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)

The current literature is devoid of a clearcut definition of mitotic catastrophe, a type of cell death that occurs during mitosis. Here, we propose that mitotic catastrophe results from a combination of deficient cell-cycle checkpoints (in particular the DNA structure checkpoints and the spindle assembly checkpoint) and cellular damage. Failure to arrest the cell cycle before or at mitosis triggers an attempt of aberrant chromosome segregation, which culminates in the activation of the apoptotic default pathway and cellular demise. Cell death occurring during the metaphase/anaphase transition is characterized by the activation of caspase-2 (which can be activated in response to DNA damage) and/or mitochondrial membrane permeabilization with the release of cell death effectors such as apoptosis-inducing factor and the caspase-9 and-3 activator cytochrome c. Although the morphological aspect of apoptosis may be incomplete, these alterations constitute the biochemical hallmarks of apoptosis. Cells that fail to execute an apoptotic program in response to mitotic failure are likely to divide asymmetrically in the next round of cell division, with the consequent generation of aneuploid cells. This implies that disabling of the apoptotic program may actually favor chromosomal instability, through the suppression of mitotic catastrophe. Mitotic catastrophe thus may be conceived as a molecular device that prevents aneuploidization, which may participate in oncogenesis. Mitotic catastrophe is controlled by numerous molecular players, in particular, cell-cycle-specific kinases (such as the cyclin B1-dependent kinase Cdk1, polo-like kinases and Aurora kinases), cell-cycle checkpoint proteins, survivin, p53, caspases and members of the Bcl-2 family.
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PMID:Cell death by mitotic catastrophe: a molecular definition. 1507 46

The gene-silencing effect of short interfering RNA (siRNA) is known to vary strongly with the targeted position of the mRNA. A number of hypotheses have been suggested to explain this phenomenon. We would like to test if this positional effect is mainly due to the secondary structure of the mRNA at the target site. We proposed that this structural factor can be characterized by a single parameter called "the hydrogen bond (H-b) index," which represents the average number of hydrogen bonds formed between nucleotides in the target region and the rest of the mRNA. This index can be determined using a computational approach. We tested the correlation between the H-b index and the gene-silencing effects on three genes (Bcl-2, hTF, and cyclin B1) using a variety of siRNAs. We found that the gene-silencing effect is inversely dependent on the H-b index, indicating that the local mRNA structure at the targeted site is the main cause of the positional effect. Based on this finding, we suggest that the H-b index can be a useful guideline for future siRNA design.
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PMID:The gene-silencing efficiency of siRNA is strongly dependent on the local structure of mRNA at the targeted region. 1511 Jul 88

Benzyl isothiocyanate (BITC), a cruciferous vegetable-derived compound, has been shown to inhibit chemically induced cancer in animal models. Moreover, epidemiological studies have provided compelling evidence to suggest that cruciferous vegetables may be protective against cancer risk. Here, we report that BITC significantly inhibits growth of human pancreatic cancer BxPC-3 cells in a concentration-dependent manner with an IC(50) of approximately 8 micro M, a concentration that can be generated through dietary intake of cruciferous vegetables. Treatment of BxPC-3 cells with growth suppressive concentrations of BITC resulted in G(2)/M phase cell cycle arrest that was associated with a marked decline in protein levels of G(2)/M regulatory proteins including cyclin-dependent kinase 1 (Cdk1), cyclin B1 and cell division cycle 25B (Cdc25B). Further, BITC-mediated growth inhibition of BxPC-3 cells correlated with apoptosis induction that was characterized by an increase in Bax/Bcl-2 ratio, cleavage of procaspase-3 and poly(ADP-ribose)polymerase (PARP), and an increase in cytoplasmic histone-associated DNA fragmentation. Interestingly, BITC treatment caused inhibition of nuclear factor kappaB (NF-kappaB) activation, which is constitutively activated in human pancreatic cancer. Western blotting revealed concentration-dependent decrease in NF-kappaB/Rel-p65 protein level in BxPC-3 cells upon exposure to BITC. An increase in protein level of inhibitory subunit kappaB (IkappaBa) in association with reduced serine-32 phosphorylation was also observed in BITC-treated BxPC-3 cells. Consistent with these findings, BITC treatment caused a decrease in nuclear translocation of NF-kappaB as reflected by reduced DNA-binding capacity of NF-kappaB. Furthermore, the protein level of cyclin D1, a transcriptional target of NF-kappaB, was reduced significantly in BITC-treated BxPC-3 cells. To the best of our knowledge, this study is the first published report to implicate suppression of NF-kappaB activation as a potential mechanism for anti-proliferative activity of BITC against human pancreatic cancer cells.
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PMID:Cell cycle arrest, apoptosis induction and inhibition of nuclear factor kappa B activation in anti-proliferative activity of benzyl isothiocyanate against human pancreatic cancer cells. 1511 14

