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Vpr cytopathicity independent of G2/M cell cycle arrest in human immunodeficiency virus type 1-infected CD4+ T cells
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The mechanism of CD4(+) T-cell depletion in human immunodeficiency virus type 1 (HIV-1)-infected individuals remains unknown, although mounting evidence suggests that direct viral cytopathicity contributes to this loss. The HIV-1 Vpr accessory protein causes cell death and arrests cells in the G(2)/M phase; however, the molecular mechanism underlying these properties is not clear. Mutation of hydrophobic residues on the surface of its third alpha-helix disrupted Vpr toxicity, G(2)/M arrest induction, nuclear localization, and self-association, implicating this region in multiple Vpr functions. Cytopathicity by virion-delivered mutant Vpr protein correlated with G(2)/M arrest induction but not nuclear localization or self-association. However, infection with whole virus encoding these Vpr mutants did not abrogate HIV-1-induced cell killing. Rather, mutant Vpr proteins that are impaired for G(2)/M block still prevented infected cell proliferation, and this property correlated with the death of infected cells. Chemical agents that inhibit infected cells from entering G(2)/M also did not reduce HIV-1 cytopathicity. Combined, these data implicate Vpr in HIV-1 killing through a mechanism involving inhibiting cell division but not necessarily in G(2)/M. Thus, the hydrophobic region of the third alpha-helix of Vpr is crucial for mediating G(2)/M arrest, nuclear localization, and self-association but dispensable for HIV-1 cytopathicity due to residual cell proliferation blockade mediated by a separate region of the protein. 相似文献
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Macroautophagy/autophagy protects against cellular stress. Renal sublethal injury-triggered tubular epithelial cell cycle arrest at G2/M is associated with interstitial fibrosis. However, the role of autophagy in renal fibrosis is elusive. Here, we hypothesized that autophagy activity in tubular epithelial cells is pivotal for inhibition of cell cycle G2/M arrest and subsequent fibrogenic response. In both renal epithelial cells stimulated by angiotensin II (AGT II) and the murine kidney after unilateral ureteral obstruction (UUO), we observed that occurrence of autophagy preceded increased production of COL1 (collagen, type I). Pharmacological enhancement of autophagy by rapamycin suppressed COL1 accumulation and renal fibrosis. In contrast, genetic ablation of autophagy by proximal tubular epithelial cell-specific deletion of Atg5, with reduction of the LC3-II protein level and degradation of SQSTM1/p62, showed marked cell cycle arrest at the G2/M phase, robust COL1 deposition, and severe interstitial fibrosis in a UUO model, as compared with wild-type mice. In vitro, AGT II exposure triggered autophagy preferentially in the G1/S phase, and increased COL1 expression in the G2/M phase in renal epithelial cells. Stimulation of Atg5-deficient primary proximal tubular cells with AGT II also resulted in elevated G2/M arrest and COL1 production. Pharmacological or genetic inhibition of autophagy increased AGT II-mediated G2/M arrest. Enhanced expression of ATG5, but not the autophagy-deficient ATG5 mutant K130R, rescued the G2/M arrest, suggesting the regulation of cell cycle progression by ATG5 is autophagy dependent. In conclusion, Atg5-mediated autophagy in proximal epithelial cells is a critical host-defense mechanism that prevents renal fibrosis by blocking G2/M arrest. 相似文献
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Razina Rouf Alexandre S. Stephens Lina Spaan Nadia X. Arndt Christopher J. Day Tom W. May Evelin Tiralongo Joe Tiralongo 《Glycoconjugate journal》2014,31(1):61-70
