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911.
912.
The inhibitor of apoptosis (IAP) family of proteins contains a subset of members characterized by the presence of highly conserved baculoviral IAP repeat (BIR) domains. Recent work has shown that some of these BIR-domain proteins play a prominent role in the regulation of cell division, in particular at the stage of chromosome segregation and cytokinesis. We and others have shown that the Schizosaccharomyces pombe BIR-domain protein, Bir1p/Pbh1p/Cut17p, is important for the regulation of mitosis. Here we further characterize S. pombe Bir1p using methods of cell biology and genetics. We show that Bir1p is dispersed throughout the nucleus during the cell cycle. In addition, a significant part of Bir1p is also detected at the kinetochores and the spindle midzone during mitosis and meiosis. Time-lapse microscopy studies suggest that Bir1p relocates from the kinetochores to the spindle at the end of anaphase A. Bir1p colocalizes with the S. pombe Aurora kinase homolog Aim1p, a protein essential for mitosis, at the kinetochores as well as the spindle midzone during mitosis, and functional Bir1p is essential for localization of Aim1p to the kinetochores and the spindle midzone. Analyses of bir1 conditional mutants revealed that Bir1p is essential for chromosome condensation during mitosis. In addition, anaphase cells show the presence of lagging chromosomes and a defect in spindle elongation. We conclude that Bir1p is important for multiple processes that occur during mitosis in S. pombe. 相似文献
913.
914.
Acetaminophen (AAP), the analgesic hepatotoxicant, is a powerful inducer of oxidative stress, DNA fragmentation, and apoptosis. The anti-apoptotic oncogene bcl-XL, and the pro-apoptotic oncogene p53 are two key regulators of cell cycle progression and/or apoptosis subsequent to DNA damage in vitro and in vivo. This study investigated the effect of AAP on the expression of these oncogenes and whether agents that modulate DNA fragmentation (chlorpromazine, CPZ) and DNA repair through poly(ADP-Ribose) polymerase (PARP) activity (4-AB: 4-aminobenzamide) can protect against AAP-induced hepatotoxicity by inhibiting oxidative stress, DNA fragmentation, and/or by altering the expression of bcl-XL and p53. In addition, the protective effect of supplemental nicotinamide (NICO), known to be depleted in cells with high PARP activity during DNA repair, is similarly evaluated. Male ICR mice (3 months old) were administered vehicle alone; nontoxic doses of 4-AB (400 mg/kg, ip), NICO (250 mg/kg, ip) or CPZ (25 mg/kg, ip), hepatotoxic dose of AAP alone (500 mg/kg, ip), or AAP plus one of the protective agents 1 h later. All animals were sacrificed 24 h following AAP administration. Serum alanine aminotransferase activity (ALT), hepatic histopathology and lipid peroxidation, DNA damage, and expression of bcl-XL and p53 (western blot analysis) were compared in various groups. All of the three agents significantly prevented AAP-induced liver injury, lipid peroxidation, DNA damage, and associated apoptotic and necrotic cell deaths, 4-AB being the most effective and NICO the least. Compared to control, there was a considerable decrease in bcl-XL expression, and an increase in p53 expression in AAP-exposed livers. The effect of AAP on bcl-XL was antagonized and that on p53 was synergized by the PARP-modulator 4-AB as well as NICO, whereas the endonuclease inhibitor CPZ was without effect on either bcl-XL or p53 expression. These results suggest that the hepatotoxic effect of AAP involves multiple mechanisms including oxidative stress, upregulation of endonuclease (or caspase-activated DNAse) and alteration of pro- and anti-apoptotic oncogenes. The observed antagonism of AAP-induced hepatocellular apoptosis and/or necrosis by modulators of multiple processes including DNA repair suggests the likelihood that a more effective therapy against AAP intoxication should involve a combination of antidotes. 相似文献
915.
916.
Shammas MA Liu X Gavory G Raney KD Balasubramanian S Shmookler Reis RJ 《Experimental cell research》2004,295(1):204-214
Telomeres are believed to stabilize chromosomes through several mechanisms that are dependent upon specific DNA-DNA and protein-DNA interactions. Telomeres are maintained by the enzyme telomerase. Telomerase activity, which is below detectable level in almost all types of diploid cells, is re-activated in most immortal and cancer cells. For this study, we designed peptide nucleic acid (PNA) oligonucleotides targeted to the telomeric G-rich strand, and tested their efficacy to reverse the immortality of transformed human fibroblasts. Anti-telomere PNAs, transfected into human fibroblasts along with a selectable marker, resulted in a significant reduction in colony size and elicited cell death by apoptosis. This PNA inhibitor does not inhibit telomerase activity in vitro, suggesting a distinct cellular mechanism from known PNA inhibitors. A combination of this class of PNA inhibitor with a PNA that does block telomerase activity resulted in nearly complete inhibition of colony growth, induction of apoptosis, and an apparent reduction in telomere length. Each effect was greater than that evoked by either agent alone, indicating enhanced efficacy for therapeutic approaches that target multiple, distinct mechanism of telomere maintenance. 相似文献
917.
