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)

Caspase-3 and caspase-7 are structurally closely related and demonstrate overlapping substrate specificity. However, during apoptosis, they are differentially regulated and show distinct subcellular localizations, implying the presence of specific substrates. In this study, to identify caspase-7 substrates, we treated the lysates derived from caspase-3-deficient MCF-7 cells with purified caspase-7 and analyzed decreased proteins by 2-DE. Intriguingly, several proteasome subunits such as alpha2, alpha6, and Rpt1 are degraded by caspase-7 during apoptosis in vitro and in vivo. Caspase-7 mediated cleavage of proteasome subunits results in the reduction of proteasome activity and thereby increases the accumulation of ubiquitinated proteins in cells. These findings suggest that caspase-7 facilitates the execution of apoptosis through down-regulation of the 26S proteasome, which regulates the turnover of proteins involved in the apoptotic process.
 ...
PMID:Caspase-7 mediated cleavage of proteasome subunits during apoptosis. 1788 Sep 20

Oxidative stress has been implicated in many physiopathologies including neurodegenerative diseases, cancer, cardiovascular and respiratory diseases, and in mechanisms of action of environmental toxicants. tert-butylhydroperoxide (t-BHP) is an organic lipid hydroperoxide analogue, which is commonly used as a pro-oxidant for evaluating mechanisms involving oxidative stress in cells and tissues. This study investigates mechanisms of apoptosis induced by oxidative stress in hepatocytes, in particular, the involvement of caspases and subcellular compartments. Freshly isolated hepatocytes were exposed to 0.4 mM t-BHP during 1 h. A general caspase inhibitor, Boc-D-FMK, reduced t-BHP-induced apoptosis (chromatin condensation), confirming the involvement of caspases in apoptosis. A caspase-9 inhibitor, Z-LEHD-FMK, also reduced t-BHP-induced apoptosis, suggesting that caspase-9 plays a critical role in this process. Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected. The caspase-9 substrates, caspase-3 and caspase-7, were not activated. Caspase-7 was translocated from the cytosol to the endoplasmic reticulum (ER), where it underwent processing; however, enzymatic activity of caspase-7 was inhibited by t-BHP. t-BHP caused cleavage of procaspase-12 at the ER and its subsequent translocation to the nucleus, where increased caspase-12 activity was found. t-BHP caused translocation of calpain from the cytosol to the ER. Calpain inhibition reduced chromatin condensation and caspase-12 activity in the nucleus, suggesting that calpain is involved in caspase-12 activation and apoptosis. This study demonstrates that caspase-9 and caspase-12 are activated in t-BHP-induced apoptosis in hepatocytes. We highlight the importance of subcellular compartments such as mitochondria, ER and nuclei in the apoptotic process.
 ...
PMID:Implication of caspases and subcellular compartments in tert-butylhydroperoxide induced apoptosis. 1831 5

Prostaglandin E(2) (PGE(2)) is a potent inhibitor of ionizing radiation (IR)-induced cell death. Exposure of colon cancer cells to IR leads to increased CUGBP2 expression. Therefore, we tested the hypothesis that PGE(2) radioprotects colon cancer cells by inhibiting CUGBP2 expression. Exposure of HCT-116 cells to gamma-IR (0-12 Gy) resulted in a dose-dependent reduction in cell growth and an increase in the G(2)-M phase of the cell cycle. Western blot analyses demonstrated increased levels of activated caspase 9 and caspase 3. In addition, whereas Bax expression is increased, that of Bcl-2 and Bcl-x(L) was reduced. Further analyses demonstrated increased activation of Chk1 and Chk2 kinases, coupled with higher levels of nuclear cyclin B1 and Cdc2. Pretreatment with PGE(2) suppressed the activation of caspase 3 and caspase 7 and inhibited Bax expression. In addition, PGE(2) treatment restored growth and colony formation to control levels. IR significantly upregulated the expression of CUGBP2 in the cells, which was suppressed when cells were pretreated with PGE(2). Ectopic overexpression of CUGBP2 also induced apoptosis. Furthermore, it reversed the PGE(2)-mediated protection from IR-induced mitotic catastrophe. Furthermore, there was an increase in nuclear localization of cyclin B1 and Cdc2 coupled with increased phosphorylation of p53, Chk1, Chk2, and Cdc25c proteins. Cell cycle analysis also demonstrated increased G(2)-M transition. In contrast, siRNA-mediated suppression of CUGBP2 expression restored normal cell cycle progression and decreased IR-induced apoptosis. Taken together, these data demonstrate that PGE(2) protects colon cancer cells from IR-induced mitotic catastrophe in part through suppression of CUGBP2 expression.
 ...
PMID:CUGBP2 downregulation by prostaglandin E2 protects colon cancer cells from radiation-induced mitotic catastrophe. 1832 84

