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)

beta-Lapachone is a naturally occurring quinone obtained from the bark of the lapacho tree (Tabebuia avellanedae) with cancer chemopreventive properties. The objective of the present study was to investigate the effect of beta-lapachone on the cell growth and apoptosis in human colon carcinoma tumor cell line HCT-116. Exposure of HCT-116 cells to beta-lapachone resulted in growth inhibition and induction of apoptosis in a dose-dependent manner as measured by hemocytometer counts, fluorescence microscopy and flow cytometric analysis. This increase in apoptosis was associated with a decrease in Bcl-2 protein expression, an increase in caspase-3 activity, a decrease in intact poly(ADP-ribose) polymerase protein levels and degradation of beta-catenin. After beta-lapachone treatment, the nuclear protein levels of NF-kappaB and the activity of NF-kappaB-DNA binding were markedly decreased. beta-Lapachone treatment also resulted in inhibition of the transcriptional activity of NF-kappaB-luciferase reporter plasmid suggesting that beta-lapachone-induced apoptosis may be partly regulated through the inactivation of NF-kappaB.
...
PMID:beta-Lapachone-induced apoptosis is associated with activation of caspase-3 and inactivation of NF-kappaB in human colon cancer HCT-116 cells. 1459 80

12-O-tetradecanoylphorbolacetate (TPA) influences proliferation, differentiation, and apoptosis in a variety of cells including prostate cancer cells. Here, we show that androgen treatment potentiates TPA-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells but not in androgen-independent prostate cancer cell lines DU145 and PC-3. The use of the antiandrogen bicalutamide (Casodex) rescued LNCaP cells from 5-alpha-dihydrotestosterone (DHT)/TPA-induced apoptosis, suggesting that DHT/TPA-induced apoptosis is mediated by androgen/androgen receptor (AR). In addition, a caspase-3 inhibitor (Ac-DEVD-CHO) reduced the level of apoptosis, suggesting that DHT/TPA-mediated apoptosis occurs through a caspase-3-dependent pathway. A functional reporter assay using nuclear factor (NF) kappaB-luciferase and an electromobility gel shift assay showed that DHT suppressed NFkappaB activity. In addition, apoptosis mediated by combined DHT/TPA treatment was abrogated by overexpression of the NFkappaB subunit p65 in LNCaP-p65 cells, suggesting that NFkappaB may play an important role in regulating the effects of androgen/AR and TPA on apoptosis. Furthermore, use of the c-Jun N-terminal kinase (JNK) inhibitor SB202190 showed that the combination of DHT/TPA increased JNK activation in LNCaP cells but not in LNCaP-p65 cells, demonstrating that NFkappaB may be able to suppress JNK activity. These results indicate that androgen/AR facilitates TPA-induced apoptosis by interruption of the NFkappaB signaling pathway, leading to activation of JNK in LNCaP cells. These data describe a signaling pathway that could potentially be useful in proposed therapeutic treatment strategies exploiting combinations of different agents that control apoptosis in prostate tumors.
...
PMID:Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells. 1461 3

Silibinin, the flavonoid found in the milk thistle, has been shown to suppress cell growth and exhibit anti-cancer effects. Some flavonoids were reported to inhibit angiogenesis which is essential for tumor growth and metastasis. In this study, to clarify the underlying mechanisms for the anti-cancer effect of silibinin, we examined the effects of silibinin on human endothelial ECV304 cells. Silibinin was found to suppress the growth and induce the apoptosis of ECV304 cells. The induction of apoptosis by silibinin was confirmed by ladder-patterned DNA fragmentation, cleaved and condensed nuclear chromatin and DNA hypoploidy. Silibinin could effectively inhibit constitutive NF-kappaB activation as revealed by electrophoretic mobility shift assay and NF-kappaB-dependent luciferase reporter study. Consistent with this, silibinin treatment resulted in a significant decrease in the nuclear level of p65 subunit of NF-kappaB. In addition, silibinin treatment caused a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. Silibinin also induced the cytochrome c release, activation of caspase-3 and caspase-9 and cleavage of PARP. These results suggest that silibinin may exert, at least partly, its anti-cancer effect by inhibiting angiogenesis through induction of endothelial apoptosis via modulation of NF-kappaB, Bcl-2 family and caspases.
...
PMID:Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. 1465 75

