UNIPROT:P42574 - FACTA Search

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

N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid is under clinical evaluation as a therapeutic agent in a variety of cancers. Its mechanism(s) of action involves multiple overlapping pathways that still remain unclear. In glioma cells its mechanism of action is not well elucidated. Here, we show that 4-HPR and not all-trans retinoic acid and 9-cis retinoic acid effectively induce apoptosis in glioma cells. 4-HPR-induced apoptosis is associated with hydroperoxide production and loss of mitochondrial membrane potential (Delta Psi(m)). Ultrastructural changes further indicate 4-HPR-induced mitochondrial swelling, endoplasmic reticulum (ER) dilation as well as close proximity of mitochondria and ER. As suggested by dilated ER, 4-HPR treatment increased the free cytosolic Ca(2+) as well as mitochondrial Ca(2+). Chelation of extracellular Ca(2+) by EGTA did not prevent Ca(2+) elevation, thus suggesting involvement of intracellular calcium stores in the release. Buffering of intracellular calcium by BAPTA-AM did not prevent 4-HPR-induced apoptosis; however, blocking the release of Ca(2+) from ER by heparin inhibited apoptosis, indicating the role of depletion of Ca(2+) from ER stores in apoptosis. 4-HPR treatment also resulted in an increase in Bax levels along with its translocation to mitochondria that promote mitochondrial membrane permeabilization. 4-HPR-induced apoptosis was further associated with the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol and nucleus, respectively, along with caspase-3 and caspase-7 activation. However, AIF nuclear translocation, peripheral chromatin condensation and apoptosis were not completely prevented by general caspase inhibitors, thus suggesting involvement of a caspase-dependent and caspase-independent pathway in 4-HPR-induced apoptosis. Taken together, these results suggest the role of mitochondrial-mediated pathway and ER stress as a key event in 4-HPR-induced apoptosis in glioma cells.
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PMID:Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress. 1667 69

Cip/Kip family protein p21, a cyclin-dependent kinase (CDK) inhibitor, is directly transactivated by retinoic acid receptor alpha (RARalpha) upon retinoic acid (RA):RARalpha binding. Yet the role of p21 upregulation by RA in lymphoma cells remains unknown. Here, we show that, in human pre-B lymphoma Nalm6 cells, RA-induced proliferation inhibition results from massive cell death characterized by apoptosis. Upregulated p21 by RA accompanies caspase-3 activation and precedes the occurrence of apoptosis. p21 induction leads to increased p21 complex formation with cyclin E/CDK2, which occurs when cyclin E and CDK2 levels remain constant. CDK2 can alternatively promote apoptosis, but the mechanisms remain unknown. Data presented here suggest a novel RA-signaling, by which RA-induced p21 induction and complex formation with cyclin E/CDK2 diverts CDK2 function from normally driving proliferation to alternatively promoting apoptosis.
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PMID:Increased p21 expression and complex formation with cyclin E/CDK2 in retinoid-induced pre-B lymphoma cell apoptosis. 1676 49

It has been postulated that the pathogenesis of Parkinson's disease (PD) is associated with mitochondrial dysfunction. Rotenone, an inhibitor of mitochondrial complex I, provides models of PD both in vivo and in vitro. We investigated the neuroprotective effect of D-beta-hydroxybutyrate (bHB), a ketone body, against rotenone toxicity by using SH-SY5Y dopaminergic neuroblastoma cells. SH-SY5Y cells, differentiated by all-trans-retinoic acid, were exposed to rotenone at concentrations ranging from 0 to 1,000 nM. We evaluated cellular oxidation reduction by the alamarBlue assay, viability by lactate dehydrogenase (LDH) assay, and survival/death ratio by live/dead assays. Exposure to rotenone for 48 hr oxidized cells and decreased their viability and survival rate in a concentration-dependent manner. Pretreatment of cells with 8 mM bHB provided significant protection to SH-SY5Y cells. Whereas rotenone caused the loss of mitochondrial membrane potential, released cytochrome c into the cytosol, and reduced cytochrome c content in mitochondria, addition of bHB blocked this toxic effect. bHB also attenuated the rotenone-induced activation of caspase-9 and caspase-3. Administration of 0-10 mM 3-nitropropionic acid, a complex II inhibitor, also decreased the reducing power of SH-SY5Y cells measured by alamarBlue assay. Pretreatment with 8 mM bHB attenuated the decrease of alamarBlue fluorescence. These data demonstrated that bHB had a neuroprotective effect that supported the mitochondrial respiration system by reversing the inhibition of complex I or II. Ketone bodies, the alternative energy source in the mammalian brain, appear to have therapeutic potential in PD.
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PMID:D-beta-hydroxybutyrate protects dopaminergic SH-SY5Y cells in a rotenone model of Parkinson's disease. 1691 40

