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

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fates of Rat1a cells expressing FosB and DeltaFosB as fusion proteins (ER-FosB, ER-DeltaFosB) with the ligand binding domain of human estrogen receptor were examined. The binding of estrogen to the fusion proteins resulted in their nuclear translocation and triggered cell proliferation, and thereafter delayed cell death was observed only in cells expressing ER-DeltaFosB. The proliferation of Rat1a cells, but not cell death triggered by ER-DeltaFosB, was completely abolished by butyrolactone I, an inhibitor of cycline-dependent kinases, and was partly suppressed by antisense oligonucleotides against galectin-1, whose expression is induced after estrogen administration. The cell death was accompanied by the activation of caspase-3 and -9, the fragmentation of the nuclear genome and cytochrome c release from the mitochondria, and was suppressed by zDEVD-fmk and zLEHD-fmk but not zIETD-fmk. The cell death was not suppressed by exogenous His-PTD-Bcl-x(L) at all, suggesting involvement of a Bcl-x(L)-resistant pathway for cytochrome c release.
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PMID:DeltaFosB, but not FosB, induces delayed apoptosis independent of cell proliferation in the Rat1a embryo cell line. 1272 48

beta-Amyloid protein (Abeta), a major component of senile plaques of Alzheimer's disease (AD) brain, causes elevation of the intracellular free Ca2+ level and the production of robust free radicals, both of which contribute greatly to the AD-associated cascade including severe neuronal loss in the hippocampus. Genistein, the most active molecule of soy isoflavones, protects diverse kinds of cells from damage caused by a variety of toxic stimuli. In the present study, we investigated the neuroprotective effect of genistein against Abeta25-35-induced apoptosis in cultured hippocampal neurons, as well as the underlying mechanism. Abeta25-35-induced apoptosis, characterized by decreased cell viability, neuronal DNA condensation, and fragmentation, is associated with an increase in intracellular free Ca2+ level, the accumulation of reactive oxygen species (ROS), and the activation of caspase-3. All these phenotypes induced by Abeta25-35 are reversed by genistein. Our results further show that at the nanomolar (100 nM) level, genistein protects neurons from Abeta25-35-induced damage largely via the estrogen receptor-mediated pathway, and at the micromolar (40 microM) level, the neuroprotective effect of genistein is mediated mainly by its antioxidative properties. Our data suggest that genistein attenuates neuronal apoptosis induced by Abeta25-35 via various mechanisms.
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PMID:Genistein ameliorates beta-amyloid peptide (25-35)-induced hippocampal neuronal apoptosis. 1474 30

Epidemiological, clinical, and experimental studies have suggested that excessive exposure to estrogens during fetal/neonatal life can lead to reproductive disorders and sperm abnormalities in adulthood. However, it is unknown whether endogenous concentrations of estrogens affect the establishment of the male fetal germ cell lineage. We addressed this question by studying the testicular development of mice in which the estrogen receptor (ER) beta or the ERalpha gene was inactivated. The homozygous inactivation of ERbeta (ERbeta-/-) increased the number of gonocytes by 50% in 2- and 6-d-old neonates. The numbers of Sertoli and Leydig cells and the level of testicular testosterone production were unaffected, suggesting that estrogens act directly on the gonocytes. The increase in the number of gonocytes did not occur during fetal life but instead occurred just after birth, when gonocytes resumed mitosis and apoptosis. It seems to result from a decrease in the apoptosis rate evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and cleaved caspase-3 immunohistochemical detection. Last, mice heterozygous for the ERbeta gene inactivation behaved similarly to their ERbeta-/- littermates in terms of the number of gonocytes, apoptosis, and mitosis, suggesting that these cells are highly sensitive to the binding of estrogens to ERbeta. ERalpha inactivation had no effect on the number of neonatal gonocytes and Sertoli cells. In conclusion, this study provides the first demonstration that endogenous estrogens can physiologically inhibit germ cell growth in the male. This finding may have important implications concerning the potential action of environmental estrogens.
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PMID:Estrogen receptor beta-mediated inhibition of male germ cell line development in mice by endogenous estrogens during perinatal life. 1504 78

