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)

Accumulation of cytoplasmic inclusion bodies in many neurodegenerative diseases, including Alzheimer's disease (AD), might result from dysfunction of the ubiquitin-proteasome system. This system degrades many cellular proteins, including beta-catenin, a member of the Wnt signaling pathway, and a presenilin-1-interacting protein. Phosphorylation of beta-catenin marks it for ubiquitination and rapid proteasomal degradation. We found phospho-beta-catenin accumulated as detergent-insoluble, punctate, cytoplasmic inclusions in hippocampal pyramidal neurons more abundantly in AD than in aged controls. In AD, beta-catenin was ubiquitin conjugated, thus suggesting impaired proteasome-dependent degradation. Phospho-beta-catenin was partially sequestered within granulovacuolar degeneration bodies but not in lysosomes, indicating sequestration within autophagosomes. Exposure of neuronal cultures to proteasome inhibitors induced formation of detergent-insoluble, phospho-beta-catenin-positive cytoplasmic inclusions that coalesced into aggresomes and colocalized with gamma-tubulin and vimentin. These aggregates were associated with apoptotic cell death and with activation of caspase-3, c-Jun-N-terminal kinases, and c-Jun. These findings suggest that phospho-beta-catenin accumulation in AD might result from impaired proteasome function.
 ...
PMID:Phospho-beta-catenin accumulation in Alzheimer's disease and in aggresomes attributable to proteasome dysfunction. 1578 69

We have investigated the effect of bismuth by autometallography, cell viability, TUNEL assay and microarray analysis of a macrophage cell line. The cells accumulate bismuth in their lysosomes in a time- and dose-dependent manner. Cell viability assays show a significant decrease in the number of viable cells related to both bismuth concentrations and exposure time. TUNEL assays after 12 h and 24 h at a bismuth-citrate concentration of 50 microM revealed the presence of 30% and 70% TUNEL-positive cells, respectively, compared with 8% in the controls. We have analysed gene expression profiles for cells exposed to 50 microM bismuth-citrate and for untreated controls at 12 h and 24 h by microarray analysis, which confirmed that bismuth is a powerful metallothionein inducer. A number of glycolytic enzymes are induced by bismuth, suggesting that bismuth is able to induce "hypoxia-like" stress. BCL2/adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) has been suggested as a regulator of hypoxia-induced cell death independent of caspase-3 activation and cytochrome c release. Bnip3 is up-regulated indicating the involvement of Bnip3 as a possible mechanism for bismuth-induced cell death. Differences have been noticed in cell viability and in the modification of the mRNA expression levels at 12 and 24 h. Only 13 genes are modified at both these times, suggesting a time-dependent molecular cascade in which bismuth-exposed cells enter a dormant stage with mRNA down-regulation being followed by cell death of susceptible cells.
 ...
PMID:Gene expression changes induced by bismuth in a macrophage cell line. 1591 5

Beclin 1, identified as a Bcl-2-interacting protein, is known to enhance autophagy. However, the effect of Beclin 1 on apoptotic signaling has remained unclear. Here, we show that overexpression of Beclin 1 in MKN28 human gastric cancer cells augmented cis-diamminedichloroplatinum (CDDP)-induced apoptosis. Conversely, "knockdown" of Beclin 1 by a small inhibitory RNA in MKN 1 cells attenuated this cytotoxicity. Furthermore, not only caspase-3/7 activities, but also caspase-9 activity was increased in Beclin 1 gene transfectants treated with CDDP, and caspase-9 inhibitor completely abolished augmentation of CDDP-induced apoptosis by Beclin 1 as did a caspase-3 inhibitor. Thus, Beclin 1 augments CDDP-induced apoptosis through enhancing caspase-9 activity and functions as a pro-apoptotic molecule.
 ...
PMID:Beclin 1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. 1592 24

The p53 tumor suppressor promotes cell cycle arrest or apoptosis in response to diverse stress stimuli. p53-mediated cell death depends in large part on transcriptional up-regulation of target genes. One of these targets, P53-induced protein with a death domain (PIDD), was shown to function as a mediator of p53-dependent apoptosis. Here we show that PIDD is a cytoplasmic protein, and that PIDD-induced apoptosis and growth suppression in embryonic fibroblasts depend on the adaptor protein receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD). We provide evidence that PIDD-induced cell death is associated with the early activation of caspase-2 and later activation of caspase-3 and -7. Our results also show that caspase-2(-/-), in contrast to RAIDD(-/-), mouse embryonic fibroblasts, are only partially resistant to PIDD. Our findings suggest that caspase-2 contributes to PIDD-mediated cell death, but that it is not the sole effector of this pathway.
 ...
PMID:Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD. 1618 42

CKIP-1 (casein kinase-2 interacting protein-1) is implicated in muscle differentiation, regulation of cell morphology and actin cytoskeleton. More recently, we showed that CKIP-1 regulated AP-1 activity and promoted apoptosis via caspase-3-dependent cleavage and translocation. Here, we report that overexpression of CKIP-1 in SK-BR-3 breast cancer cells prevents p53 degradation induced by cycloheximide treatment through increase of p53 N-terminal Ser-15 phosphorylation level. CKIP-1 could interact with ATM, which is an upstream kinase of p53, thereby enhance the stability of p53. Interestingly, CKIP-1 is localized both at the plasma membrane and in the nucleus dependent on the cell types, and only the plasma membrane-localized CKIP-1 could form a complex with ATM. Importantly, CKIP-1 recruits nuclear ATM proteins partially to the plasma membrane. Our data provide the first evidence that ATM, a predominantly nuclear kinase, could be relocalized to the plasma membrane by CKIP-1 and shed new light on the multi-functional CKIP-1.
 ...
PMID:CKIP-1 recruits nuclear ATM partially to the plasma membrane through interaction with ATM. 1632 75