Retinoids such as all trans-retinoic acid (ATRA) have been used as chemopreventive agents for a number of premalignant conditions. To explore a potential role for retinoids as chemopreventive agents for Barrett's esophagus, we studied ATRA's effects on apoptosis in a nonneoplastic, telomerase-immortalized, metaplastic Barrett's cell line. We treated the Barrett's cells with ATRA in the presence and absence of inhibitors to p53 (pSRZ-siRNA-p53), p38 (SB-203580 and p38 siRNA), and the caspase cascade (z-Val-Ala-Asp-fluoromethyl ketone). We determined the effects of ATRA and the various inhibitors on apoptosis using cell morphology, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling staining, cleaved caspase-3 immunofluorescence, and Annexin V staining. We also determined how ATRA in the presence and absence of the inhibitors affected apoptosis following low-dose UV-B irradiation. ATRA induced apoptosis and increased the expression of p53 protein in a dose-dependent fashion. The apoptotic effect of ATRA was abolished by treatment with inhibitors of both p38 and caspase, but not by p53 interfering RNA (RNAi). Inhibition of p38 also prevented expression of cleaved caspase-3, suggesting that ATRA activates p38 upstream of the caspase cascade. We found that ATRA sensitized immortalized Barrett's cells to apoptosis induced by low-dose UV-B irradiation via a similar mechanism. ATRA induces apoptosis in Barrett's epithelial cells and sensitizes them to apoptosis induced by UV-B irradiation via activation of p38 and the caspase cascade, but not through p53. This study elucidates molecular pathways whereby retinoid treatment might prevent carcinogenesis in Barrett's metaplasia and suggests a potential role for the use of safer retinoids for chemoprevention in Barrett's esophagus.
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PMID:All trans-retinoic acid induces apoptosis via p38 and caspase pathways in metaplastic Barrett's cells. 1693 49

Glioblastoma is the most common and highly malignant brain tumor. It is also one among the most therapy-resistant human neoplasias. Patients die within a year of diagnosis despite the use of available treatment strategies such as surgery, radiotherapy, and chemotherapy. Thus, there is a critical need to find a novel therapeutic strategy for treating this disease. Here, we have investigated the molecular mechanisms for induction of apoptosis as well as for activation of immune components in human malignant glioblastoma T98G and U87MG cells following treatment with all-trans retinoic acid (ATRA) plus interferon-gamma (IFN-gamma). Treatment of glioblastoma cells with ATRA alone prevented cell proliferation and induced astrocytic differentiation, while IFN-gamma alone induced apoptosis and modulated expression of human leukocyte antigen (HLA) class II molecules such as HLA-DRalpha, HLA-DR complex, invariant chain (Ii), HLA-DM (an important catalyst of the class II-peptide loading), and gamma interferon-inducible lysosomal thiol-reductase (GILT). Interestingly, both T98G and U87MG cells showed more increase in apoptosis with expression of the HLA class II components for an effective immune response following treatment with ATRA plus IFN-gamma than with IFN-gamma alone. Apoptotic mode of cell death was confirmed morphologically by Wright staining and biochemically by measuring an increase in caspase-3 activity. While conversion of tumor cells into HLA class II+/Ii- cells by stimulation with the helper CD4+ T cells is thought to be challenging, this study reports for the first time that treatment of glioblastoma cells with ATRA plus IFN-gamma can simultaneously enhance apoptosis and expression of the HLA class II immune components with a marked suppression of Ii expression. Taken together, this study suggests that induction of apoptosis and immune components of the HLA class II pathway by ATRA plus IFN-gamma may be a promising chemoimmunotherapeutic strategy for treatment of human malignant glioblastoma.
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PMID:Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells. 1694 22