Genistein, a natural isoflavone phytoestrogen present in soybeans, has been extensively studied as a chemopreventive or therapeutic agent in several types of cancer. The traditional Asian diet is rich in soy products may explain in part why the incidence of breast cancer in Asian women is relatively low. To improve therapeutic benefits, we investigated the combination of genistein with chemotherapeutic agents in phenotypically dissimilar human breast cancer cells, MCF-7 and MDA-MB-231, in which estrogen receptor expression is positive and negative, respectively. In the present study, genistein significantly decreased cell apoptosis induced by tubulin-binding agents, paclitaxel and vincristine. FACScan analysis revealed that genistein also diminished the accumulation of the G2/M phase in the cell cycle caused by tubulin-binding agents. In situ staining of microtubules revealed that genistein could decrease paclitaxel-induced tubulin polymerization. However, in vivo tubulin polymerization assay revealed that simultaneous treatment of genistein did not change the tubulin/microtubule dynamic. Genistein reduced Bcl-2 phosphorylation triggered by paclitaxel and vincristine without changing Bax protein expression. p53 and p21 expression, monitored by Western blotting, was not altered by genistein. However, the expression of cyclin B1 and CDC2 kinase was markedly decreased in combination with genistein. In conclusion, genistein inversely affected tubulin-binding agent-induced apoptosis via down-regulation of cyclin B1/CDC2 kinase expression resulting in reduced Bcl-2 phosphorylation.
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PMID:Genistein inversely affects tubulin-binding agent-induced apoptosis in human breast cancer cells. 1513

BPR0L075 is a novel synthetic compound discovered through research to identify new microtubule inhibitors. BPR0L075 inhibits tubulin polymerization through binding to the colchicine-binding site of tubulin. Cytotoxic activity of BPR0L075 in a variety of human tumor cell lines has been ascertained, with IC(50) values in single-digit nanomolar ranges. As determined by flow cytometry, human cervical carcinoma KB cells are arrested in G(2)-M phases in a time-dependent manner before cell death occurs. Terminal deoxynucleotidyl transferase-mediated nick end labeling assay indicates that cell death proceeds through an apoptotic pathway. Additional studies indicate that the effect of BPR0L075 on cell cycle arrest is associated with an increase in cyclin B1 levels and a mobility shift of Cdc2 and Cdc25C. The changes in Cdc2 and Cdc25C coincide with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. Furthermore, phosphorylated forms of Bcl-2, perturbed mitochondrial membrane potential, and activation of the caspase-3 cascade may be involved in BPR0L075-induced apoptosis. Notably, several KB-derived multidrug-resistant cell lines overexpressing P-gp170/MDR and MRP are resistant to vincristine, paclitaxel, and colchicine but not to BPR0L075. Moreover, BPR0L075 shows potent activity against the growth of xenograft tumors of the gastric carcinoma MKN-45, human cervical carcinoma KB, and KB-derived P-gp170/MDR-overexpressing KB-VIN10 cells at i.v. doses of 50 mg/kg in nude mice. These findings indicate BPR0L075 is a promising anticancer compound with antimitotic activity that has potential for management of various malignancies, particularly for patients with drug resistance.
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PMID:BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo. 1523 74

