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)

Sulindac sulfone (FGN-1, Aptosyn), a metabolite of the nonsteroidal anti-inflammatory drug sulindac, lacks cyclooxygenase inhibitory activity. Although its ability to inhibit tumorigenesis in both carcinogen-treated animals and patients with familial adenomatous polyposis has been attributed to the induction of apoptosis, its complete mechanism of action remains unclear. The purpose of the present study was to determine the ability of sulindac metabolites to regulate cellular levels of beta-catenin and downstream targets of the adenomatous polyposis coli (APC)/beta-catenin pathway in vitro. Sulindac sulfone was consistently more potent than the sulfide metabolite in all analyses, significantly decreasing the expression of total cellular beta-catenin (50% of control), pro-caspase 3 (49%), cyclin D1 (51%), and PPARdelta (65%) in SW480 cells. No significant alteration in pro-caspase 3 or beta-catenin expression was found in HCA7, LS174, or Caco-2 cells treated with sulindac sulfone. A dose-dependent reduction in TCF-mediated transcriptional activity was also observed in SW480 cells. These data demonstrate that sulindac sulfone can modulate the APC/beta-catenin pathway in vitro and that its efficacy is dependent upon the mutational status of APC and beta-catenin.
 ...
PMID:Sulindac sulfone is most effective in modulating beta-catenin-mediated transcription in cells with mutant APC. 1638 42

Cell polarity regulates diverse biological events such as localization of embryonic determinants and establishment of tissue and organ architecture. Epithelial cell polarity is regulated by the polarity complex Par6/Par3/atypical protein kinase C (aPKC). We previously found that the nucleotide exchange factor ECT2 associates with this polarity complex and regulates aPKC activity, but the role of ECT2 in cell polarity is still unclear. Here we show that expression of a dominant negative (ECT2-N2) or constitutively active (ECT2-DeltaN5) form of ECT2 inhibits normal cyst formation of MDCK cells in 3-dimensional collagen gels. Central lumens were not observed in cysts formed by cells expressing either ECT2-DeltaN5 or ECT2-N2. Apical localization of ZO-1 and basolateral localization of beta-catenin were no longer observed in these cells. Interestingly, cells expressing ECT2-N2 did form normal cysts when cultured in the basement membrane matrix Matrigel instead of collagen gels. Addition of a major Matrigel component, laminin, partially rescued the normal cyst formation inhibited by ECT2-N2 in 3-dimensional collagen gels. Thus, signaling through laminin might override the defects of signaling through collagen and ECT2. Whereas ECT2-N2 inhibited the lumen formation of MDCK cysts, caspase-3, which is reportedly involved in lumen formation through apoptosis, was activated at various locations of cells in the cysts. It is likely that perturbation of ECT2 signaling inhibits the establishment of epithelial cell polarity leading to the inhibition of selected elimination of cells at the center of cysts. Thus, ECT2 appears to play a critical role in epithelial cell polarity.
 ...
PMID:Nucleotide exchange factor ECT2 regulates epithelial cell polarity. 1649 35

The objective of the present study was to investigate the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on the cell growth and apoptosis and its effect on the telomerase activity in human leukemic cell line U937. Exposure of U937 cells to TSA resulted in growth inhibition and induction of apoptosis in a dose-dependent manner as measured by hemocytometer counts, fluorescence microscopy, agarose gel electrophoresis and flow cytometry analysis. The increase in apoptosis was associated with the up-regulation in proapoptotic Bax expression and down-regulation of antiapoptotic Bcl-2 and Bcl-X(L). TSA treatment inhibited the levels of cIAP family members and induced the proteolytic activation of caspase-3, which was associated with concomitant degradation of poly(ADP-ribose)-polymerase and beta-catenin protein. TSA treatment markedly inhibited the activity of telomerase in a dose-dependent fashion. Additionally, the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively down-regulated by TSA treatment. We therefore conclude that TSA demonstrated antiproliferative and apoptosis-inducing effects on U937 cells in vitro, and that changes in Bcl-2 family protein levels as well as telomerase activity may play an important role in its mechanism of action.
 ...
PMID:Induction of apoptosis and inhibition of telomerase activity by trichostatin A, a histone deacetylase inhibitor, in human leukemic U937 cells. 1657 1

