UNIPROT:P42574 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fusion between nonsynchronized cells leads to the formation of heterokarya which transiently activate Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 and enter the prophase of the cell cycle, where they arrest due to a loss of Cdk1/cyclin B1 activity, activate p53, disorganize centrosomes, and undergo apoptosis. Here, we show that the down regulation of Cdk1/cyclin B is secondary to the activation of the DNA structure checkpoint kinase Chk2. Thus, syncytia generated by the fusion of asynchronous HeLa cells contain elevated levels of active Chk2 but not Chk1. Chk2 bearing the activating phosphorylation on threonine-68 accumulates in BRCA1 nuclear bodies when the cells arrest at the G2/M boundary. Inhibition of Chk2 by transfection of a dominant-negative Chk2 mutant or a chemical inhibitor, debromohymenialdesine, stabilizes centrosomes, maintains high cyclin B1 levels, and allows for a prolonged activation of Cdk1. Under these conditions, multinuclear HeLa syncytia do not arrest at the G2/M boundary and rather enter mitotis and subsequently die during the metaphase of the cell cycle. This mitotic catastrophe is associated with the activation of the pro-apoptotic caspase-3. Inhibition of caspases allows the cells to go beyond the metaphase arrest, indicating that apoptosis is responsible for cell death by mitotic catastrophe. In another, completely different model of mitotic catastrophe, namely 14.3.3 sigma-deficient HCT116 colon carcinoma cells treated with doxorubicin, Chk2 activation was also found to be deficient as compared to 14.3.3 sigma-sufficient controls. Inhibition of Chk2 again facilitated the induction of mitotic catastrophe in HCT116 wild-type cells. In conclusion, a conflict in cell cycle progression or DNA damage can lead to mitotic catastrophe, provided that the checkpoint kinase Chk2 is inhibited. Inhibition of Chk2 thus can sensitize proliferating cells to chemotherapy-induced apoptosis.
...
PMID:The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. 1504 74

Bladder cancer is the fourth and eighth most common cancer in men and women in the USA, respectively. Flavonoid phytochemicals are being studied for both prevention and therapy of various human malignancies including bladder cancer. One such naturally occurring flavonoid is silibinin isolated from milk thistle. Here, we assessed the effect of silibinin on human bladder transitional cell carcinoma (TCC) cell growth, cell cycle modulation and apoptosis induction, and associated molecular alterations, employing two different cell lines representing high-grade invasive tumor (TCC-SUP) and high-grade TCC (T-24) human bladder cancer. Silibinin treatment of these cells resulted in a significant dose- and time-dependent growth inhibition together with a G(1) arrest only at lower doses in TCC-SUP cells but at both lower and higher doses in T-24 cells; higher silibinin dose showed a G(2)/M arrest in TCC-SUP cells. In other studies, silibinin treatment strongly induced the expression of Cip1/p21 and Kip1/p27, but resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins involved in G(1) progression. Silibinin treatment also showed an increased interaction between cyclin-dependent kinase inhibitors (CDKIs)-CDKs and a decreased CDK kinase activity. Further, the G(2)/M arrest by silibinin in TCC-SUP cells was associated with a decrease in pCdc25c (Ser216), Cdc25c, pCdc2 (Tyr15), Cdc2 and cyclin B1 protein levels. In additional studies, silibinin showed a dose- and a time-dependent apoptotic death only in TCC-SUP cells that was associated with cleaved forms of caspase 3 and poly(ADP-ribose) polymerase. Together, these results suggest that silibinin modulates CDKI-CDK-cyclin cascade and activates caspase 3 causing growth inhibition and apoptotic death of human TCC cells, providing a strong rationale for future studies evaluating preventive and/or intervention strategies for silibinin in bladder cancer pre-clinical models.
...
PMID:Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. 1511 15

