Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteolytic cleavage pathways of E-cadherin endogenously expressed in MDCK (Madin-Darby canine kidney) cells were characterized in cells treated with antimycin A and deoxyglucose to examine transmembrane protein processing under cellular stress. E-cadherin is a type I transmembrane protein which operates as the cell adhesion molecule component of the adherens junction, a complex of proteins involved in epithelial tissue development and integrity. We now demonstrate that treatment of MDCK cells with antimycin A and deoxyglucose activates caspase mediated pathways that cleave E-cadherin. E-cadherin is cleaved into two major fragments, with the sizes predicted by the location of a caspase-3 cleavage consensus sequence. Cleavage of E-cadherin and deposition of the C-terminal fragment into the cytoplasm are inhibited by the caspase inhibitor DEVD-CHO. Thus, a major mechanism for E-cadherin cleavage and dissolution of the adherens junction under antimycin/deoxyglucose treatment is caspase mediated, initiated by activation of an apoptosis pathway.
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PMID:Biochemical processing of E-cadherin under cellular stress. 1285 42

It is well known that inflammatory conditions of the intestinal mucosa result in compromised barrier function. Inflammation is characterized by an influx into the mucosa of immune cells that influence epithelial function by releasing proinflammatory cytokines such as IFN-gamma and TNF-alpha. Mucosal barrier function is regulated by the epithelial apical junctional complex (AJC) consisting of the tight junction and the adherens junction. Since the AJC regulates barrier function, we analyzed the influence of IFN-gamma and TNF-alpha on its structure/function and determined the contribution of apoptosis to this process using a model intestinal epithelial cell line, T84, and IFN-gamma and TNF-alpha. AJC structure/function was analyzed by confocal microscopy, biochemical analysis, and physiologic measurement of epithelial gate/fence function. Apoptosis was monitored by determining cytokeratin 18 cleavage and caspase-3 activation. IFN-gamma induced time-dependent disruptions in epithelial gate function that were potentiated by coincubation with TNF-alpha. Tight junction fence function was somewhat disrupted. Cytokine treatment was associated with internalization of AJC transmembrane proteins, junction adhesion molecule 1, occludin, and claudin-1/4 with minimal effects on the cytoplasmic plaque protein zonula occludens 1. Detergent solubility profiles of junction adhesion molecule 1 and E-cadherin and their affiliation with "raft-like" membrane microdomains were modified by these cytokines. Inhibition of cytokine-induced apoptosis did not block induced permeability defects; further emphasizing their primary influence on the epithelial AJC structure and barrier function. Our findings for the first time clearly separate the proapoptotic effects of IFN-gamma and TNF-alpha from their abilities to disrupt barrier function.
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PMID:Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. 1463 32

Cisplatin is a commonly used antitumor agent in the treatment of various human cancers, with nephrotoxicity as a major side effect. Cisplatin causes the loss of cell-cell contacts of renal proximal tubular epithelial cells prior to the onset of apoptosis. We studied the involvement of protein kinase C in these events in the renal epithelial cell line LLC-PK1. Cisplatin caused apoptosis in LLC-PK1 cells, which was directly related to the activation of caspase-3 and DNA fragmentation. Apoptosis was almost completely inhibited by the protein kinase C inhibitors bisindolylmaleimide (Bis) I and Go6983 [2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide], but not by Go6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole]. Also, in primary cultured rat renal proximal tubular cells, inhibition of protein kinase C (PKC) inhibited apoptosis. Cisplatin also caused the early loss of cell-cell adhesions, which was associated with the altered localization of the adherens junction-associated protein beta-catenin in association with PKC-mediated phosphorylation of the actincapping protein adducin. These events preceded and were independent of caspase activation. beta-Catenin did not dissociate from E-cadherin. Cisplatin-induced loss of cell-cell contacts was associated with the increased formation of F-actin stress fibers, which was inhibited by Bis I and Go6983 as well as dominant-negative PKC-epsilon. Also, the loss of cell-cell adhesions by cisplatin was prevented by Bis I and Go6983. Activation of protein kinase C with phorbol esters promoted cisplatin-induced loss of cell-cell adhesions as well as apoptosis. In conclusion, the combined data fit a model whereby protein kinase C mediates the cisplatin-induced loss of cellular interactions. Such a loss of these interactions has a role in the onset of apoptosis.
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PMID:Protein kinase C mediates cisplatin-induced loss of adherens junctions followed by apoptosis of renal proximal tubular epithelial cells. 1538 33

