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)

Apoptosis requires the activation of caspases (formerly interleukin 1beta-converting enzyme-like proteases), in particular those related to the caspase-3/7/6 subfamily. Recent data, however, revealed that, although caspase-specific inhibitors delay apoptosis, they are often incapable of preventing it. To obtain evidence for caspase-independent steps of apoptosis, we artificially created a high amount of short-lived or aberrant proteins by blocking the ubiquitin degradation pathway. A temperature-sensitive defect in the ubiquitin-activating enzyme E1 induced apoptosis independent of the activation of caspase-3 and -6 and the cleavage of their respective substrates poly(ADP-ribose) polymerase and lamin A. In addition, neither the caspase 3/7-specific inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone nor the general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone were capable of blocking this type of cell death. By contrast, Bcl-2 overexpression effectively protected cells from apoptosis induced by a defect in the E1 enzyme at the nonpermissive temperature. Bcl-2 acted downstream of the accumulation of short-lived or aberrant proteins because it did not prevent the overexpression of the short-lived proteins p53, p27(kip1), and cyclins D1 and B1 under conditions of decreased ubiquitination. These results suggest the existence of short-lived proteins that may serve the role of caspase-independent effectors of apoptosis and attractive targets of the death-protective action of Bcl-2.
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PMID:Defects in the ubiquitin pathway induce caspase-independent apoptosis blocked by Bcl-2. 949 30

We investigated the in vitro effect of As2O3 on proliferation, cell cycle regulation, and apoptosis in human myeloma cell lines. As2O3 significantly inhibited the proliferation of all of eight myeloma cell lines examined in a dose-dependent manner with IC50 of approximately 1-2 microM. DNA flow cytometric analysis indicated that As2O3 (2 microM) induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of As2O3, we examined the effect of As2O3 on cell cycle-related proteins in MC/CAR cells in which both G1 and G2-M phases were arrested. Western blot analysis demonstrated that treatment with As2O3 (2 microM) for 72 h did not change the steady-state levels of CDK2, CDK4, cyclin D1, cyclin E, and cyclin B1 but decreased the levels of CDK6, cdc2, and cyclin A. The mRNA and protein levels of CDKI, p21 were increased by treatment with As2O3, but those of p27 were not. In addition, As2O3 markedly enhanced the binding of p21 with CDK6, cdc2, cyclin E, and cyclin A compared with untreated control cells. Furthermore, the activity of CDK6-associated kinase was reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by the up-regulation of cdc2 phosphorylation (cdc2-Tyr15 phosphorylation) resulting from reduction of cdc25B and cdc25C phosphatases. As2O3 also induced apoptosis in MC/CAR cells as evidenced by flow cytometric detection of sub-G1 DNA content and annexin V binding assay. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondrial transmembrane potential (delta psi(m)), and an increase of caspase-3 activity. These results suggest that As2O3 inhibits the proliferation of myeloma cells, especially MC/CAR cells, via cell cycle arrest in association with induction of p21 and apoptosis.
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PMID:Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. 1085 Apr 58

Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. In a study of the anti-proliferative activity of ginsenosides using human prostate carcinoma LNCaP cell line, ginsenoside Rg3 displayed growth inhibitory activity. The cells lost its adherent property after incubation in the presence of 250 microM of ginsenoside for 48h. The expression of biomarker genes, including prostate specific antigen (PSA), androgen receptor (AR) and 5alpha-reductase (5alphaR), and that of the proliferating cell nuclear antigen (PCNA), were suppressed. Ginsenoside Rg3 induced classic apoptotic morphology and interfered with the expression of apoptosis-related genes, bcl-2 and caspase-3, in LNCaP cells, as demonstrated by fluorescence microscopy, flow cytometry and reverse transcriptase-polymerase chain reaction. Taken our results together, we suggested that ginsenoside Rg3 activated the expression of cyclin-kinase inhibitors, p21 and p27, arrested LNCaP cells at G1 phase, and subsequently inhibited cell growth through a caspase3-mediated apoptosis mechanism.
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PMID:Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. 1097 98