Epidemiologic studies reported that the prevalence of hereditary non-polyposis colon cancer (HNPCC) in male is about 1.5-fold higher than that in female. Decreases in circulatory estrogen (E(2)) have been reported to downregulate the expression of E(2) receptor (ER) and significantly increase the risk of colorectal cancer. Patients that received E(2) replacement therapy were found to have a reduction in the incidence of colon adenoma and carcinoma. Furthermore, significant decreases in the expression of ER have been found in colorectal cancer specimens. Evidences strongly suggest the protective roles of E(2) and ER against colorectal cancer. However, the mechanisms of ERalpha effects on colorectal cancer cells remained un-clear. LoVo cells were transient transfected to overexpress ERalpha, DNA fragmentation and the activated caspases measurements were performed to evaluate apoptotic effects. Western blotting was used to evaluate protein levels, and luciferase activity assay to measure the Htnf-a promoter activity. The results clearly demonstrated that overexpressed ERalpha with or without E(2) (10(-8) M) treatment could activate caspase -8, -9, and 3 and induce DNA fragmentation in LoVo cell. At the same time, overexpressed ERalpha plus E(2) significantly increases the expression and promoter activity of hTNF-alpha, and the DNA fragmentation effect induced by E(2) plus ERalpha were reduced by the addition of hTNF antibody (0.1 ng(ml). In addition, E(2) plus ERalpha significantly upregulated p21 and p27 levels and downregulated the beta-catenin and its target genes, cyclin D1 and Rb, which regulate the cell cycle and cell proliferation. The results indicate that E(2) plus overexpressed ERalpha induce LoVo cell apoptosis might mediate through the increase of hTNF-alpha gene expression, which in turn activate caspase-8, -9 and caspase-3 and lead to the DNA fragmentation and apoptosis. E(2) plus ERalpha also showed the downregulation of beta-catenin signalings implicating the suppression of proliferation and metastasis of colorectal cells. Efforts aiming at enhancing ERalpha expression and(or activity may be proved to be an alternative therapy against colorectal cancer.
 ...
PMID:Over-expressed estrogen receptor-alpha up-regulates hTNF-alpha gene expression and down-regulates beta-catenin signaling activity to induce the apoptosis and inhibit proliferation of LoVo colon cancer cells. 1662 68

Noxa is a pro-apoptotic BH3-only member of the Bcl-2 family of proteins that is up-regulated at a transcriptional level by the nuclear protein p53 in response to cellular stresses such as DNA damage or growth factor deprivation. Noxa is able to interact with anti-apoptotic members of the Bcl-2 family and causes release of cytochrome c into the cytosol, leading to the activation of caspases and induction of apoptosis. Here we demonstrate that MG132, a proteasomal inhibitor, rapidly induces Noxa mRNA and protein in two human cell lines, T/C28a and Saos2. The induction of Noxa is associated with a significant reduction in the number of metabolically active cells over the first 24 h of exposure to MG132 and progressive activation of caspase-3, a hallmark of caspase-dependent apoptosis. Partial rescue of the phenotype is observed when cells are transfected with Noxa siRNA prior to treatment with MG132, indicating functional significance of the induction of Noxa. p53 has previously been shown to be non-functional in the T/C28a cell line and is absent by Western blotting in Saos2 cells, suggesting that the induction of Noxa is through a p53 independent mechanism. Western blotting and confocal microscopy showed that total beta-catenin protein is increased in both cell lines at the time of Noxa induction, with the bulk of the beta-catenin present in the nucleus. Transfection with the Tcf reporter vector pTOPFLASH confirms that treatment with MG132 leads to early increased transcriptional activity of beta-catenin in both T/C28a and Saos2 cells. However, although over-expression of transcriptionally active beta-catenin in T/C28a cells also induced apoptosis through a p53-independent mechanism, the levels of Noxa protein were unchanged, suggesting that beta-catenin mediated signaling and Noxa may play independent roles in MG132 induced apoptosis. In summary, our results demonstrate that MG132 induces the pro-apoptotic protein Noxa via a p53-independent mechanism that leads to caspase-dependent apoptosis. This is the first report showing that treatment with MG132 induces Noxa. This study also provides further evidence for a link between beta-catenin mediated signaling and the induction of apoptosis.
 ...
PMID:MG132 induced apoptosis is associated with p53-independent induction of pro-apoptotic Noxa and transcriptional activity of beta-catenin. 1667 57