A new N-acetyl-D-glucosamine (GlcNAc) specific lectin was identified and purified from the fruiting body of the Australian indigenous mushroom Psathyrella asperospora. The functional lectin, named PAL, showed hemagglutination activity against neuraminidase treated rabbit and human blood types A, B and O, and exhibited high binding specificity towards GlcNAc, as well as mucin and fetuin, but not against asialofetuin. PAL purified to homogeneity by a combination of ammonium sulfate precipitation, chitin affinity chromatography and size exclusion chromatography, was monomeric with a molecular mass of 41.8 kDa, was stable at temperatures up to 55 °C and between pH 6–10, and did not require divalent cations for optimal activity. De novo sequencing of PAL using LC-MS/MS, identified 10 tryptic peptides that revealed substantial sequence similarity to the GlcNAc recognizing lectins from Psathyrella velutina (PVL) and Agrocybe aegerita (AAL-II) in both the carbohydrate binding and calcium binding sites. Significantly, PAL was also found to exert a potent anti-proliferative effect on HT29 cells (IC50 0.48 μM) that was approximately 3-fold greater than that observed on VERO cells; a difference found to be due to the differential expression of cell surface GlcNAc on HT29 and VERO cells. Further characterization of this activity using propidium iodine staining revealed that PAL induced cell cycle arrest at G2/M phase in a manner dependent on its ability to bind GlcNAc. 相似文献
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Shu CH Yang WK Shih YL Kuo ML Huang TS 《Apoptosis : an international journal on programmed cell death》1997,2(5):463-470
Paclitaxel is a potential anti-cancer agent for several malignancies including ovary, breast, and head and neck cancers. This
study investigated the kinetics of paclitaxel-induced cell cycle perturbation in two human nasopharyngeal carcinoma (NPC)
cell lines, NPC-TW01 and NPC-TW04. NPC cells treated with higher concentrations (0.1 or 1 μM) of paclitaxel showed obvious
G2/M arrest and then converted to a cell population with reduced DNA content, which was detected as a sub-G2 peak in the flow
cytometric histographs. If a low concentration (5 nM) of paclitaxel was used instead, transient G2/M arrest was observed in
NPC cells, which subsequently converted to a sub-G1 form during the treatment period. Internucleosomal fragmentation and chromatin
condensation were detectable in these sub-G1 and sub-G2 cells, suggesting that persistent or transient G2/M arrest is a prerequisite
step for apoptosis elicited by varying doses of paclitaxel. The levels of cyclins A, B1, D1, E, CDK 1 (CDC 2), CDK 2 and proliferating
cell nuclear antigen (PCNA) were unchanged in NPC cells following treatment with any concentration of paclitaxel; however,
apoptosis-related cyclin B1-associated CDC 2 kinase was highly activated by paclitaxel even at concentrations as low as 5
nM, which is consistent with the finding that low-dose paclitaxel is also able to induce apoptosis in NPC cells. Activation
of cyclin B1-associated CDC 2 kinase seems to be an important G2/M event required for paclitaxel-induced apoptosis, and this
activation of cyclin B1/CDC 2 kinase could be attributed to the increased activity of CDK 7 kinase.
This revised version was published online in November 2006 with corrections to the Cover Date. 相似文献
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Kun‐Zhi Jia Bo Tang Lu Yu Wei Cheng Rong Zhang Jian‐Fa Zhang Zi‐Chun Hua 《Cell biology international》2010,34(1):49-52
Cellular adenosine accumulates under stress conditions. Few papers on adenosine are concerned with its function in the cell cycle. The cell cycle is the essential mechanism by which all living things reproduce and the target machinery when cells encounter stresses, so it is necessary to examine the relationship between adenosine and the cell cycle. In the present study, adenosine was found to induce G2/M cell‐cycle arrest. Furthermore, adenosine was found to modulate the expression of some important proteins in the cell cycle, such as cyclin B and p21, and to inhibit the transition of metaphase to anaphase in mitosis. 相似文献
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Kang Seong Hee Bak Dong-Ho Chung Byung Yeoup Bai Hyoung-Woo 《Molecular biology reports》2021,48(2):1081-1091
Molecular Biology Reports - Melanoma is aggressive, highly metastatic, and potentially fatal. In the case of patients with advanced melanoma, it is difficult to expect a good prognosis, since this... 相似文献
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Yuying Li ;Shizhao Duan ;Haiyan Jia ;Chongzhi Bai ;Liwei Zhang ;Zhuanhua Wang 《Acta biochimica et biophysica Sinica》2014,(6):460-470