In a previous study, we prepared short-chain fatty acid (SCFA) mixtures mimicking the composition of the digested fibers from wheat bran, oat bran, pectin, and cellulose and tested the products on U4 cells, a cell-line model for normal colonocytes. These SCFA mixes induced the cyclin-dependent kinase (cdk) inhibitors p21 and p27, which bound to cdk2/cyclin E and cdk4/cyclin D1 complexes, blocking their kinase activity and arresting cell growth. SCFAs from digested fiber may control intestinal crypt height in vivo by inducing apoptosis in growth-arrested cells at the top of the crypt. In the present study, we report that SCFA mixes induced apoptosis of U4 cells and unexpectedly caused both a sustained activation of the stress-activated protein kinase c-jun N-terminal kinase 1 (JNK1) and downregulation of the tumor suppressor protein p53. JNK1 bound to p53, and the amount of JNK1-bound p53 accurately reflected the amount of total cellular p53. After activation by SCFAs, JNK1 phosphorylated its bound p53. This phosphorylation is likely to have converted p53 into an apoptotic target because p53 breakdown correlated with caspase-3 activity, was inhibited by a caspase-3 inhibitor in a dose-dependent manner, and was inhibited by transfection of dominant-negative JNK1. Because JNK1 activation was sustained in SCFA-treated U4 cells, JNK1 can bind, phosphorylate, and release p53 for proteolysis and then continue this cycle until many p53 molecules have been phosphorylated. Loss of p53 protein was likely due to proteolysis and not to transcriptional changes because a sixfold decrease in p53 protein occurred within 3-24 h of SCFA treatment, whereas p53 mRNA levels were downregulated as much only after 2-3 d. SCFA mixes targeted p53 and possibly other cellular proteins for degradation during apoptosis by causing a sustained activation of JNKs.
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PMID:Downregulation of p53 by sustained JNK activation during apoptosis. 1110 63

Expression of retinoic acid receptor beta (RARbeta) is reported to be absent or down-regulated in oral squamous cell carcinomas. Recently, we found that the growth-inhibitory effect of 9-cis-retinoic acid (9CRA) on oral squamous cell carcinoma may depend on the expression levels of endogenous RARbeta. In order to clarify the role of RARbeta in growth and differentiation, we transfected RARbeta expression vector into oral squamous carcinoma cell lines, HSC-4 and Ho-1-N-1. Both RARbeta-transfected cell lines displayed growth inhibition. Moreover, RARbeta-transfected clones underwent morphological changes, and RARbeta-transfected HSC-4 clones underwent apoptosis even in the absence of 9CRA treatment. In contrast, RARbeta-transfected Ho-1-N-1 clones exhibited cell cycle arrest without undergoing apoptosis initially; however, apoptosis was induced in these cells after 6 days of 9CRA treatment. RARalpha and RARgamma expression was reduced at both the protein and mRNA levels in RARbeta transfectants, whereas the expression of retinoid X receptor alpha (RXRalpha) was not altered. RARb transfectants exhibited alterations in the levels of cell cycle-associated proteins, histone acetyltransferase (HAT) and apoptosis-associated proteins. After 6 days of 9CRA treatment, RARbeta transfectants overexpressed Waf1 / Cip1 / Sdi1 / p21, Kip1 / p27, chk1, p300 / CBP, BAX, Bak, Apaf 1, caspase 3 and caspase 9. Conversely, E2F1, cdc25B and HDAC1 were down-regulated in these transfectants. In addition, histone H4 acetylation was induced in RARb transfectants. These findings suggest that histone acetylation mediated by histone acetyltransferase and p300 / CBP may play a role in the growth arrest and apoptosis induced by RARbeta transfection in oral squamous cell carcinoma.
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PMID:Overexpression of retinoic acid receptor beta induces growth arrest and apoptosis in oral cancer cell lines. 1117 43