Metabotropic glutamate receptors are expressed throughout the nervous system, but their function as well as their ability to promote neuronal survival rests heavily upon the intracellular mechanisms governed by this family of G-proteins. In this regard, we examined one of the primary pathways that can oversee cell survival, namely protein kinase B (Akt1), and its functional integration with some of its substrates that may work in concert with group I metabotropic glutamate receptor (mGluRI) activation to protect primary hippocampal neurons during oxidative stress. We demonstrate that neuroprotection against free radical injury through mGluRI activation with DHPG requires the activation of Akt1, since loss of Akt1 activity assessed through its GSK-3alpha/beta substrate by pharmacological blockade of the phosphatidylinositide-3-kinase pathway or the gene silencing of Akt1 expression prevents neuronal protection during mGluRI activation. Closely coupled to the robust neuroprotection by mGluRI activation are the inhibitory phosphorylation and prevention of caspase 3 cleavage of the Forkhead transcription factor FOXO3a, the down-regulation of Bim expression, and the protection of beta-catenin by Akt1 against phosphorylation and degradation to promote its translocation from the cytoplasm to the nucleus and allow it to assist with a "pro-survival" cellular program. Further insight into the cellular mechanisms that determine neuronal protection by the metabotropic glutamate system will foster the successful therapeutic development of mGluRs for neurodegenerative disorders.
 ...
PMID:Group I metabotropic receptor neuroprotection requires Akt and its substrates that govern FOXO3a, Bim, and beta-catenin during oxidative stress. 1671 94

In the small intestines, cell renewal from stem cells present in the crypts is balanced by cell extrusion from the tips of the villi. The mechanism by which extrusion occurs is unknown. Recent in vitro data suggested that loss of E-cadherin could contribute to cell extrusion and induction of programmed cell death (PCD) in mouse small intestinal epithelium. We have studied if this also occurs in the intact rodent small intestine. Our results confirm that extruded cells are negative for E-cadherin. However, loss of the E-cadherin-interacting protein beta-catenin preceded both extrusion and loss of E-cadherin. Thus, all extruded cells as well as all cells in the process of extrusion lacked staining for beta-catenin. Moreover, almost 80% of all cells undergoing programmed cell death, as detected by the TUNEL reaction, lacked beta-catenin whereas over 70% of such cells were positive for E-cadherin. However, most cells lacking beta-catenin did not display signs of PCD as detected by the TUNEL method or by staining for active caspase-3. Therefore, these results suggest that loss of beta-catenin precedes the onset of programmed cell death, loss of E-cadherin and extrusion from the villi.
 ...
PMID:Distribution of E-cadherin and beta-catenin in relation to cell maturation and cell extrusion in rat and mouse small intestines. 1673 63

Hint1 is a member of the evolutionarily conserved family of histidine triad proteins that acts as a haplo-insufficient tumor suppressor inducing spontaneous tumor formation in Hint+/- and Hint-/- mouse models. However, the molecular mechanisms for the tumor-suppressing activity are poorly defined. In this respect, we have recently shown that Hint1, by interaction with Pontin and Reptin, inhibits T-cell factor/beta-catenin-mediated transcription of Wnt target genes. In this study, we have found that, after transient transfection with Hint1, SW480 and MCF-7 cells undergo apoptosis as analyzed by pro-caspase-3 and poly(ADP-ribose) polymerase cleavage, M30 CytoDEATH staining, cytochrome c release, and DNA fragmentation enzyme-linked immunosorbent assay. Hint1 is involved in the regulation of apoptotic pathways by inducing an up-regulation of p53 expression coinciding with an up-regulation of the proapoptotic factor Bax and a concomitant down-regulation of the apoptosis inhibitor Bcl-2. Bad and Puma levels remained unchanged. Further analyses revealed that Hint1 is associated with the Bax promoter and is a component of the Tip60 histone acetyltransferase complex and, in this context, appears to be involved in the regulation of Bax expression. Knockdown of Hint1 by short hairpin RNA resulted in down-regulation of p53 and Bax but had no effect on Bcl-2 expression. A mutant Hint1 (H112N) protein defective in enzymatic activity as an AMP-NH2 hydrolase was not impaired in induction of apoptosis, suggesting that the Hint1 pro-apoptotic activity is independent of the Hint1 enzymatic activity.
 ...
PMID:The histidine triad protein Hint1 triggers apoptosis independent of its enzymatic activity. 1683 43

