Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We show that Cdc6, an essential initiation factor for DNA replication, undergoes caspase-3-mediated cleavage in the early stages of apoptosis in HeLa cells and SK-HEP-1 cells induced by etoposide, paclitaxel, ginsenoside Rh2, or tumor necrosis factor-related apoptosis-inducing ligand. The cleavage occurs at the SEVD442/G motif and generates an N-terminal truncated Cdc6 fragment (p49-tCdc6) that lacks the carboxy-terminal nuclear export sequence. Cdc6 is known to be phosphorylated by cyclin A-cyclin dependent kinase 2 (Cdk2), an event that promotes its exit from the nucleus and probably blocks it from initiating inappropriate DNA replication. In contrast, p49-tCdc6 translocation to the cytoplasm is markedly reduced under the up-regulated conditions of Cdk2 activity, which is possibly due to the loss of nuclear export sequence. Thus, truncation of Cdc6 results in an increased nuclear retention of p49-tCdc6 that could act as a dominant negative inhibitor of DNA replication and its accumulation in the nucleus could promote apoptosis. Supporting this is that the ectopic expression of p49-tCdc6 not only promotes apoptosis of etoposide-induced HeLa cells but also induces apoptosis in untreated cells. Thus, the caspase-mediated cleavage of Cdc6 creates a truncated Cdc6 fragment that is retained in the nucleus and induces apoptosis.
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PMID:Caspase-3-mediated cleavage of Cdc6 induces nuclear localization of p49-truncated Cdc6 and apoptosis. 1451 33

We first report the mechanism for the inhibitory effect of the lysine analog, thialysine on human acute leukemia Jurkat T cells. When Jurkat T cells were treated with thialysine (0.32-2.5 mM), apoptotic cell death along with several biochemical events such as mitochondrial cytochrome c release, caspase-9 activation, caspase-3 activation, degradation of poly (ADP-ribose) polymerase, and DNA fragmentation was induced in a dose- and time-dependent manner. However, these thialysine-induced apoptotic events were significantly abrogated by an ectopic expression of Bcl-xL, which is known to block mitochondrial cytochrome c release. Decylubiquinone, a mitochondrial permeability transition pore inhibitor, also suppressed thialysine-induced apoptotic events. Comparison of the thialysine-induced alterations in the cell cycle distribution between Jurkat T cells transfected with Bcl-xL gene (J/Bcl-xL) and Jurkat T cells transfected with vector (J/Neo) revealed that the apoptotic cells were mainly derived from the cells accumulated in S and G2/M phases following thialysine treatment. The interruption of cell cycle progression in the presence of thialysine was accompanied by a significant decline in the protein level of cdk4, cdk6, cdc2, cyclin A, cyclin B1, and cyclin E. These results demonstrate that the cytotoxic activity of thialysine toward Jurkat T cells is attributable to not only apoptotic cell death mediated by a mitochondria-dependent death signaling pathway, but also interruption of cell cycle progression by a massive down-regulation in the level of cdks and cyclins.
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PMID:Mechanism underlying cytotoxicity of thialysine, lysine analog, toward human acute leukemia Jurkat T cells. 1463 87

Endocrine disruptors (EDs) are a great concern throughout the world, because they have adverse effects on human health and wildlife. In the present study, we investigated the effects of EDs on the proliferation and survival of murine neural stem cells (NSCs). In contrast to bisphenol A, phthalic acid benzyl n-butyl ester, phthalic acid di-n-butyl ester and phthalic acid di(2-ethylhexyl) ester, the treatment of NSCs with 4-nonylphenol for 24 h inhibited cell growth in a concentration-dependent manner. In addition, treatment with 4-nonylphenol resulted in nuclear condensation and DNA fragmentation (morphological changes due to apoptosis) in NSCs after 12 h of exposure, and activated caspase-3 after 6 h and 9 h of exposure. Furthermore, an exposure to 4-nonylphenol led to the accumulation of cells at the G2/M phase interface and down-regulated the protein levels of cyclin A and B1, which are the major regulatory proteins at the G2 to M transition of the cell cycle. Together, these results indicate that, in contrast to other EDs, 4-nonylphenol may exhibit a potent cytotoxicity through apoptosis via the caspase cascade and cell cycle arrest at the G2/M phase, and suggest that 4-nonylphenol may affect neurogenesis in the CNS.
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PMID:Nonylphenol induces the death of neural stem cells due to activation of the caspase cascade and regulation of the cell cycle. 1500 42