Evodiamine, isolated from a Chinese herbal drug named Wu-Chu-Yu, possesses many biological functions. Recently, it has been reported that Wu-Chu-Yu exerts an antiproliferative effect on several cancers. Prostate carcinoma initially occurs as an androgen-dependent tumor and is the second leading cause of cancer death in American males. In the present study, the effect of evodiamine on the growth of androgen-dependent prostate cancer cell line LNCaP in vitro was examined. Based on [3-(4,5-dimethylthiazol-2-yle)2,5-diphenyltetrazolium bromide] (MTT) assay, evodiamine significantly inhibited the growth of LNCaP cells in a concentration-dependent manner. A significant and concentration-dependent inhibitory effect of evodiamine on LNCaP cell growth was observed at 24 hr and persisted for 96 hr. The examination of lactate dehydrogenase (LDH) assay showed that the cytotoxic effects of evodiamine on LNCaP cells were concentration dependent. Furthermore, we examined the influences of evodiamine on cell death and cell cycle. The flow cytometric analysis of evodiamine-treated cells indicated a block of G2/M phase and an elevated level of DNA fragmentation. The G2/M arrest reached a maximum at 24 hr after evodiamine treatment. The G2/M arrest was accompanied by an elevated p34(cdc2) kinase activity and an increase in the protein expression of cyclin B1 and phosphorylated form of p34(cdc2) (Thr 161). Examination of TUNEL showed that evodiamine-induced apoptosis was observed at 24 hr and extended for 72 hr. Evodiamine elevated caspase-3, and caspase-9 activities and the processing of caspase-3 and caspase-9. These results suggested that evodiamine inhibits the growth of prostate cancer cell line, LNCaP, through an accumulation of cell cycle at G2/M phase and an induction of apoptosis.
...
PMID:Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP. 1514 52

In this study, we have evaluated the chemopreventive role of aloe-emodin in human promyelocytic leukemia HL-60 cells in vitro by studying the regulation of proliferation, cell cycle and apoptosis. Aloe-emodin inhibited cell proliferation and induced G2/M arrest and apoptosis in HL-60 cells. Investigation of the levels of cyclins B1, E and A by immunoblot analysis showed that cyclin E level was unaffected, whereas cyclin B1 and A levels increased with aloe-emodin in HL-60 cells. Investigation of the levels of cyclin-dependent kinases, Cdk1 and 2, showed increased levels of Cdk1 but the levels of Cdk2 were not effected with aloe-emodin in HL-60 cells. The levels of p27 were increased after HL-60 cells were cotreated with various concentrations of aloe-emodin. The increase of the levels of p27 may be the major factor for aloe-emodin to cause G2/M arrest in these examined cells. Flow cytometric assays and DNA fragmentation gel electrophoresis also confirmed aloe-emodin induced apoptosis in HL-60 cells. The levels of caspase-3 were increased after HL-60 cells were cotreated with 10 microM aloe-emodin for 12, 24, 48, and 72 hours. Taken together, aloe-emodin therefore appears to exert its anticarcinogenesis properties by inhibiting proliferation and inducing cell cycle arrest and apoptosis underwent activation of caspase-3 in human leukemia HL-60 cells.
...
PMID:Aloe-emodin induced in vitro G2/M arrest of cell cycle in human promyelocytic leukemia HL-60 cells. 1520 75

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.
...
PMID:BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo. 1523 74