Apoptosis plays a causative role in acute lung injury in part due to epithelial cell loss. We recently reported that zinc protects the lung epithelium during inflammatory stress whereas depletion of intracellular zinc enhances extrinsic apoptosis. In this investigation, we evaluated the relationship between zinc, caspase-3, and cell-to-cell contact via proteins that form the adherens junction complex. Cell adhesion proteins are directly responsible for formation of the mechanical barrier of the lung epithelium. We hypothesized that exposure to inflammatory cytokines, in conjunction with zinc deprivation, would induce caspase-3, leading to degradation of junction proteins, loss of cell-to-cell contact, and compromised barrier function. Primary human upper airway and type I/II alveolar epithelial cultures were obtained from multiple donors and exposed to inflammatory stimuli that provoke extrinsic apoptosis in addition to depletion of intracellular zinc. We observed that zinc deprivation combined with tumor necrosis factor-alpha, interferon-gamma, and Fas receptor ligation accelerates caspase-3 activation, proteolysis of E-cadherin and beta-catenin, and cellular apoptosis, leading to increased paracellular leak across monolayers of both upper airway and alveolar lung epithelial cultures. Zinc supplementation inhibited apoptosis and paracellular leak, whereas caspase inhibition was less effective. We conclude that zinc is a vital factor in the lung epithelium that protects against death receptor-mediated apoptosis and barrier dysfunction. Furthermore, our findings suggest that although caspase-3 inhibition reduces lung epithelial apoptosis it does not prevent mechanical dysfunction. These findings facilitate future studies aimed at developing therapeutic strategies to prevent acute lung injury.
 ...
PMID:Zinc modulates cytokine-induced lung epithelial cell barrier permeability. 1684 47

Glomerulosclerosis and diabetic nephropathy are attributable to high glucose induction of mesangial cell apoptosis. Whereas Wnt signaling has been found to regulate renal morphogenesis and pathogenesis, the biologic role of Wnt/beta-catenin signaling in controlling high glucose-induced mesangial cell apoptosis is not well defined. Herein is reported that Wnt/beta-catenin signaling is required for protecting glomerular mesangial cells from high glucose-mediated cell apoptosis. High glucose downregulated Wnt4 and Wnt5a expression and the subsequent nuclear translocation of beta-catenin, whereas it increased glycogen synthase kinase-3beta (GSK-3beta) and caspase-3 activities and apoptosis of glomerular mesangial cells. Suppression of GSK-3beta activation or increase in nuclear beta-catenin by transfection of Wnt4 or Wnt5a or stable beta-catenin (S33Y) reversed Akt activation and reduced the high glucose-mediated caspase-3 cleavage and cell apoptosis. Pharmacologic inhibition of GSK-3beta by recombinant Wnt5a or bromoindirubin-3'-oxime or LiCl increased Akt phosphorylation and beta-catenin translocation and abrogated high glucose-mediated proapoptotic activities. Exogenous bromoindirubin-3'-oxime treatment reduced phospho-Ser(9)-GSK-3beta and beta-catenin expression and apoptosis of cells adjacent to glomeruli in diabetic kidneys and attenuated urinary protein secretion in diabetic rats. Taken together, mesangial cells responded to high glucose by impairing that canonical Wnt pathway to increase proapoptotic activities. Sustaining Wnt/beta-catenin signaling is beneficial for promoting survival of mesangial cells that are exposed to high glucose stress.
 ...
PMID:Wnt/beta-catenin signaling modulates survival of high glucose-stressed mesangial cells. 1694 6


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