NT2 cells are a human teratocarcinoma cell line that, upon treatment with retinoic acid (RA), begin differentiating into a neuronal phenotype. The transformation of undifferentiated NT2 cells into hNT neurons presents an opportunity to investigate the mechanisms involved in neurogenesis because a key component is cell apoptosis, which is essential for building neural networks. Protein kinase Cdelta (PKCdelta) plays an important role as a mediator of cellular apoptosis in response to various stimuli. PKCdelta (deltaI) is proteolytically cleaved at its hinge region (V3) by caspase 3 and the catalytic fragment is sufficient to induce apoptosis in various cell types. Mouse PKCdeltaII is rendered caspase resistant due to an insertion of 78 bp within the caspase recognition site in its V3 domain. No functional role has been attributed to these alternatively spliced variants of PKCdelta. We sought to find a correlation between the onset of apoptosis, neurogenesis, and the expression of PKCdelta isoforms. Our results indicate that RA regulates the expression of PKCdelta alternative splicing variants in NT2 cells. Further, overexpression of PKCdeltaI promotes apoptosis while PKCdeltaII overexpression shields the cells from apoptosis. This is the first report to attribute physiological function to PKCdeltaI and -deltaII isoforms. Next we demonstrated that mouse embryonic stem cells differentiate in vitro into dopaminergic neurons upon stimulation with RA and ciliary neurotrophic factor. These cells showed a simultaneous increase in tyrosine hydroxylase and PKCdeltaII expression. We suggest that the molecular mechanisms regulating differentiation and apoptosis could be understood by alternative expression of PKCdelta isoforms.
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PMID:PKCdelta alternatively spliced isoforms modulate cellular apoptosis in retinoic acid-induced differentiation of human NT2 cells and mouse embryonic stem cells. 1701 22

Liver X receptors (LXRs) form functional heterodimers with the retinoid X receptors (RXRs) and regulate cholesterol, lipid, and glucose metabolism. We demonstrated previously that activation of LXR modulates insulin secretion in MIN6 cells and pancreatic islets. In this study we investigated the effects of the LXR agonist T0901317 and the RXR agonist 9-cis-retinoic acid (9cRA) on cell proliferation and apoptosis in MIN6 cells. Whereas T0901317 showed no effect on proliferation of MIN6 cells, combination of T0901317 with 9cRA inhibited cell proliferation. Flow cytometry analysis of cell cycle demonstrated that activation of LXR/RXR prevented MIN6 cells from G1 to G2 phase progression. Combination of T0901317 and 9cRA increased apoptosis rate and caspase-3/7 activity in MIN6 cells. Moreover, T0901317 or its combination with 9cRA significantly increased the cell susceptibility to free fatty acid- and cytokine-induced apoptosis. Treatment of MIN6 cells with LXR and RXR agonists produced a strong increase in expression of mothers against decapentaplegic homolog 3, a protein known to inhibit cell cycle G1/S phase progression and induce apoptosis. In isolated rat islets, the effect of palmitic acid on caspase-3/7 activity was increased with T0901317 alone and even more with the combination of T0901317 and 9cRA. Thus, activation of LXR/RXR signaling inhibits cell proliferation and induces apoptosis in pancreatic beta-cells.
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PMID:Activation of liver X receptors and retinoid X receptors induces growth arrest and apoptosis in insulin-secreting cells. 1719 44

The role of alpha1,3fucosyltransferase-VII (alpha1,3 FucT-VII) in cell apoptosis was studied in human hepatocellular carcinoma H7,721 cells. After the cells were transfected with alpha1,3 FucT-VII cDNA, the expression of apoptotic protease, procaspase-3, was decreased, while the anti-apoptotic proteins, phospho-PKB and phospho-Bad were increased as compared with mock (vector) transfected cells, indicating that alpha1,3FucT-VII is a potential anti-apoptotic factor in H7,721 cells. After "alpha1,3FucT-VII" cells were irradiated by UV to induce apoptosis, the anti-apoptotic potential of alpha1,3FucT-VII became more apparent, as evidenced by the less apoptotic cell % and active cleaved caspase-3, more phospho-p38 MAPK and JNK (two anti-apoptotic signaling molecules in H7,721 cells responsible to UV stress) when compared with the "Mock" cells. In contrast, "alpha1,3FucT-VII" cells facilitated the apoptosis induced by all-trans retinoic acid (ATRA), which was verified by the greater sub-G1 (apoptotic cells) peak in flow cytometry analysis, more expressions of active caspase-3 and pro-apoptotic protein Bax, as well as less expressions of anti-apoptotic proteins, Bcl-2 and Bcl-X(L). The up regulation of alpha1,3FucT-VII mRNA and cell surface SLe(x) (alpha1,3FucT-VII product) by UV and down regulation of them by ATRA was speculated to be one of the mechanisms that alpha1,3FucT-VII decreased and increased the susceptibility of apoptosis induced by UV and ATRA respectively.
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PMID:Alpha1,3 Fucosyltransferase-VII modifies the susceptibility of apoptosis induced by ultraviolet and retinoic acid in human hepatocarcinoma cells. 1743 81

