q22-23) maps to a region that is deleted in some cancers, consistent with a role for Btf in tumor suppression. Thus, btf may represent a novel tumor suppressor gene residing in a unique pathway by which the Bcl-2 family can regulate apoptosis.
Mol Cell Biol 1999 Jun
PMID:Btf, a novel death-promoting transcriptional repressor that interacts with Bcl-2-related proteins. 1033 Jan 79

The purpose of this study was to assess the role of apoptosis and cell cycle arrest in the trophoblast during early gestation by determining the location of apoptotic cells and examining the expression of Bcl-2 and p21. Using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) method on human chorionic villi, a cluster of apoptotic nuclei was demonstrated in perivillous fibrin-type fibrinoid, but no apoptotic changes were identified in the syncytiotrophoblast or in other subtypes of the trophoblast. The syncytiotrophoblast was diffusely positive for Bcl-2, but fibrin-type fibrinoid was negative for Bcl-2. Hence, there was an inverse relationship between apoptosis and Bcl-2 expression in both fibrin-type fibrinoid and syncytiotrophoblast. Expression of p21 was present to some extent in the syncytiotrophoblast, but not in fibrin-type fibrinoid. These results suggest that Bcl-2 may play an important role in preventing apoptosis in the syncytiotrophoblast; this may be necessary to prevent any DNA degradation from being spread to other nuclei in a multinuclear cell like the syncytiotrophoblast.
Mol Hum Reprod 1999 Mar
PMID:Inverse relationship between apoptosis and Bcl-2 expression in syncytiotrophoblast and fibrin-type fibrinoid in early gestation. 1033 59

Pancreatic adenocarcinoma is the fifth leading cause of cancer related deaths in the United States. Treatment for this disease has largely been unsuccessful, which may partly be due to insufficient data regarding the molecular mechanisms of chemotherapeutic drugs currently being used as single agents or in combined modality regimens. In this study, we investigated the molecular mechanisms by which auristatin-PE, a newly developed experimental agent, and gemcitabine, a commercially available anti-cancer agent, exert their inhibitory effects on pancreatic cancer cell lines containing wild-type p53 (HPAC) and mutant p53 (PANC-1). Our results showed that auristatin-PE and gemcitabine inhibited cell growth and induced cell cycle arrest in G2/M and S phase, respectively. Auristatin-PE also induced apoptosis in both cell lines. Western blot analysis showed that auristatin-PE up-regulated the expression of wt-p53, p21WAF1 and Bax, and down-regulated Bcl-2 and cyclin B in HPAC cells, while only up-regulation of p21WAF1 and Bax was observed in PANC-1 cells. These results suggest that auristatin-PE may induce apoptosis and p21WAF1 expression through p53-dependent or independent pathways, and that up-regulation of p21WAF1 and Bax and down-regulation of Bcl-2 may be the molecular mechanism through which auristatin-PE inhibits cell growth and induces apoptosis. Furthermore, the up-regulation of p21WAF1 and down-regulation of cyclin B may contribute to the G2/M cell cycle arrest. Combination of auristatin-PE and gemcitabine showed significantly greater inhibition of cell growth and up-regulated expression of p21WAF1 and Bax. From these results, we conclude that the selection of therapeutic agents based on their molecular mechanism may improve therapeutic outcome, and that auristatin-PE may be more effective in the treatment of pancreatic cancer when given in combination with gemcitabine, rather than as a single agent.
Int J Mol Med 1999 Jun
PMID:Induction of growth inhibition and apoptosis in pancreatic cancer cells by auristatin-PE and gemcitabine. 1034 Dec 97