beta-Lapachone, a novel anti-neoplastic drug, induces various cancer cells to undergo apoptosis. In a previous report, we showed that beta-lapachone-induced apoptosis of HL-60 cells is mediated by oxidative stress. However, in the present study, we found that beta-lapachone-induced apoptosis of human prostate cancer (HPC) cells may be independent of oxidative stress. In contrast to the 10-fold beta-lapachone-induced increase in H(2)O(2) production seen in HL-60 cells, only a 2- to 4-fold increase was observed in HPC cells. N-acetyl-L-cysteine (NAC), a thiol antioxidant, inhibited the apoptosis in DU145 cells after 12 h exposure to beta-lapachone. Nonetheless, NAC, along with other antioxidants, failed to exert similar effect in HPC cells subjected to beta-lapachone treatment for 24 h. Under this premise, we suggest that the oxidative stress may not play a crucial role in beta-lapachone-mediated HPC cell apoptosis. Here we demonstrate that damage to genomic DNA is the trigger for the apoptosis of HPC cells induced by beta-lapachone. According to our results, beta-lapachone stimulates DNA dependent kinase expression and poly(ADP-ribose) polymerase cleavage in advance of significant morphological changes. beta-Lapachone promotes the expression of cyclin-dependent kinase (cdk) inhibitors (p21(WAF1) and p27(Kip1)), induces bak expression, and subsequently stimulates the activation of caspase-7 but not of caspase-3 or caspase-8 during the apoptosis of HPC cells. Taken together, these results suggest that the signaling pathway involving the beta-lapachone-induced apoptosis of HPC cell may be by DNA damage, induction of cdk inhibitors (p21 and p27), and then subsequent stimulation of caspase-7 activation.
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PMID:Induction of CDK inhibitors (p21(WAF1) and p27(Kip1)) and Bak in the beta-lapachone-induced apoptosis of human prostate cancer cells. 1125 23

Peripheral blood progenitor cells (PBPC) mobilized by granulocyte colony-stimulating factor (G-CSF) promptly engraft allogeneic recipients after myeloablative chemotherapy for hematologic malignancies. Surprisingly, no exacerbation of acute graft-vs-host disease has been observed despite a 10-fold higher T-cell content in PBPC compared with bone marrow allografts. Because G-CSF can suppress T-cell proliferation in response to mitogens and enhance their activation-induced apoptosis, we examined the molecular mechanisms underlying G-CSF-induced immune dysfunction. Normal allogeneic lymphocytes were challenged with phytohemagglutinin in the presence of serum collected after G-CSF administration (postG) to healthy PBPC donors, and the expression of key components of the cell cycle and apoptotic machineries was investigated by flow cytometry and Western blotting. Lymphocyte stimulation was associated with collapse of mitochondrial transmembrane potential, hypergeneration of reactive oxygen intermediates, and activation of caspase-3 and DNA fragmentation. Lymphocytes were arrested in a G(1)-like phase of the cell cycle, as measured by G(1)-phase cyclin expression and bromodeoxyuridine (BrdUrd) incorporation. Cell tracking experiments confirmed the occurrence of a lower number of population doublings in postG compared with preG cultures. Unexpectedly, the phosphorylation state of the protein encoded by the retinoblastoma susceptibility gene (pRB) was unaltered in postG cultures, and the inhibition of cell cycle progression occurred without the recruitment of the cyclin-dependent kinase inhibitors p15(INK4B), p16(INK4A), and p27(Kip1). We eventually evaluated the ability of antioxidant/cytoprotectant agents to prevent the G-CSF-induced mitochondrial dysfunction and inhibition of cell cycle progression. Of interest, both N-acetylcysteine and amifostine reduced apoptotic cell death by 45% on average, inhibited the activation/processing of caspase-3, and increased BrdUrd incorporation in postG cultures. Based on these experimental findings, a model is proposed in which T-cell activation in the presence of serum immunoregulatory factor(s) induced by G-CSF is associated with a molecular phenotype mimicking the G(1)-S transition and consisting of pRB phosphorylation, lack of CDKI recruitment, and reduced cyclin-E expression. The putative relationship between lymphocyte mitogenic unresponsiveness and apoptosis induction would occur at the level of key molecules shared by the cell cycle and apoptotic machineries. Whether the G-CSF-mediated modulation of lymphocyte functions in vitro is beneficial in transplantation medicine remains to be determined.
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PMID:T-cell apoptosis induced by granulocyte colony-stimulating factor is associated with retinoblastoma protein phosphorylation and reduced expression of cyclin-dependent kinase inhibitors. 1130 Nov 80