The cytotoxicity and antioxidant activity on human hepa toma cell line HepG2 of three flavonoids homogenous com pounds from tartary buckwheat seeds and bran, namely quercetin, isoquercetin, and rutin, were investigated. The total antioxidant competency detection results indicated that the antioxidant capacity of quercetin was the strongest in a biological response system. A [3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide] assay showed that quercetin exhibited the strongest cytotoxic effects against the HepG2 cell line. Flow cytometric analysis indicated that quercetin significantly increased the production of reactive oxygen species, and led to the G2/M phase arrest accom panied by an increase of apoptotic cell death after 48 h of incubation. Quercetininduced cell apoptosis was shown to involve p53 and p21 upregulation, Cyclin D1, Cdk2, and Cdk7 downregulation. These results suggested that the in duction of G2/M arrest, apoptosis, and cell death by quer cetin may associate with increased expression of p53 and p21, decrease of Cyclin D1, Cdk2, and Cdk7 levels, and generation of reactive oxygen species in cells. This study will help to better understand and fully utilize medicinal resources of plant flavonoids. 相似文献
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The C terminus of human immunodeficiency virus type 1 matrix protein is involved in early steps of the virus life cycle. 总被引:3,自引:19,他引:3
Deletion mutations at the C terminus of the matrix (MA) protein of human immunodeficiency virus type 1 (HIV-1) were generated by site-directed mutagenesis. The resultant mutant viruses had a severe defect in virus infectivity. This defect did not involve late steps of the virus life cycle, as the synthesis and processing of the Gag polyprotein and the assembly and release of mutant virions were not greatly affected. The incorporation of viral proteins and the viral RNA genome was similar for mutant and wild-type virions. In contrast, the early steps of the virus life cycle were severely affected, as the synthesis of viral DNA postinfection was dramatically reduced in mutant-virus-infected cells. One stretch of amino acids that was deleted in one of the mutants has significant homology with a region in VP1 of the picornavirus family. This region of VP1 is presumably involved in poliovirus penetration into cells. These results suggest that in addition to its functional role in virus assembly, the MA protein of HIV-1, and possibly of other retroviruses, plays an important role in virus entry. 相似文献
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Rotenone-induced G2/M cell cycle arrest and apoptosis in a human B lymphoma cell line PW. 总被引:5,自引:0,他引:5
J S Armstrong B Hornung P Lecane D P Jones S J Knox 《Biochemical and biophysical research communications》2001,289(5):973-978
Concentrations of rotenone (ROT) that block electron flow through mitochondrial complex I (100 nM) did not significantly alter either cell viability or the growth of PW cells. However, 10- to 50-fold higher concentrations (1-5 microM) were found to induce a dose-dependent cell cycle arrest predominantly at the G2/M stage of the cycle and apoptosis. Apoptosis was dependent on the cell cycle arrest, since apoptosis but not the G2/M arrest was prevented with the broad spectrum caspase inhibitor zVADfmk. Biochemical features of apoptosis included mitochondrial cytochrome c release, reactive oxygen species generation, and the activation of procaspase 3. Thus, ROT inhibition of mitochondrial electron transport may be insufficient to induce apoptosis in PW cells. Instead, apoptosis in these cells occurs as a consequence of disruption of the cell cycle and is only indirectly dependent upon mitochondrial electron transport. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(9):1468-1476