Adrenomedullin (AM) is a potent vasoactive peptide and plays an important role in cardiovascular function. In this study, we delivered the AM gene locally into the heart, using a catheter-based technique to investigate the signaling mechanism mediated by AM in protection against cardiomyocyte apoptosis induced by acute ischemia/reperfusion. After adenovirus-mediated gene delivery, highly efficient and specific expression of luciferase, green fluorescent protein, or recombinant human AM was identified in the left ventricle. Delivery of the AM gene 5 days before ischemia/reperfusion attenuated myocardial apoptosis identified by in situ dUTP nick-end labeling and DNA laddering, and the effect was blocked by the AM antagonist human calcitonin gene-related peptide (CGRP 8 to 37). AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta) but reduced GSK-3beta and caspase-3 activities in the heart. The effects of AM on GSK-3beta and caspase-3 activities were blocked by CGRP (8-37) and by adenovirus containing dominant-negative Akt (DN-Akt). Furthermore, in cultured cardiomyocytes, AM also attenuated apoptosis induced by hypoxia/reoxygenation, which was accompanied by increased phospho-GSK-3beta but reduced GSK-3 and caspase-3 activities. GSK-3 and caspase-3 activities were both blocked by Ad.DN-Akt and lithium, whereas only caspase-3 was inhibited by its inhibitor Z-VAD. The effects of AM on anti-apoptosis and promoting cell viability were blocked by DN-Akt but not by constitutively active Akt, lithium, or Z-VAD. These results indicate that AM protects against cardiomyocyte apoptosis induced by ischemia/reperfusion injury through the Akt-GSK-caspase signaling pathway.
...
PMID:Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through activation of Akt-GSK signaling. 1466 48

Kallikrein/kinin has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of kallikrein gene transfer in cerebral ischemia. Adult, male Sprague-Dawley rats were subjected to a 1-hour occlusion of the middle cerebral artery followed by intracerebroventricular injection of adenovirus harboring either the human tissue kallikrein gene or the luciferase gene. Kallikrein gene transfer significantly reduced ischemia-induced locomotor deficit scores and cerebral infarction after cerebral ischemia injury. Expression of recombinant human tissue kallikrein was identified and localized in monocytes/macrophages of rat ischemic brain by double immunostaining. Morphological analyses showed that kallikrein gene transfer enhanced the survival and migration of glial cells into the ischemic penumbra and core, as identified by immunostaining with glial fibrillary acidic protein. Cerebral ischemia markedly increased apoptotic cells, and kallikrein gene delivery reduced apoptosis to near-normal levels as seen in sham control rats. In primary cultured glial cells, kinin stimulated cell migration but inhibited hypoxia/reoxygenation-induced apoptosis in a dose-dependent manner. The effects of kinin on both migration and apoptosis were abolished by icatibant, a bradykinin B2 receptor antagonist. Enhanced cell survival after kallikrein gene transfer occurred in conjunction with markedly increased cerebral nitric oxide levels and phospho-Akt and Bcl-2 levels but reduced caspase-3 activation, NAD(P)H oxidase activity, and superoxide production. These results indicate that kallikrein gene transfer provides neuroprotection against cerebral ischemia injury by enhancing glial cell survival and migration and inhibiting apoptosis through suppression of oxidative stress and activation of the Akt-Bcl-2 signaling pathway.
...
PMID:Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. 1469 96