Signal transduction pathway and a new function of TIS21/BTG2/PC3 were investigated in p53 null U937 cells; Expression of TIS21 by 12-O-tetradecanoyl phorbol-13-acetate (TPA) stimulation was mediated by PKC-delta activation, however, was strongly inhibited by cPKC isozymes. When U937 cells were treated with TPA+Go6976, but not TPA+Go6850, the level of TIS21 mRNA was maintained over that of TPA alone. When analyzed by FACS, TPA-induced G2/M arrest was significantly inhibited by Go6850, but not by Go6976, suggesting the involvement of TIS21 and nPKC isozymes. Indeed, PKC-delta was found to be a regulator of the G2/M arrest and TIS21 expression, confirmed by employing rottlerin and dnPKC-delta experiments. In vivo accumulation of TIS21 protein significantly induced cell death through caspase 3 activation, which was supported further by degradations of procaspase 3, full-length PKC-delta, pRB, and p21(WAF1) in TIS21DeltaC expresser. When the cells were synchronized by nocodazole, TIS21 overexpressers inhibited degradations of cyclin A and cyclin B1 in 3 h after release from the synchronization. Furthermore, TIS21 inhibited cyclin B1-Cdc2 binding and its kinase activity in vivo. In summary, TPA-induced TIS21 mRNA expression is mediated by PKC-delta, and TIS21 induces G2/M arrest and cell death by inhibiting cyclin B1-Cdc2 binding and the kinase activity through its binding to Cdc2.
...
PMID:TIS21/BTG2/PC3 is expressed through PKC-delta pathway and inhibits binding of cyclin B1-Cdc2 and its activity, independent of p53 expression. 1530 83

Poliovirus and some other picornaviruses trigger relocation of certain nuclear proteins into the cytoplasm. Here, by using a protein changing its fluorescence color with time and containing a nuclear localization signal (NLS), we demonstrate that the poliovirus-triggered relocation is largely due to the exit of presynthesized nuclear protein into the cytoplasm. The leakiness of the nuclear envelope was also documented by the inability of nuclei from digitonin-permeabilized, virus-infected (but not mock-infected) cells to retain an NLS-containing derivative of green fluorescent protein (GFP). The cytoplasm-to-nucleus traffic was also facilitated during infection, as evidenced by experiments with GAPDH (glyceraldehyde-3-phosphate dehydrogenase), cyclin B1, and an NLS-lacking derivative of GFP, which are predominantly cytoplasmic in uninfected cells. Electron microscopy demonstrated that a bar-like barrier structure in the channel of the nuclear pores, seen in uninfected cells, was missing in the infected cells, giving the impression of fully open pores. Transient expression of poliovirus 2A protease also resulted in relocation of the nuclear proteins. Lysates from poliovirus-infected or 2A-expressing cells induced efflux of 3xEGFP-NLS from the nuclei of permeabilized uninfected cells. This activity was inhibited by the elastase inhibitors elastatinal and N-(methoxysuccinyl)-L-alanyl-L-alanyl-L-prolyl-L-valine chloromethylketone (drugs known also to be inhibitors of poliovirus protease 2A), a caspase inhibitor zVAD(OMe), fmk, and some other protease inhibitors. These data suggest that 2A elicited nuclear efflux, possibly in cooperation with a zVAD(OMe).fmk-sensitive protease. However, poliovirus infection facilitated nuclear protein efflux also in cells deficient in caspase-3 and caspase-9, suggesting that the efflux may occur without the involvement of these enzymes. The biological relevance of nucleocytoplasmic traffic alterations in infected cells is discussed.
...
PMID:Bidirectional increase in permeability of nuclear envelope upon poliovirus infection and accompanying alterations of nuclear pores. 1533 49

Apoptosis is a particular process that leads to the programmed cell death, and it has been a potentially therapeutic target of cancer. In this study, we evaluated the possible apoptotic effects of glycolic acid on human leukemia cell line (HL-60) in vitro. The morphological changes, cell viability, apoptosis induction, and caspase-3 activity were measured by phase microscopy, flow cytometry, and Western blot analysis. Morphological changes including shrinkage of cells were clearly demonstrated in HL-60 cells treated with increasing concentrations of glycolic acid. Cell viability was significantly affected by glycolic acid treatment in a dose- and time-dependent manner. In comparison to the control group, glycolic acid treatment had a profound effect in the induction of apoptosis by flow cytometric assays. In the cell cycle analysis, glycolic acid caused the increased percentage of cells in G2/M phase and the decreased expression of the cyclin A and cyclin B1, suggesting the induction of G2/M arrest of cell cycle by glycolic acid. Moreover, glycolic acid treatment promoted caspase-9 and -3 activity in a dose-dependent manner, but caspse-8 activity was not affected during the same process. Glycolic acid co-administrated with broad-spectrum caspase inhibitor, z-VAD-fmk, caspase-3 activity was blunted and apoptosis was also markedly blocked in HL-60 cells. In conclusion, glycolic acid-induced apoptosis in HL-60 cells may be through the activation of caspase-3. Future studies focusing on cell signaling and biological significance of glycolic acid-induced apoptosis would lead to exploring the mechanisms of chemotherapeutic potency of glycolic acid in human cancers.
...
PMID:Effects of glycolic acid on the induction of apoptosis via caspase-3 activation in human leukemia cell line (HL-60). 1535 Jun 75