Galectin-2 is structurally closely related to galectin-1, but has a distinct expression profile primarily confined to the gastrointestinal tract. Prominent differences in the proximal promoter regions between galectins-2 and -1 concern Sp1-, hepatocyte NF-3, and T cell-specific factor-1 binding sites. Of note, these sequence elements are positioned equally in the respective regions for human and rat galectins-2. Labeled galectin-2 binds to T cells in a beta-galactoside-specific manner. In contrast to galectin-1, the glycoproteins CD3 and CD7 are not ligands, while the shared affinity to beta1 integrin (or a closely associated glycoprotein) accounts for a substantial extent of cell surface binding. The carbohydrate-dependent binding of galectin-2 induces apoptosis in activated T cells. Fluorogenic substrate and inhibitor assays reveal involvement of caspases-3 and -9, in accordance with cleavage of the DNA fragmentation factor. Enhanced cytochrome c release, disruption of the mitochondrial membrane potential, and an increase of the Bax/Bcl-2 ratio by opposite regulation of expression of both proteins add to the evidence that the intrinsic apoptotic pathway is triggered. Cell cycle distribution and expression of regulatory proteins remained unaffected. Notably, galectins-1 and -7 reduce cyclin B1 expression, defining functional differences between the structurally closely related galectins. Cytokine secretion of activated T cells was significantly shifted to the Th2 profile. Our study thus classifies galectin-2 as proapoptotic effector for activated T cells, raising a therapeutic perspective. Of importance for understanding the complex galectin network, it teaches the lesson that selection of cell surface ligands, route of signaling, and effects on regulators of cell cycle progression are markedly different between structurally closely related galectins.
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PMID:Human galectin-2: novel inducer of T cell apoptosis with distinct profile of caspase activation. 1535 30

The proteasome plays a pivotal role in controlling cell proliferation, apoptosis, and differentiation in a variety of normal and tumor cells. PS-341, a novel boronic acid dipeptide that inhibits 26S proteasome activity, has prominent effects in vitro and in vivo against several solid tumors. We examined its antiproliferation, proapoptotic effects using three human glioblastoma multiforme (GBM) cell lines and five primary GBM explants. PS-341 markedly inhibited proliferation of GBM cell lines and explants in liquid and soft agar culture. These cells developed a G2/M cell cycle arrest with a concomitant decreased percentage of cells in S phase ( approximately 2-fold), associated with an increased expression of p21(WAF1), p27(KIP1), as well as cyclin B1 and decreased levels of CDK2, CDK4, and E2F4. About 35-40% of the cells became apoptotic when exposed to PS-341 (10(-7) M, 24-48 h) as shown by Annexin V analysis; in concert with these findings, immunobloting showed a C-terminal 85 kDa apoptotic fragment of poly ADP-ribose polymerase (PARP), and a decreased level of Bcl2 and Bcl-xl. PS-341 downregulated the expression of Bcl-2 and Bcl-xl in protein levels at an early time of treatment. These changes occurred irrespective of the p53 mutational status of the cells. PS-341 activated JNK/c-Jun signaling in GBM cells, and the JNK inhibitor SP600125 blocked the JNK signaling to reverse partially the PS-341 growth inhibition. PS-341 (10(-7) M, 24 h) decreased nuclear NF-kappaB levels as shown by Western blot, and reduced transcriptional activity of NF-kappaB as measured by reporter assays in these transformed cells. Also, PS-341 enhanced TRAIL (TNF-related apoptosis-inducing ligand) and TNFalpha (tumor necrosis factor alpha) induced cell death and apoptosis (two- to five-fold) in GBM cells. In summary, PS-341 has profound effects on growth and apoptosis of GBM cells, suggesting that PS-341 may be an effective therapy for patients with gliomas.
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PMID:Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). 1553 18