Anti-cancer properties of palm oil have been attributed to the presence of tocotrienols and carotenoids. Studies from various laboratories have shown that tocotrienol-rich fraction (TRF) of palm oil inhibits cell growth and induces apoptosis in both preneoplastic and neoplastic cells. However, the mechanism by which TRF induces apoptosis remains largely unknown. Since several chemopreventive agents have been shown to utilize p53 pathway in negative regulation of cell growth, using human colon carcinoma RKO cells which express wild type p53, we investigated the effect of TRF on components of p53 signaling network. Treatment of cells with TRF resulted in a dose- and time- dependent inhibition of growth and colony formation. Further, TRF treatment of RKO cells resulted in the induction of WAF1/p21 which appears to be independent of cell cycle regulation and is transcriptionally upregulated in p53 dependent fashion. These results were further confirmed by using cells that express luciferase from a p53 responsive promoter where TRF treatment leads to activation of p53 reporter activity. TRF treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1. This altered expression of Bcl2 family members triggered the activation of initiator caspase-9 followed by activation of effector caspase-3. These signaling cascades lead to condensed chromatin, DNA fragmentation and shrinkage of cell membrane resulting into apoptosis. Our data suggest that TRF-induced apoptosis in colon carcinoma cells is mediated by p53 signaling network which appears to be independent of cell cycle association.
...
PMID:Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. 1471 90

Expression of the cytokine receptor CD30 is a characteristic feature of anaplastic large cell lymphoma (ALCL). Reports regarding CD30-mediated signaling in ALCL cells are highly controversial, especially with respect to the regulation of cell survival. In this study, we stimulated 6 ALCL-derived cell lines with immobilized anti-CD30 antibody. CD30-induced cell death was investigated by Western blot and FACS analysis. CD30-dependent cell proliferation and activation was analyzed by applying the trypan blue exclusion method and a luciferase-based ATP assay. The expression of cell cycle relevant proteins and the activation of mitogen-activated protein (MAP) kinases were also examined. We demonstrated that activation of CD30 did not lead to the cleavage of pro-caspase-3. FACS analysis confirmed that in all examined cells cell death was not mediated by CD30. Cell growth was strongly inhibited in 2 of the 6 cell lines and restrained cell growth was accompanied by expression of the cell cycle inhibitor p21(WAF1/CIP1). Furthermore, stimulation of CD30 led to the activation of the p38 MAP kinase but not of the extracellular signal-regulated kinase (ERK) or the jun N-terminal kinase (JNK). Interestingly, activation of CD30 induced a strong synergistic reduction of cell activity, if the p38 MAP kinase activity was blocked by SB203580. The aim of the study was to elucidate CD30-induced signaling in different ALCL-cells. Our results suggest that CD30-mediated apoptosis is not a common feature in this cell type and that p38 MAP kinase is involved in CD30-mediated singal transduction.
...
PMID:Signal transduction in anaplastic large cell lymphoma cells (ALCL) mediated by the tumor necrosis factor receptor CD30. 1529 61

We examined the effect of inhibiting p38 MAPK on UVA-irradiated HaCaT cells, a spontaneously immortalized human keratinocyte cell line. Recent work from our laboratory has shown that UVA (250 kJ/m2) induces a rapid phosphorylation of p38 MAPK in the HaCaT cell line. Inhibition of p38 MAPK activity through the use of a specific inhibitor, SB202190, in combination with UVA treatment induced a rapid cleavage of caspase-9, caspase-8, and caspase-3, whereas UVA irradiation alone had no effect. Similarly, cleavage of the caspase substrate poly(ADP-ribose) polymerase was observed in UVA-irradiated HaCaT cells treated with SB202190 or in cells expressing a dominant-negative p38 MAPK. No effect of p38 MAPK inhibition upon caspase cleavage was observed in mock-irradiated HaCaT cells. In addition, increases in apoptosis were observed in UVA-irradiated cells treated with SB202190 by morphological analysis with no significant apoptosis occurring from UVA irradiation alone. Similar results were obtained by using normal human epidermal keratinocytes. UVA induced expression of the anti-apoptotic Bcl-2 family member, Bcl-XL, with abrogation of expression by using the p38 MAPK inhibitor SB202190. Overexpression of Bcl-XL prevented poly(ADP-ribose) polymerase cleavage induced by the combination of UVA and p38 MAPK inhibition. UVA enhanced the stability of Bcl-XL mRNA through increases in p38 MAPK activity. We determined that increases in UVA-induced expression of Bcl-XL occur through a posttranscriptional mechanism mediated by the 3'-untranslated region (UTR). We used Bcl-XL 3'-UTR luciferase constructs to determine the mechanism by which UVA increased Bcl-XL mRNA stability. Additionally, RNA binding studies indicate that UVA increases the binding of RNA-binding proteins to Bcl-XL 3'-UTR mRNA, which can be decreased by using SB202190. In conclusion, p38 MAPK and Bcl-XL expression play critical roles in the survival of UVA-irradiated HaCaT cells.
...
PMID:Ultraviolet A-induced modulation of Bcl-XL by p38 MAPK in human keratinocytes: post-transcriptional regulation through the 3'-untranslated region. 1529 26