Apoptosis is an essential physiological process in embryonic development. In the developing eye of vertebrates, three periods of developmental apoptosis can be distinguished: early, intermediate and later. Within the apoptosis pathway, caspases play a crucial role. It has also been shown that HSP110 may have a potential role in apoptosis. The aim of this research was to study the expression of HSP110, caspase-3 and -9 in physiological, retinoic- or irradiation-induced apoptosis during early eye development. Seven pregnant C57Bl/6J mice received 80 mg kg(-1) of all-trans retinoic acid mixed with sesame oil. Seven pregnant NMRI mice received 2 Gy irradiation at the same gestational day. Control mice of both strains (seven mice of each) were not submitted to any treatment. Embryos were harvested at 3, 6, 12 and 24 h after exposition, fixed, dehydrated and embedded. Coronal sections (5 microm) were made. Slide staining occurred alternatively using anti-caspase-3, anti-caspase-9 and anti-HSP110 immunohistochemistry. HSP110 and caspase-3 expression presented similar topographic and chronological patterns, whereas expression of HSP110 was more precocious in retinoic acid-treated embryos. After retinoic exposure, caspase-3- and HSP110-positive cells were increased in the region of the optic vesicle. By contrast, after irradiation, caspase-3- and HSP110-positive cells were noticeably increased in the optic vesicle, peri-optical mesoderm but less in lens placode. HSP110 was expressed before caspase-3. By contrast, caspase-9 was expressed by a very small number of cells in the optic vesicle either under physiological or under teratogenic conditions. Thus, it seems that activation of caspase-9 is dispensable in early eye developmental apoptosis.
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PMID:HSP110, caspase-3 and -9 expression in physiological apoptosis and apoptosis induced by in vivo embryonic exposition to all-trans retinoic acid or irradiation during early mouse eye development. 1745 30

Hydroxysteroid (17beta) dehydrogenase 2 (HSD17B2) has been shown to inactivate both estrogens and androgens and activate 20alpha-hydroxyprogesterone to progesterone. In the present study, we generated transgenic (TG) mice ubiquitously expressing human HSD17B2. The TG mice produced showed growth retardation and delayed eye opening at the postnatal age. Disrupted spermatogenesis was evident in the presence of normal serum and intratesticular testosterone, progesterone, and normal circulating LH concentrations. A proper androgen action in the target tissues was confirmed by normal histological appearance of the prostate and epididymis. Furthermore, quantitative RT-PCR analysis indicated only a slight decrease in androgen-dependent gene expression in the prostate. The disrupted spermatogenesis was not associated with increased germ cell apoptosis as analyzed by caspase-3 activation. However, it resulted in infertility in the HSD17B2 TG males after the age of 3 months, and at the age of 6 months the seminiferous tubules showed a Sertoli cell-only phenotype. The data indicate that the growth retardation and disrupted spermatogenesis are not due to a lack of proper estrogen or androgen action. Interestingly, the testicular phenotype and some of the other phenotypic changes described are typically observed in mice with reduced action of retinoic acid signaling. This, together with the rescue of the testis phenotype by a synthetic retinoic acid receptor agonist (4-[(E)-2-(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl)-1-propenyl] benzoic acid), suggests a role for HSD17B2 in the action of retinoids, in addition to its oxidative HSD17B activity on sex steroids.
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PMID:Transgenic male mice expressing human hydroxysteroid dehydrogenase 2 indicate a role for the enzyme independent of its action on sex steroids. 1751 Feb 38

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