The cytotoxic mechanism of protein-bound polysaccharide isolated from Phellinus linteus (PL, Mesima) has been investigated. PL inhibited the proliferation and colony formation of SW480 human colon cancer cells. Flow cytometry analysis showed that PL increased the populations of both apoptotic sub-G1 and G2/M phase. The result obtained from TUNEL assay corroborated apoptosis which was shown in flow cytometry. Western blot analysis suggested that PL-induced apoptosis and growth inhibition were associated with decrease in Bcl-2, increase of the release of cytochrome c, and reduced expression of cyclin B1. These results suggest that PL has a direct antitumor effect through apoptosis and cell cycle blockade in certain cancer cells.
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PMID:Protein-bound polysaccharide from Phellinus linteus induces G2/M phase arrest and apoptosis in SW480 human colon cancer cells. 1553 93

There have been no therapeutic agents that provide a survival advantage in hormone-refractory prostate cancer. Recently, the Food and Drug Administration approved docetaxel combined with prednisone for the treatment of patients with advanced metastatic prostate cancer, and it does show a survival benefit. Hence, anti-microtubule drugs might be of benefit in chemotherapy of hormone-refractory prostate cancer. We used metastatic hormone-refractory prostate cancer PC-3 cells to investigate potential molecular mechanisms for CIL-102, a semisynthetic alkaloid derivative. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide and sulforhodamine B assays indicated that CIL-102 inhibits cell growth dose-dependently. Immunofluorescence microscopy and in vitro tubulin assembly assays indicated that CIL-102 binds to tubulin and disrupts microtubule organization. Flow cytometry showed that CIL-102 causes cells to accumulate in G(2)/M phase and sub-G(0)/G(1) phase. CIL-102-induced apoptosis was also characterized by immunofluorescence microscopy. Western blotting and kinase assays showed that CIL-102 exposure induced up-regulation of cyclin B1 and p34(cdc2) kinase activity and olomoucine, a p34(cdc2) inhibitor, profoundly reduced the number of cells accumulated in mitotic phase. Moreover, Bcl-2 phosphorylation, Cdc25C phosphorylation, and survivin expression were increased. CIL-102-induced apoptosis was associated with activation of caspase-3, but a noncaspase pathway may also be involved, since benzyloxycarbonyl-VAD-fluoromethyl ketone, a pancaspase inhibitor, only partially inhibited the apoptosis, and apoptosis-inducing factor was translocated from mitochondria to cytosol. We conclude that CIL-102 induces mitotic arrest and apoptosis by binding to tubulin and inhibiting tubulin polymerization. CIL-102 causes mitotic arrest, at least partly, by modulating cyclin-dependent kinases and then apoptosis executed by caspase and noncaspase pathways.
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PMID:CIL-102 interacts with microtubule polymerization and causes mitotic arrest following apoptosis in the human prostate cancer PC-3 cell line. 1553 83

Mcl-1 (myeloid cell leukaemia-1) is a Bcl-2 family member with short-term pro-survival functions but whose other functions, demonstrated by embryonic lethality of knockout mice, do not involve apoptosis. In the present study, we show a cell-cycle-regulatory role of Mcl-1 involving a shortened form of the Mcl-1 polypeptide, primarily localized to the nucleus, which we call snMcl-1. snMcl-1 interacts with the cell-cycle-regulatory protein Cdk1 (cyclin-dependent kinase 1; also known as cdc2) in the nucleus, and Cdk1 bound to snMcl-1 was found to have a lower kinase activity. The interaction with Cdk1 occurs in the absence of its cyclin partners and is enhanced on treatment of cells with G2/M blocking agents, but not by G1/S blocking. The snMcl-1 polypeptide is present during S and G2 phases and is negligible in G1. Overexpression of human Mcl-1 in a murine myeloid progenitor cell line resulted in a lower rate of proliferation. Furthermore, Mcl-1-overexpressing cells had lower total Cdk1 kinase activity compared with parental cells, in both anti-Cdk1 and anti-cyclin B1 immunoprecipitates. The latter results suggest that binding to snMcl-1 alters the ability of Cdk1 to bind its conventional partner, cyclin B1. Given the important role of Cdk1 in progression through G2 and M phases, it is probable that the inhibition of Cdk1 activity accounts for the inhibitory effect of Mcl-1 on cell growth.
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PMID:A proteolytic fragment of Mcl-1 exhibits nuclear localization and regulates cell growth by interaction with Cdk1. 1555 78


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