Venkitraman PR Jayalakshmy KV Balasubramanian T Nair M Nair KK 《Indian journal of experimental biology》2004,42(4):403-412
Penaeid prawns M. dobsoni of two different size ranges were ablated both unilaterally (UEA) and bilaterally (BEA) and subjected to individual study. The UEA prawns consumed almost the same amount of food as the control prawns in the size group, 35-40mm, but consumed about 57.8% more food than the control prawns in the larger size group, 48-53mm. Growth was estimated as length and weight changes and significant variation was observed. The moult rate and dry moult weight showed marked differences. Average intermoult period increases with second ablation. Dry weight of moult in every succeeding moult was found to decrease irrespective of the level of ablation. Unilateral eyestalk ablation resulted in increase in dry weight whereas bilateral eyestalk ablation reduced the dry weight of moult and this decrease in the rate increased after each subsequent moult. In the larger size group, values of protein efficiency ratio (PER) were almost same as that of the lower size group. The UEA prawns exhibited highest conversion efficiency. The production rate of UEA prawns was 84% more than that of the control whereas BEA prawns indicated negative production. The same trend followed for net growth efficiency also. The results suggest that unilateral eyestalk ablation can be resorted to accelerate growth and conversion efficiency. Eyestalk ablation has been frequently resorted in matured forms for inducing maturation of gonads. For the first time attempts have been made to compare between the effects of removing one eyestalk versus two and changes taking place in juvenile forms especially in their physiology related to growth. 相似文献
918.
Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases 总被引:1,自引:0,他引:1
Sah JF Balasubramanian S Eckert RL Rorke EA 《The Journal of biological chemistry》2004,279(13):12755-12762
Epidermal growth factor receptor (EGFR) activation is absolutely required for cervical cell proliferation. This suggests that EGFR-inhibitory agents may be of therapeutic value. In the present study, we investigated the effects of epigallocatechin-3-gallate (EGCG), a bioactive green tea polyphenol, on EGFR signaling in cervical cells. EGCG inhibits epidermal growth factor-dependent activation of EGFR, and EGFR-dependent activation of the mitogen-activated protein kinases ERK1/2. EGCG also inhibits EGFR-dependent AKT activity. The EGCG-dependent reduction in ERK and AKT activity is associated with reduced phosphorylation of downstream substrates, including p90RSK, FKHR, and BAD. These changes are associated with increased p53, p21(WAF-1), and p27(KIP-1) levels, reduced cyclin E level, and reduced CDK2 kinase activity. Consistent with these findings, flow cytometry and TUNEL (terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling) staining revealed EGCG-dependent G(1) arrest. Moreover, sustained EGCG treatment caused apoptotic cell death. In addition to inhibiting EGFR, cell-free studies demonstrated that EGCG directly inhibits ERK1/2 and AKT, suggesting that EGCG acts simultaneously at multiple levels to inhibit EGF-dependent signaling. Importantly, the EGCG inhibition is selective, as EGCG does not effect the EGFR-dependent activation of JNK. These results suggest that EGCG acts to selectively inhibit multiple EGF-dependent kinases to inhibit cell proliferation. 相似文献
919.
The synaptophysin/synaptobrevin complex dissociates independently of neuroexocytosis 总被引:6,自引:0,他引:6
Reisinger C Yelamanchili SV Hinz B Mitter D Becher A Bigalke H Ahnert-Hilger G 《Journal of neurochemistry》2004,91(1):1-8
Synaptophysin is one of the most abundant membrane proteins of small synaptic vesicles. In mature nerve terminals it forms a complex with the vesicular membrane protein synaptobrevin, which appears to modulate synaptobrevin's interaction with the plasma membrane-associated proteins syntaxin and SNAP25 to form the SNARE complex as a prerequisite for membrane fusion. Here we show that synaptobrevin is preferentially cleaved by tetanus toxin while bound to synaptophysin or when existing as a homodimer. The synaptophysin/synaptobrevin complex is, however, not affected when neuronal secretion is blocked by botulinum A toxin which cleaves SNAP25. Excessive stimulation with alpha-latrotoxin or Ca(2+)-ionophores dissociates the synaptophysin/synaptobrevin complex and increases the interaction of the other SNARE proteins. The stimulation-induced dissociation of the synaptophysin/synaptobrevin complex is not inhibited by pre-incubating neurones with botulinum A toxin, but depends on extracellular calcium. However, the synaptophysin/synaptobrevin complex cannot be directly dissociated by calcium alone or in combination with magnesium. The dissociation of synaptobrevin from synaptophysin appears to precede its interaction with the other SNARE proteins and does not depend on the final fusion event. This finding further supports the modulatory role the synaptophysin/synaptobrevin complex may play in mature neurones. 相似文献
920.
Increased oxidative stress has been suggested to be involved in the pathogenesis and progression of diabetic tissue damage. The aim of this study was to investigate the effect of ethanolic extract of Eugenia jambolana seed kernel on antioxidant defense systems of plasma and pancreas in streptozotocin-induced diabetes in rats. The levels of glucose, vitamin-C, vitamin-E, ceruloplasmin, reduced glutathione and lipidperoxides were estimated in plasma of control and experimental groups of rats. The levels of lipidperoxides, reduced glutathione and activities of superoxide dismutase, catalase and glutathione peroxidase were assayed in pancreatic tissue of control and experimental groups of rats. A significant increase in the levels of plasma glucose, vitamin-E, ceruloplasmin, lipid peroxides and a concomitant decrease in the levels of vitamin-C, reduced glutathione were observed in diabetic rats. The activities of pancreatic antioxidant enzymes were altered in diabetic rats. These alterations were reverted back to near normal level after the treatment with Eugenia jambolana seed kernel and glibenclamide. Histopathological studies also revealed that the protective effect of Eugenia jambolana seed kernel on pancreatic beta-cells. The present study shows that Eugenia jambolana seed kernel decreased oxidative stress in diabetic rats, which inturn may be due to its hypoglycemic property. 相似文献