Members of the Bcl-2 family serve as central checkpoints for cell death regulation, and overexpression of Bcl-2 is known to inhibit apoptosis in many cell types. To determine whether targeted expression of Bcl-2 could be used to protect female germ cells from apoptosis, we generated transgenic mice expressing fully functional human Bcl-2 protein only in oocytes. Transgenic mice were produced using a previously characterized 480-bp fragment of the mouse zona pellucida protein-3 (ZP3) gene 5'-flanking region to direct oocyte-specific expression of a human bcl-2 complementary DNA. Immunohistochemical analyses using a human Bcl-2-specific antibody showed that transgene expression was restricted to growing oocytes and was not observed in the surrounding ovarian somatic cells or in any other nonovarian tissues. Histomorphometric analyses revealed that ovaries collected from transgenic female mice possessed significantly fewer atretic small preantral follicles compared with wild-type sisters, resulting in a larger population of healthy maturing follicles per ovary. However, the number of oocytes ovulated in response to exogenous gonadotropin priming and the number of pups per litter were not significantly different among wild-type vs. transgenic female mice. Nonetheless, oocytes obtained from transgenic mice and cultured in vitro were found to be resistant to spontaneous and anticancer drug-induced apoptosis. We conclude that targeted expression of Bcl-2 only in oocytes can be achieved as a means to convey resistance of the female germ line to naturally occurring and chemotherapy-induced apoptosis.
Mol Endocrinol 1999 Jun
PMID:Targeted expression of Bcl-2 in mouse oocytes inhibits ovarian follicle atresia and prevents spontaneous and chemotherapy-induced oocyte apoptosis in vitro. 1037 84

The S100beta protein is overexpressed in the brain of patients with Alzheimer's disease and Down's syndrome and is able to induce apoptosis in neurons at high concentrations. The intracellular events that regulate the apoptotic effect are largely unknown. This study investigates the roles of the bcl-2 proto-oncogene, one of the best-defined apoptotic genes, on cell death induced by S100beta. Human neuronal precursor NT2/D1 cells showed a high degree of cell death by apoptosis after exposure to 2 microM S100beta in serum-free medium. Death was preceded by a down-regulation of the Bcl-2 protein. Gene transfer with a full-length bcl-2 cDNA under the control of a constitutive promoter in NT2 cells elevated Bcl-2 protein levels and repressed S100beta-mediated cell death. When exposed to retinoic acid, the NT2/D1 cells differentiated into a neuronal phenotype. The differentiated cells up-regulated their levels of Bcl-2 and became resistant to S100beta-induced cell death. Downregulation of Bcl-2 by an antisense oligonucleotide in the differentiated cells, however, increased their susceptibility to S100beta-related cytotoxicity. Therefore, apoptosis induced through S100beta signaling is subject to regulation by Bcl-2. A combined alteration such as up-regulation of S100beta together with down-regulation of Bcl-2 may be important in the pathogenesis of Alzheimer's disease and Down's syndrome.
Brain Res Mol Brain Res 1999 Jun 18
PMID:Bcl-2 expression regulates cell sensitivity to S100beta-mediated apoptosis. 1038 57

Efforts in metastasis research have centered on the phenotypic and genetic differences between primary site and metastatic site tumors. However, genes that may be used as molecular markers of metastasis in circulating tumor cells remain unidentified. Genes regulating the dissemination and survival of solid tumor cells in the blood, as well as their adaptation to new environments, could be candidates for unique metastatic tumor markers. Differential display (DD) was conducted to compare the blood of tumor-free individuals with the blood of patients with lung, breast, and colon cancers. Twenty-one up-expressed genes in the tumor patient blood samples but none in the tumor-free donor blood samples were identified. Nine of these samples were isolated, amplified, and directly sequenced. A gene AB-1 homologous to a Bcl-2 family member, which might function as an apoptosis inhibitor, was identified. The overexpression of an apoptosis inhibitor in blood from patients with metastatic tumors might be correlated with the capability of solid tumor cells to survive in peripheral blood. This is the first demonstration of the usefulness of comparing control and patient blood samples by DD to find novel potential genetic markers identifying metastasis in the blood. http://link.springer-ny. com/link/service/journals/00020/bibs/5n5p313.html
Mol Med 1999 May
PMID:A strategy to identify genes associated with circulating solid tumor cell survival in peripheral blood. 1039 May 47


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