The RON (recepteur d'origine nantais) receptor belongs to the MET proto-oncogene family that is implicated in the oncogenesis of the gastrointestinal epithelium. The present study aimed to determine the role of RON in regulating epithelial phenotypes in response to transforming growth factor (TGF)-beta1. Expression and activation of RON in SV40-immortalized mouse intestinal epithelial MODE-K cells result in reduction of cellular sensitivities towards apoptotic signals elicited by TGF-beta1. This effect is dependent on RON expression and phosphorylation that inhibit the TGF-beta1-induced activation of caspase-3 and truncation of BAD. Among cellular signaling components, the activation of MAP kinase is critical in the RON-mediated inhibitory effect. PD98059, a specific MAP kinase inhibitor, prevented RON-mediated anti-apoptotic activities. PD98059 also prevented the inhibitory effect of RON on TGF-beta1-induced cleavage of caspase-3 and BAD. By protecting cells from apoptotic death, activated RON collaborates with TGF-beta1 in the induction of cell morphological changes with decreased E-cadherin expression and increased migration and morphogenesis. Thus, RON expression and activation modulate phenotypes of gastrointestinal epithelial cells in response to TGF-beta1 with reduced sensitivity to apoptosis and increased migration. These activities might represent a mechanism by which RON activation increases tumorigenic activities and facilitates the progression of transformed epithelial cells towards malignancy.
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PMID:Activation of the RON receptor tyrosine kinase attenuates transforming growth factor-beta1-induced apoptotic death and promotes phenotypic changes in mouse intestinal epithelial cells. 1544 77

Beta-catenin functions both as a regulator of cadherin-mediated cell-cell adhesion and a mediator of Wnt signaling. Recently, caspase-3-dependent cleavage of beta-catenin was demonstrated to occur during apoptosis. Here, we show that beta-catenin is proteolytically cleaved in G401 Wilms' tumor cells that were detached from the culture dish. Beta-catenin cleavage products of the same electrophoretic mobility were detected in G401 cells after induction of apoptosis with staurosporine and cell cycle arrest by aphidicolin. The detached cells show no sign of anoikis and approximately 90% of the floating cells were able to reattach to new dishes. Furthermore, beta-catenin was not cleaved in cells cultured on dishes coated with poly(2-hydroxyethylmethacrylate), which inhibits cellular attachment on the dishes, with approximately 90% of cells viable under these conditions. All beta-catenin cleavage products lost N-terminal and C-terminal regions and were unable to associate with alpha-catenin, which is responsible for actin filament binding and organization. However, they were still able to associate with E-cadherin. Aggregation assays revealed that the floating cells had weak aggregation compared with the attached cells. These results suggest that the cleavage of beta-catenin during cell detachment functions at least in part to remove the alpha-catenin-binding domain, thereby reducing cell adhesion activity.
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PMID:Beta-catenin cleavage in non-apoptotic cells with reduced cell adhesion activity. 1587 Sep 2