Fifteen percent of all U.S. infants are fed soy formulas containing up to 47 mg/L of isoflavones (>65% as genistin + genistein); thus, these infants' intestines are exposed to a high dose of genistein, a phytoestrogen and tyrosine kinase inhibitor. Little attention has been focused on genistein's impact on the developing intestine. We hypothesized that a high dose of genistein would inhibit intestinal cell growth. Caco-2BBe human intestinal cells were exposed to 0, 3.7, and 111 micro mol/L (0, 1, and 30 mg/L) genistein in DMEM + 0.5% fetal bovine serum for 24-48 h. Cell number, thymidine incorporation, apoptosis, and cell cycle analyses were performed. The low genistein concentration increased intestinal cell proliferation by 28% (P = 0.001), but did not affect cell number or caspase-3 activity compared to the control. Furthermore, the addition of ICI, an estrogen receptor antagonist, negated the proliferative effect of the low genistein. In contrast, the high genistein concentration reduced cell number by 40%, proliferation by 94%, and caspase-3 activity by 50% compared to the control (P < 0.05). Cell cycle analysis after 48 h exposure to high genistein revealed 37% of cells in G0/G1 and 35% in G2/M vs. 71% in G0/G1 and 17% in G2/M for the control and low genistein groups. Thus, a biphasic effect of genistein was seen with a low dose stimulating intestinal cell proliferation through the estrogen receptor, whereas a high dose of genistein inhibited intestinal cell proliferation and altered cell cycle dynamics. A high dose of genistein may potentially compromise intestinal growth.
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PMID:Genistein at a concentration present in soy infant formula inhibits Caco-2BBe cell proliferation by causing G2/M cell cycle arrest. 1517 88

Retinoids are vitamin A derivatives, which cause growth inhibition, differentiation and/or apoptosis in various cell types, including some breast cancer cells. In general, estrogen receptor (ER)-positive cells are retinoic acid (RA) sensitive, whereas ER-negative cells are resistant. In this report, we show that ER-negative MDA-MB-231 cells are strongly growth inhibited by retinoids in combination with a PKC inhibitor. While neither RA nor GF109203X (GF) has a significant growth inhibitory effect in these cells, RA+GF potently suppress proliferation. We found that RA+GF induce apoptosis, as shown by an increase in fragmented DNA, Annexin-V-positive cells and caspase-3 activation. Apoptosis was also induced by GF in combination with two synthetic retinoids. Expression of phosphorylated as well as total PKC was decreased by GF and this was potentiated by RA. In addition, treatment with GF caused a strong and sustained activation of ERK1/2 and p38-MAPK, as well as a weaker activation of JNK. Importantly, inhibition of ERK but not p38 or JNK suppressed apoptosis induced by RA+GF, indicating that activation of ERK is specifically required. In support of this novel finding, the ability of other PKC inhibitors to cause apoptosis in combination with RA correlates with ability to cause sustained activation of ERK.
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PMID:Enhanced retinoid-induced apoptosis of MDA-MB-231 breast cancer cells by PKC inhibitors involves activation of ERK. 1527 18

Histone deacetylase inhibitors are new class of chemotherapeutic drugs able to induce tumor cell apoptosis and/or cell cycle arrest. Trichostatin A, an antifungal antibiotic, and HC-toxin are potent and specific inhibitors of histone deacetylase activity. In this study, we have examined the antiproliferative activities of trichostatin A and HC-toxin in estrogen receptor positive human breast cancer, T47D cells. Both trichostatin A and HC-toxin showed potent antiproliferative efficacy and cell cycle arrest at G2/M in T47D human breast cancer cells in a dose-dependent manner. Trichostatin A caused potent apoptosis of T47D human breast cancer cells and trichostatin A-induced apoptosis might be involved in an increase of caspase-3/7 activity. HC-toxin evoked apoptosis of T47D cells and HC-toxin induced apoptosis might not be mediated through direct increase in caspase-3/7 activity. We have identified potent activities of antiproliferation, apoptosis, and cell cycle arrest of trichostatin A and HC-toxin in estrogen receptor positive human breast cancer cell line T47D.
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PMID:Antiproliferative effect of trichostatin A and HC-toxin in T47D human breast cancer cells. 1528 67

The constitutively active catalytic domain of protein kinase C (PKC)delta is an apoptotic effector generated by caspase-3 cleavage of full-length PKCdelta in response to a wide variety of apoptotic stimuli, including UV radiation. The PKCdelta catalytic domain induces apoptosis when ectopically expressed, however, the mechanism of apoptosis induction is unclear. We constructed a chimeric protein encoding the PKCdelta catalytic domain fused to a mutated estrogen receptor ligand-binding domain in order to selectively activate the PKCdelta catalytic domain. The enzymatic activity of the PKCdelta catalytic domain fusion protein was induced in human keratinocytes treated with 4-hydroxytamoxifen, and its activation triggered loss of mitochondrial membrane potential and apoptosis. The apoptosis was associated with release of cytochrome c from the mitochondria and caspase activation, and was blocked by caspase inhibitors and the anti-apoptotic proteins Bcl-2, and Bcl-x(L), suggesting a role for mitochondrial pore formation. Consistent with this, the activated PKCdelta catalytic domain triggered the redistribution and activation of Bax, a Bcl-2 family protein that can directly induce cytochrome c release. In summary, despite being an apoptotic effector activated late in the apoptotic cascade, PKCdelta also activates upstream components of the death effector pathway to insure the demise of cells committed to apoptosis.
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PMID:Bax activation and induction of apoptosis in human keratinocytes by the protein kinase C delta catalytic domain. 1530 79