The p53 tumor suppressor protein is a critical mediator of cell cycle arrest and apoptosis in response to genotoxic stress. Abrogation of p53 function is a major feature of tumor development and may result in a compromised DNA-damage response. In our study, we examined the effect of expressing a human p53 cDNA, encoding a histidine to leucine amino acid substitution at codon 179 (H179L), on the ability of wild-type p53-containing NIH3T3 cells to respond to treatment with the chemotherapeutic cisplatin. After 72 hr of cisplatin treatment control cells underwent apoptosis preceded by a combination of S- and G(2) arrest, as judged by flow cytometry of propidium iodide-stained cells, and TUNEL and caspase-3 assays. This correlated with increased expression of the pro-apoptotic protein Bax. In contrast, cells stably expressing H179L-p53 arrested in S-phase following cisplatin treatment, which correlated with a marked decrease in the expression of cdc2, cyclin B1 and cyclin A, and a decrease in CDK2 and cyclin A-associated kinase activity. Interestingly, H179L p53 expressing cells underwent apoptosis earlier than control cells, indicating that this aberrant p53 may enhance cisplatin chemosensitivity. These data suggest that dominant-negative p53 can influence the expression and activity of CDK complexes, thereby modifying cell behavior following cisplatin-induced genotoxicity.
...
PMID:Aberrant p53 alters DNA damage checkpoints in response to cisplatin: downregulation of CDK expression and activity. 1538 87

Anticancer effects of the dietary isothiocyanate sulforaphane were investigated in the human pancreatic cancer cell lines MIA PaCa-2 and PANC-1. Sulforaphane-treated cells accumulated in metaphase as determined by flow cytometry [4C DNA content, cyclin A(-), cyclin B1(+), and phospho-histone H3 (Ser(10))(+)]. In addition, treated cells showed nuclear apoptotic morphology that coincided with an activation of caspase-8, loss of mitochondrial membrane potential, and loss of plasma membrane integrity. The initial detection of caspase-3 cleavage occurring in G(2)-M arrest was independent of a change in phospho-cdc2 (Tyr(15)) protein; consequently, sulforaphane treatment combined with UCN-01 had no significant impact on cellular toxicity. Incubations at higher sulforaphane doses (>10 micromol/L) resulted in cleavage of caspase-3 in the G(1) subpopulation, suggesting that the induction of apoptosis and the sulforaphane-induced mitosis delay at the lower dose are independently regulated. Cellular toxicity in MIA PaCa-2, and to a greater extent in PANC-1, was positively correlated with a decrease in cellular glutathione levels, whereas sustained increases in glutathione observed in MIA PaCa-2 cells or the simultaneous incubation with N-acetyl-L-cysteine in PANC-1 cells were associated with resistance to sulforaphane-induced apoptosis. Daily sulforaphane i.p. injections (375 micromol/kg/d for 3 weeks) in severe combined immunodeficient mice with PANC-1 s.c. tumors resulted in a decrease of mean tumor volume by 40% compared with vehicle-treated controls. Our findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may have activity in established pancreatic cancer.
...
PMID:The dietary isothiocyanate sulforaphane targets pathways of apoptosis, cell cycle arrest, and oxidative stress in human pancreatic cancer cells and inhibits tumor growth in severe combined immunodeficient mice. 1548 91

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>