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is the only non-steroidal anti-inflammatory drug so far which has been approved by the FDA for adjuvant treatment of patients with familial adenomatous polyposis. The molecular mechanism responsible for the anticarcinogenic effects of celecoxib is still not fully understood. To investigate the extent to which the anticarcinogenic effect of celecoxib depends on COX-2 expression, we transfected human colon carcinoma cells (Caco-2) with the human COX-2 cDNA, in both sense and in antisense orientation, to generate cells which either overexpress COX-2 (human COX-2-sense, hCOX-2-s), express no COX-2 (human COX-2-antisense, hCOX-2-as) or express only very small amounts of COX-2 (control cells). Treatment of these cells with celecoxib dose-dependently (0-100microM) reduced cell survival which was accompanied by an induction of a G(0)/G(1) phase block and apoptosis. The effect of celecoxib treatment on both, cell survival and induction of apoptosis in hCOX-2-as cells was less marked than in the COX-2-expressing cells. Apoptosis was accompanied by an activation of caspase-3 and caspase-9 and cytochrome c release. In contrast, we observed no difference in sensitivity with regard to the induction of a cell cycle block between the different cell clones. The G(0)/G(1) phase block caused by celecoxib correlated with a decrease in expression levels of cyclin A and cyclin B1 and an increase in the expression of the cell cycle inhibitory proteins p21(Waf1) and p27(Kip1) irrespective of the type of cell used. These data indicate that apoptosis-inducing effects of celecoxib partly depend on COX-2 expression of the cells, whereas induction of a cell cycle block occurred COX-2 independently. Thus, the anticarinogenic effects of celecoxib can be explained by both COX-2-dependent and -independent mechanisms.
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PMID:Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. 1504 64

Cell death is of two types; necrosis and apoptosis. In histiocytic necrotising lymphadenitis (HNL), apoptosis is the main form of cell death. Apoptosis results in the formation of nuclear debris, which is one of the characteristic features of HNL. We previously reported that in HNL it is predominantly CD8-positive cytotoxic T cells that undergo apoptosis; however, the majority of proliferating cells are also CD8-positive T cells. Recent advances in technical and analytical methods have facilitated the parallel quantitation of expression of numerous genes using DNA microarrays. The technology is particularly well suited to compare differences in gene expression between normal tissues and inflammatory disease. To investigate the apoptosis- and cell cycle-associated gene expression in HNL, we analysed five cases each of HNL and non-specific lymphadenitis (NSL), using ready-made microarrays, including cyclins and caspases, and immunohistochemical staining of caspase-3, ssDNA, bcl-2 and NF-kappaB. Caspase-3- and ssDNA-positive apoptotic cells were frequently detected in HNL, but were rare in NSL. However, bcl-2- and NF-kappaB-positive cells were rare in HNL. Gene expression tree analysis of DNA microarrays showed different clustering of HNL and NSL. In comparison with NSL, HNL exhibited diffuse upregulation of these gene profiles, particularly of cyclins and caspases (ratio; cyclin A2, 2.72; caspase-6, 2.43; caspase-3, 2.02); whereas, Mcl-1, which has been shown to delay apoptosis, was downregulated (ratio, 0.71), as confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). Almost all apoptosis-associated genes, especially caspases, were upregulated, and apoptosis inhibitory genes, including bcl-2 by immunohistochemistry, were downregulated in all five cases with HNL. In addition, cell cycle-associated genes were upregulated in all. These findings confirm that both apoptosis and proliferation are simultaneously present in HNL lesions.
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PMID:Apoptosis- and cell cycle-associated gene expression profiling of histiocytic necrotising lymphadenitis. 1505 66

Previous studies have shown that sigma receptors are overexpressed in tumor cells. However, the role of sigma receptors remains enigmatic. Recently, we and others have demonstrated that sigma-1 receptor modulates K+ channels in pituitary. In the present report, patch-clamp and Western blot assays were used in small cell lung cancer (SCLC, NCI-H209, and NCI-H146) and leukemic (Jurkat) cell lines to investigate the effects of sigma ligands on voltage-gated K+ channels and cell proliferation. The sigma ligands (+)-pentazocine, igmesine, and 1,3-di(2-tolyl)guanidine (DTG) all reversibly inhibited voltage-activated K+ currents in both cell lines. The potency of sigma ligand-induced inhibition (10 microM) was igmesine = (+)-pentazocine > DTG, pointing to the involvement of sigma-1 receptors. Addition of the K+ channel blockers tetraethylammonium (TEA) and 4-aminopyridin or one of cited sigma ligands in the culture media reversibly inhibited Jurkat cell growth. Interestingly, K+ channel blockers and sigma ligands caused an accumulation of the cyclin-dependent kinase inhibitor p27kip1 and a decrease in cyclin A expression in Jurkat and SCLC cells, whereas no effect could be detected on p21cip1. Moreover, sigma ligands and TEA had no effect on caspase 3 activity. Accordingly, incubation of cells with sigma ligands did not provoke DNA laddering. These data demonstrate that sigma ligands and voltage-dependent channel blockers inhibit cell growth through a cell cycle arrest in the G1 phase but not via an apoptotic mechanism. Altogether, these results indicate that the sigma-1 receptor-induced inhibition of the cell cycle is, at least in part, the consequence of the inhibition of K+ channels.
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PMID:Inhibition of tumor cell proliferation by sigma ligands is associated with K+ Channel inhibition and p27kip1 accumulation. 1527 83

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.
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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

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.
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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.
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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.
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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


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