The mouse breast cancer cell lines 4T1, 4T07, and 67NR are highly tumorigenic but vary in metastatic potential: 4T1 widely disseminates, resulting in secondary tumors in the lung, liver, bone, and brain; 4T07 spreads to the lung and liver but is unable to establish metastatic nodules; 67NR is unable to metastasize. The Bcl-2/adenovirus E1B 19 kDa interacting protein-3 (Bnip-3) was recently shown to be absent after hypoxia in pancreatic cancer cell lines whereas its overexpression restored hypoxia-induced cell death. We found that Bnip-3 expression increased after 6 hours of hypoxia in all cell lines tested but was highest in the nonmetastatic 67NR cells and lowest in the highly metastatic 4T1 cells. Hypoxia-induced expression of Bnip-3 in the disseminating but nonmetastatic 4T07 cells was intermediate compared with 4T1 and 67NR cells. Cleaved caspase-3, a key downstream effector of cell death, increased after 6 hours of hypoxia in the 67NR and 4T07 cells by 1.9- and 2.5-fold, respectively. Conversely, cleaved caspase-3 decreased by 45% in the highly metastatic 4T1 cells after hypoxia. Small interfering RNA oligonucleotides targeting endogenous Bnip-3 blocked cell death and increased clonigenic survival after hypoxic challenge in vitro and increased primary tumor size and enabled metastasis to the lung, liver, and sternum of mice inoculated with 4T07 cells in vivo. These data inversely correlate the hypoxia-induced expression of the cell death protein Bnip-3 to metastatic potential and suggest that loss of Bnip-3 expression is critical for malignant and metastatic evasion of hypoxia-induced cell death.
 ...
PMID:Bcl-2/adenovirus E1B 19 kDa interacting protein-3 knockdown enables growth of breast cancer metastases in the lung, liver, and bone. 1635 80

To decipher the pathway of apoptosis induction downstream to caspase-8 activation by exogenous expression of Hippi, an interactor of huntingtin-interacting protein Hip1, we studied apoptosis in HeLa and Neuro2A cells expressing GFP-tagged Hippi. Nuclear fragmentation, caspase-1, caspase-8, caspase-9/caspase-6 and caspase-3 activation were increased significantly in Hippi expressing cells. Cleavage of Bid, release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria were also increased in GFP-Hippi expressing cells. It was observed that caspase-1 and caspase-8 activation was earlier than caspase-3 activation and nuclear fragmentation. Expression of caspase-1, caspase-3 and caspase-7 was increased while anti-apoptotic gene Bcl-2 and mitochondrial genes ND1 and ND4 were reduced in Hippi expressing cells. Besides, the expression SDHA and SDHB, nuclear genes, subunits of mitochondrial complex II were decreased in GFP-Hippi expressing cells. Taken together, we concluded that Hippi expression induced apoptosis by releasing AIF and cytochrome c from mitochondria, activation of caspase-1 and caspase-3, and altering the expression of apoptotic genes and genes involved in mitochondrial complex I and II.
 ...
PMID:Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1. 1636 50

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

Exenatide (Ex-4) is a novel anti-diabetic drug that stimulates insulin secretion and enhances beta-cell mass, but the mechanisms involved are not fully understood. We found that Ex-4 protects INS-1 beta-cells against oxidative stress-induced apoptosis (TUNEL) and also reduces expression (mRNA and protein) of thioredoxin-interacting protein (TXNIP), a pro-apoptotic factor involved in beta-cell glucose toxicity and oxidative stress. This reduction was observed in INS-1 cells, mouse, and human islets as well as in wild-type mice receiving Ex-4 and was accompanied by decreased expression of the apoptotic factors caspase-3 and Bax. To determine whether Ex-4-mediated TXNIP reduction is critical for this inhibition of apoptosis, we stably overexpressed TXNIP in INS-1 cells, which completely blunted the anti-apoptotic Ex-4 effects. Thus, Ex-4 inhibits apoptosis by reducing TXNIP expression and early initiation of Ex-4 treatment may help preserve endogenous beta-cell mass, protect against oxidative stress, and delay type 2 diabetes progression.
 ...
PMID:Exenatide inhibits beta-cell apoptosis by decreasing thioredoxin-interacting protein. 1678 54

Apoptosis is a genetically determined cell suicide program. Mitochondria play a central role in this process and various molecules have been shown to regulate apoptosis in this organelle. In the present study, we firstly identified that protein tyrosine phosphatase interacting protein 51 (PTPIP51) is a novel mitochondrial protein, which may induce apoptosis in HEK293T and HeLa cell lines. PTPIP51 transfection resulted in the externalization of phosphatidylserine (PS), activation of caspase-3, cleavage of PARP, and condensation of nuclear DNA. Further investigation revealed that PTPIP51 over-expression caused a decrease in mitochondrial membrane potential and release of cytochrome c, suggesting that it may be involved in a mitochondria/cytochrome c mediated apoptosis pathway. We also found that a putative TM domain near the N terminus of PTPIP51 is required for its targeting to mitochondria, as evidenced by the finding that deletion of the PTPIP51 TM domain prevented the protein's mitochondiral localization. Furthermore, this deletion significantly influenced the ability of PTPIP51 to induce apoptosis. Taken together, the results of the present study suggest that PTPIP51 is a mitochondrial protein with apoptosis-inducing function and that the N-terminal TM domain is required for both the correct targeting of the protein to mitochondria and its apoptotic functions.
 ...
PMID:Protein tyrosine phosphatase interacting protein 51 (PTPIP51) is a novel mitochondria protein with an N-terminal mitochondrial targeting sequence and induces apoptosis. 1682 Sep 67


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