The flavanone naringenin (Nar), especially abundant in the Mediterranean diet, is reported to have anti-proliferative effects in many cancer cell lines. Antioxidant activities, kinase and glucose uptake inhibition have been proposed as molecular mechanisms for these effects. In addition, an anti-estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity could play a role in the Nar anti-tumoral effects. Here, we tested the ability of Nar to activate a specific, rapid signal transduction pathway committed to the generation of an apoptotic cascade in the presence of one of the two estrogen receptor (ER) isoforms (i.e., ERalpha or ERbeta). Cancer cells containing transfected (human cervix epitheloid carcinoma HeLa cells) or endogenous ERalpha (human hepatoma HepG2 cells) or ERbeta (human colon adenocarcinoma DLD-1 cells) were used. Our results show that Nar exerts an anti-proliferative effect only in the presence of ERalpha or ERbeta. Moreover, Nar stimulation induces the activation of p38/MAPK leading to the pro-apoptotic caspase-3 activation and to the poly(ADP-ribose) polymerase cleavage in all cancer cell lines considered. Notably, Nar shows an anti-estrogenic effect only in ERalpha containing cells; whereas in ERbeta containing cells, Nar mimics the 17beta-estradiol effects. These findings indicate new steps in the mechanism underlying ER-dependent anti-proliferative effects of Nar suggesting new potential chemopreventive actions of flavonoids on cancer growth.
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PMID:Mechanisms of naringenin-induced apoptotic cascade in cancer cells: involvement of estrogen receptor alpha and beta signalling. 1554 29

Epigallocatechin-3-gallate (EGCG) has been shown to have anticarcinogenic effects in in vitro and in vivo models, and this effect is mediated at least in part by its ability to induce apoptosis in cancer cells without affecting normal cells. It has been recognized that estrogen receptor (ER)-dependent breast cancers generally have a better prognosis and are often responsive to antiestrogen therapy; however, ER-independent breast cancers are more aggressive and unresponsive to antiestrogens. Using the MDA-MB-468 human breast cancer cell line as an in vitro model of ER-negative breast cancers, we found that treatment of EGCG resulted in dose-dependent (5-80 microg/mL) and time-dependent (24-72 hours) inhibition of cellular proliferation (15-100%) and cell viability (3-78%) in MDA-MB-468 cells. Decrease in cell viability was associated with the induction of apoptosis (18-66%) which was analyzed by DNA ladder assay, fluorescence staining, and flow cytometry. Induction of apoptosis by EGCG could be corroborated to the increased expression of tumor suppressor protein p53 and its phosphorylation at Ser 15 residue. EGCG decreased the expression of antiapoptotic protein Bcl-2 but increased proapoptotic protein Bax in these cells. The increased ratio of Bax/Bcl-2 proteins after EGCG treatment may have resulted in increased release of cytochrome c from mitochondria into cytosols, increased expression of Apaf-1, and activation of caspase-3 and poly(ADP-ribose) polymerase, which may lead to apoptosis in MDA-MB-468 cells. Together, the results of this study provide evidence that EGCG possesses anticarcinogenic effect against ER-negative breast cancer cells and thus provide the molecular basis for the future development of EGCG as a novel and pharmacologically safe chemopreventive agent for breast cancer prevention.
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PMID:Epigallocatechin-3-gallate induces apoptosis in estrogen receptor-negative human breast carcinoma cells via modulation in protein expression of p53 and Bax and caspase-3 activation. 1565 56

Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro. To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P=0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P=0.029). Analysis of proliferating cell nuclear antigen (PCNA) expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and was not caused by a decline in T antigen expression. The effect of MIS on tumor growth was also evaluated on xenografted human breast cancer cell line MDA-MB-468, which is estrogen receptor- and retinoblastoma-negative and expresses mutant p53, and thus complements the C3(1)Tag mouse mammary tumors that do not express estrogen receptor and have functional inactivation of retinoblastoma and p53. In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared with vehicle-treated controls (P=0.004). These results suggest that MIS can suppress the growth of mammary tumors in vivo.
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PMID:Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model. 1572 72


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