Although TGF-beta1, a growth inhibitor, is known to also induce apoptosis, the molecular mechanism of this apoptosis is largely undefined. Here, we identify the mechanism of TGF-beta1-induced apoptosis in SNU-16 human gastric cancer cells. Cell cycle and TUNEL analysis showed that, upon TGF-beta1 treatment, cells were initially arrested at the G1 phase and then driven into apoptosis. Of note, caspase-3 was activated in accordance with TGF-beta1-induced G1 arrest. Activated caspase-3 is targeted to cleave p21(cip1), p27(kip1), and Rb, which play important roles in TGF-beta-induced G1 arrest, into inactive fragments. Subsequently, Cdk2 was aberrantly activated due to the cleavage of p21 and p27. We found that the inhibition of Cdk2 activity efficiently blocks TGF-beta1-induced apoptosis, whereas it did not prevent caspase-3 activation or the subsequent cleavage of target proteins. In contrast, the suppression of caspase-3 activity inhibited the cleavage of target proteins, the activation of Cdk2, and the induction of apoptosis. Taken together, our results suggest that activation of caspase-3 by TGF-beta1 may initiate the conversion from G1 cell cycle arrest to apoptosis via the cleavage of p21, p27 and Rb, which in turn causes Cdk2 activation and, most significantly, Cdk2 activation as a downstream effector of caspase is a critical step for the execution of TGF-beta1-induced apoptosis.
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PMID:Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-beta1-induced apoptosis in human gastric cancer cells. 1131 70

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins and cell cycle control. Dysregulating the degradation of such proteins should have profound effects on tumor growth and causes cells to undergo apoptosis. The aims of this study are to evaluate the ubiquitin-proteasome pathway in gastric cancer and the potential role of pharmacological inhibition of proteasome on induction of apoptosis in gastric cancer cells. Gastric cancer cell lines AGS (p53 wild-type) and MKN-28 (p53 mutant) were treated with proteasome inhibitor MG132. The results showed that MG132 inhibited cell proliferation in AGS and MKN-28 cells in a time- and dose-dependent manner. The inhibition of cell proliferation was caused by apoptosis which was also time- and dose-dependent. AGS cells were more responsive to MG132 than MKN-28 cells. Induction of apoptosis was preceded by the activation of caspase-3, as measured by a colorimetric caspase-3 cellular activity and Western blotting of the cleavage of caspase-3 and its substrate PARP. Activation of caspase-7 was also exhibited. In addition, z-VAD-fmk, a broad spectrum caspase inhibitor, reversed apoptosis induced by MG132 in AGS and MKN28 cells. Although z-DEVD-fmk, a specific caspase-3 inhibitor, suppressed MG132-induced apoptosis in MKN28 cells, it only partially rescued the apoptotic effect in AGS cells. Caspase-3 activation was the result of release of cytochrome c from mitochondria into the cytosol, as a consequence of upregulation of bax. There were overexpressions of all the proteasome-related proteins p53, p21(waf1) and p27(kip1) at 4 hr after proteasome inhibition which was identified by the accumulation of ubiquitin-tagged proteins. This was accompanied by accumulation of cells at G(1) phase. Our present study suggests that inhibition of proteasome function in gastric cancer cells induces apoptosis and proteasomal inhibitors have potential use as novel anticancer drugs in gastric cancer.
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PMID:Inhibition of proteasome function induced apoptosis in gastric cancer. 1147 51

We examined the immunohistochemical expressions of cell-cycle- and apoptosis-related factors to investigate the possible role of these factors in odontogenic keratocyst (OKC). Expression of cyclin D1 and p16 protein was detected in the basal and parabasal cells in lining epithelium of OKCs and was found more frequently in basal cell nevus syndrome (BCNS)-associated OKCs than in primary or recurrent OKCs. Positivity for p21 protein was detected in basal to superficial cells, whereas that for p27 protein was detected in parabasal to superficial cells in lining epithelium of OKCs. DNA topoisomerase IIalpha reacted with nuclei in basal and parabasal cells of the lining epithelium of OKCs, and positive cells were observed in BCNS-associated OKCs significantly more frequently than in primary or recurrent OKCs. Expression of Fas in suprabasal to superficial cells and expression of Fas-L in basal and parabasal cells were detected in lining epithelium of OKCs. Immunoreactivity for caspase-3 was detected in basal to suprabasal or superficial cells in lining epithelium of OKCs. Single stranded (ss)DNA-positive nuclei were detected in superficial cells in lining epithelium of OKCs. Fas was more broadly distributed in BCNS-associated OKCs than in primary OKCs, and ssDNA-positive cells were observed in BCNS-associated OKCs significantly more frequently than in primary or recurrent OKCs. These results suggest that BCNS-associated OKCs might be a distinguishable entity from solitary OKCs.
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PMID:Immunohistochemical analysis of cell-cycle- and apoptosis-related factors in lining epithelium of odontogenic keratocysts. 1148 22


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