Cell cycle checkpoint is a self-protective mechanism for cells to monitor genome integrity and ensure the high-fidelity transmission of genetic information to daughter cells. Insufficient function of cell cycle checkpoints has been demonstrated to partially account for tumor initiation, promotion and progression. In the ten melanoma cell lines that we tested in preliminary experiments, two human uveal melanoma cell lines, 92-1 and OCM-1, were found to be significantly different in terms of radiosensitivity but similar in DNA repair ability. Evident G2 arrest was induced in both cell types and the maximum was reached at 16 h after irradiation regardless of X-rays or high-LET carbon beams. OCM-1 cells overrode the G2 arrest and reentered the cell cycle right after reaching the maximum, whereas 92-1 could not. Upon 10 Gy of radiation, the cell cycle of 92-1 was suspended and remained unchanged for up to 5 d. The cell cycle suspension is a unique process lurking in G2 arrest and related to cellular radiosensitivity. Its induction is dose-dependent and there is a dose threshold for it. The degradation of Cyclin B1 has been found related to the cell cycle suspension though, the mechanism of cell cycle suspension is still under investigation. Basing on our knowledge, this is the first report on cell cycle suspension and we present here a de novo mechanism to cellular radiosensitivity. Further clarification of the mechanism underlying cell cycle suspension is believed to be of significance in tumor radiosensitization or even direct tumor control. 相似文献
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Exposure of single-stranded telomeric DNA causes G2/M cell cycle arrest in Saccharomyces cerevisiae 总被引:3,自引:0,他引:3
In Saccharomyces cerevisiae, Cdc13p is a single-stranded TG(1-3) DNA binding protein that protects telomeres and maintains telomere length. A mutant allele of CDC13, cdc13-1, causes accumulation of single-stranded TG(1-3) DNA near telomeres along with a G(2)/M cell cycle arrest at non-permissive temperatures. We report here that when the single-stranded TG(1-3) DNA is masked by its binding proteins, such as S. cerevisiae Gbp2p or Schizosaccharomyces pombe Tcg1, the growth arrest phenotype of cdc13-1 is rescued. Mutations on Gbp2p that disrupt its binding to the single-stranded TG(1-3) DNA render the protein unable to complement the defects of cdc13-1. These results indicate that the presence of a single-stranded TG(1-3) tail in cdc13-1 cells serves as the signal for the cell cycle checkpoint. Moreover, the binding activity of Gbp2p to single-stranded TG(1-3) DNA appears to be associated with its ability to restore the telomere-lengthening phenotype in cdc13-1 cells. These results indicate that Gbp2p is involved in modulating telomere length. 相似文献
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Tu HY Huang AM Teng CH Hour TC Yang SC Pu YS Lin CN 《Bioorganic & medicinal chemistry》2011,19(18):5670-5678
Thirteen anthraquinone derivatives 5-17 including two 3-(3-alkylaminopropoxy)-9,10-anthraquinone (NHA) derivatives 5 and 6, and 11 1-hydroxy-3-(3-alkylaminopropoxy)-9,10-anthraquinone (MHA) derivatives 7-17 were synthesized, evaluated for cytotoxicities against two cancer cell lines, and assayed the generation of reactive oxygen species (ROS) in NTUB1 cells (a human bladder carcinoma cell line). Compound 9 bearing a pyrrolidinyl group induced the stronger cytotoxic effect than those of other synthesized NHA and MHA derivatives. Exposure of NTUB1 cells to 9, 13, and 17 for 24h significantly increased the production of ROS, respectively. Flow cytometric analysis exhibited that the exposure of NTUB1 cells to the selective 9 led to the G2/M phase arrest accompanied by an increase of apoptotic cell death after the incubation for 24h. Compound 9 induced up-regulation of cyclinB1 and p21 expressions. Biological results suggested that the induction of G2/M arrest, apoptosis, and cell death by 9 may associate with increased expression of p21 and cyclin B1, elevation of Bax and p53 levels, and generation of ROS in the cell. In conclusion, these series of compounds may be used as anticancer agents. 相似文献
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在细胞周期检测点信号传导通路中,Chkl和Chk2起着重要作用,主要参与G2/M期细胞周期检测点信号传导.首先采用RNAi技术在BGC823细胞中将Chk1、Chk2基因沉默,Chk1、Chk2 siRNA转染BGC823细胞后24h加入15mg/L二烯丙基二硫(diallyl disulfide,DADS),接着通过Real-timePCR、Western blot分析Chk1、Chk2基因在转染前后的表达差异,然后运用流式细胞术和Western blot分析Chk1、Chk2基因沉默后对DADS诱导的细胞周期G2/M期阻滞作用及相关周期蛋白CDC25C和cyclinB1表达的影响.实验结果表明,与未转染对照组相比,转染Chk1、Chk2siRNA后BGC823细胞中Chk1、Chk2表达明显被抑制,二者的mRNA表达分别下降84.7%和69.0%,蛋白质水平分别下降73.4%和78.5%.流式细胞术分析结果发现,ChklsiRNA转染的BGC823细胞在15mg/LDADS处理24h后,G2/M期比例由单纯DADS处理组的58.1%降至10.4%(P<0.05).但Chk2 siRNA转染后加入15mg/... 相似文献