Increased levels of Mcl-1 (myeloid cell factor-1) have been reported in several cancers, suggesting an important role played by Mcl-1 in cancer cell survival. Mcl-1 is an anti-apoptotic protein shown to delay or block apoptosis. In this work, using semiquantitative immunofluorescence, real-time PCR, and RNase protection assay, an increase in Mcl-1 expression was detected in hepatoma HepG2 cells incubated under hypoxia or in the presence of cobalt chloride. Through analysis of the Mcl-1 promoter sequence, a putative HIF-1 (hypoxiainducible factor-1) binding site was identified. A Mcl-1 promoter fragment containing this hypoxia-responsive element was able to bind HIF-1 in vitro. It also induced hypoxia-dependent transcription of a luciferase reporter gene, which was suppressed by anti-HIF-1alpha short interfering RNA. Finally, overexpression of Mcl-1 protected HepG2 cells against apoptosis induced by tert-butyl hydroperoxide as shown by inhibition of caspase-3 activation and DNA fragmentation. All these data suggest a potential anti-apoptotic role of HIF-1 that could protect cells against apoptosis under hypoxia by overexpression of the Mcl-1 protein.
...
PMID:Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tert-butyl hydroperoxide-induced apoptosis. 1561 Oct 89

Expanded CUG triplet repeats carrying mRNA seem to be responsible for myotonic dystrophy type 1 (DM1). To study the pathogenesis of DM1, we constructed a DM1 cell culture model using a PC12 neuronal cell line and screened flavonoids that ameliorate this mRNA gain of function. The expanded 250 CTG repeat was subcloned into the 3'-untranslated region of the luciferase gene yielding a stable transformant of PC12 (CTG-250). The cytotoxicity of CTG-250 was evaluated by intracellular LDH activity, and the cis-effect by luciferase activity. To find agents that alter CTG-250 toxic effects, 235 bioflavonoids were screened. An increased cis-effect and cytotoxicity were found when CTG-250 was treated with nerve growth factor to induce differentiation. Western blotting with anti-caspase-3 antibody suggested that cell death was caused by apoptosis. Screening analysis confirmed that a flavone (toringin), an isoflavones (genistein and formononetin), a flavanone (isosakuranetin), and DHEA-S prevent both the cytotoxicity and cis-effect of CTG-250 and that a flavanone (naringenin), isoflavone (ononin), and xanthylatin strongly inhibit the cis-effect of CTG repeats. In conclusion, we found that this neuronal cell line, which expresses the CUG repeat-bearing mRNA, showed cis-effects through the reporter gene and neuronal death after cell differentiation in vitro. However, some flavonoids and DHEA-S inhibit both the cis-effect and cytotoxicity, indicating that their chemical structures work to ameliorate both these toxic effects. This system makes it easy to evaluate the toxic effects of expanded CTG repeats and therefore should be useful for screening other DM1 treatments for their efficacies.
...
PMID:Some flavonoids and DHEA-S prevent the cis-effect of expanded CTG repeats in a stable PC12 cell transformant. 1565 41

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