The aim of the current study was to evaluate the protein expression involved in the progression from dysplasia to invasive esophageal squamous cell carcinomas and to analyze the prognostic value of markers. Immunohistochemistry was performed for cell cycle regulators [p53, p21, p27, p16, cyclin D1, Rb], apoptosis-related proteins [Fas, Fas-L, FADD, TRAIL, DR4, DR5, caspase-8, caspase-3, bcl-2, Bax], tumor suppressor proteins [beta-catenin, E-cadherin, FHIT, Smad 4, VHL, PTEN, KAI-1], and oncoproteins [c-myc, COX-2, EGFR]. Caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR revealed significant differences between dysplasia and their corresponding invasive cancer portion in 25 cases. In a total of 118 cases of invasive cancer, proteins with frequent (> or = 60% of the cases) alterations were p53 (overexpression in 64% of SCCs), p27 (loss in 91%), p16 (loss in 81%), and FHIT (loss in 75%). Early clinical stage and bcl-2 immunopositivity were related to the survival rate of patients. In conclusion, caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR may be involved in the progression from dysplasia to invasive esophageal SCCs. Clinical stage and bcl-2 are independent prognostic factors throughout the multivariate analysis.
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PMID:Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. 1613 47

It has been reported that ultraviolet B (UVB) irradiation causes the loss of E-cadherin of melanocytes, leading them to escape from neighboring keratinocytes during melanoma development. However, little has been paid on its effect on E-cadherin of keratinocytes. In the present study we therefore focus on whether UVB affects expression of E-cadherin-catenin complex in human HaCaT keratinocytes. We found that E-cadherin, beta-, and gamma-catenin but not alpha-catenin were proteolytically cleaved in UVB-irradiated HaCaT keratinocytes. The effect was only observed in keratinocyte undergoing apoptosis. Cleavage of beta- and gamma-catenin was fully abolished by caspase-3 and caspase-8 inhibitors, whereas cleavage of E-cadherin was inhibited by neither caspase nor metalloproteinase inhibitors. Functional analysis showed that the cleavage resulted in the disruption of the physical association between E-cadherin and catenins, indicating that E-cadherin signaling was compromised in UVB-irradiated HaCaT keratinocytes. Because E-cadherin in keratinocytes plays important roles in mediating cell-cell adhesion in epidermis of skin, the loss of E-cadherin and signaling components in keratinocytes may lead to the disruption of skin integrity after UVB exposure.
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PMID:E-cadherin and its downstream catenins are proteolytically cleaved in human HaCaT keratinocytes exposed to UVB. 1651 79

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.
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PMID:Distribution of E-cadherin and beta-catenin in relation to cell maturation and cell extrusion in rat and mouse small intestines. 1673 63

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.
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PMID:Zinc modulates cytokine-induced lung epithelial cell barrier permeability. 1684 47

Cell-cell adhesion is considered to be important in the development and maintenance of organ tissue. The spatial association between melanocytes and keratinocytes within human epidermis is achieved by homophilic interaction of E-cadherin molecules located on adjacent cells. In contrast, downregulation of E-cadherin expression in melanoma cells is considered as a key event in metastasis. Besides the adhesive properties, E-cadherin serves as a signal receptor linking to the cadherin-catenin signaling complex. As cadherins act as negative regulators of beta-catenin, a contribution to tumor formation seems likely. In the present study, it was tested whether ectopic expression of E-cadherin triggers apoptosis in human melanoma cell lines (G-361, JPC-298, SK-Mel-13). It was found that restoration of E-cadherin caused sensitization against drug-induced apoptosis. Particularly, the release of mitochondrial cytochrome c was increased in response to staurosporine. Moreover, activation of caspase-3 and caspase-8 was elevated. Similarly, DNA fragmentation, serving as a marker for advanced apoptosis, was amplified in cells transduced with E-cadherin. Interestingly, transduction with an E-cadherin construct lacking the extracellular domain showed no modified apoptosis. In conclusion, our findings suggest therapeutic strategies that enable expression of E-cadherin in order to sensitize human melanoma cells towards apoptosis.
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PMID:Restoration of E-cadherin sensitizes human melanoma cells for apoptosis. 1701 88


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