We introduce human proteome-derived, database-searchable peptide libraries for characterizing sequence-specific protein interactions. To identify endoprotease cleavage sites, we used peptides in such libraries with protected primary amines to simultaneously determine sequence preferences on the N-terminal (nonprime P) and C-terminal (prime P') sides of the scissile bond. Prime-side cleavage products were tagged with biotin, isolated and identified by tandem mass spectrometry, and the corresponding nonprime-side sequences were derived from human proteome databases using bioinformatics. Identification of hundreds to over 1,000 individual cleaved peptides allows the consensus protease cleavage site and subsite cooperativity to be readily determined from P6 to P6'. For the highly specific GluC protease, >95% of the 558 cleavage sites identified displayed the canonical selectivity. For the broad-specificity matrix metalloproteinase 2, >1,200 peptidic cleavage sites were identified. Profiling of HIV protease 1, caspase 3, caspase 7, cathepsins K and G, elastase and thrombin showed that this approach is broadly applicable to all mechanistic classes of endoproteases.
 ...
PMID:Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites. 1853 87

Caspase-3, -6 and -7 cleave many proteins at specific sites to induce apoptosis. Their recognition of the P5 position in substrates has been investigated by kinetics, modeling and crystallography. Caspase-3 and -6 recognize P5 in pentapeptides as shown by enzyme activity data and interactions observed in the crystal structure of caspase-3/LDESD and in a model for caspase-6. In caspase-3 the P5 main-chain was anchored by interactions with Ser209 in loop-3 and the P5 Leu side-chain interacted with Phe250 and Phe252 in loop-4 consistent with 50% increased hydrolysis of LDEVD relative to DEVD. Caspase-6 formed similar interactions and showed a preference for polar P5 in QDEVD likely due to interactions with polar Lys265 and hydrophobic Phe263 in loop-4. Caspase-7 exhibited no preference for P5 residue in agreement with the absence of P5 interactions in the caspase-7/LDESD crystal structure. Initiator caspase-8, with Pro in the P5-anchoring position and no loop-4, had only 20% activity on tested pentapeptides relative to DEVD. Therefore, caspases-3 and -6 bind P5 using critical loop-3 anchoring Ser/Thr and loop-4 side-chain interactions, while caspase-7 and -8 lack P5-binding residues.
 ...
PMID:Structural basis for executioner caspase recognition of P5 position in substrates. 1878 Jan 84

Endometrial and ovarian cancers are the most common and the most lethal gynecologic malignancies worldwide, respectively. By performing differential expression analysis using annealing control primer-based reverse transcription (RT)-polymerase chain reaction (PCR) on pooled complementary DNA (cDNA) from 45 endometrial and 36 ovarian cancers and their non-tumor samples, reduced expression of the follistatin-like 1 (FSTL1) was identified. Downregulation of FSTL1 was further confirmed on individual samples and cell lines by quantitative real-time RT-PCR and western blotting. For in vitro functional study, full-length cDNA of FSTL1 was cloned and transiently transfected into the ovarian cancer cell line Ovca420 and endometrial cancer cell line AN3CA. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and cell count demonstrated significantly slower proliferation rate. By terminal uridine deoxynucleotidyl transferase dUTP nick end labeling and flow cytometric analysis, higher apoptotic activity and a remarkable increase in sub-G(1) cell population were observed in transfected cells, suggesting that FSTL1 induced apoptosis in cancer cells. Subsequent messenger RNA and protein expression analysis on downstream apoptotic molecules revealed upregulation and/or activation of FAS, FASLG, TRADD, Caspase-3, Caspase-7 and PARP by FSTL1 transfection, suggesting that FSTL1-induced apoptosis may be initiated mainly by FAS/FASLG death receptor-ligand binding. Cell migration and invasion assays demonstrated a remarkably lower cell migration and invasion capability in FSTL1-transfected cells in relation to downregulation of matrix metallopeptidase-2. Our findings suggested that a tumor suppressor role of FSTL1 may be important in ovarian and endometrial carcinogenesis.
 ...
PMID:Tumor suppressor effect of follistatin-like 1 in ovarian and endometrial carcinogenesis: a differential expression and functional analysis. 1879 37

Although apoptosis (programmed cell death type I) is more frequently reported in the literature in imatinib-treated gastrointestinal stromal tumor (GIST) cell lines,morphological features consistent with autophagic changes aremore often encountered in surgical specimens of treated patients. Autophagy (programmed cell death type II) is highly regulated by a tumor-suppressor mechanism that mainly involves the genes beclin1, PI3KIII, and bcl2. Being our material not suitable for electron microscopy analysis (not paraformaldehyde-glutaraldehyde-fixed), we evaluated the morphological, biochemical, and immunophenotypical profiles expected to be related to autophagy and apoptosis in a series of surgically resected samples taken from 11 imatinib-treated patients with molecularly characterized GISTs. The samples were examined for imatinib-induced morphological changes, the presence/interactions of the autophagic-related proteins (beclin1, PI3KIII, bcl2, and LC3-II) and the presence of apoptosis-related proteins (caspase 3, caspase 7, and lamin A/C) by means ofWestern blot analysis and coimmunoprecipitation, complemented by immunohistochemistry. We also studied samples of two untreated GISTs used as controls. Sampling areas with different residual cellularity scores fromboth the imatinib-treated and untreated patients showed biochemical and immunohistochemical evidence of high levels of proautophagy beclin1/PI3KIII and low levels of antiautophagy beclin1/bcl2 complexes, together with the presence of LC3-II detected by Western blot analysis, thus supporting the presence of autophagy. There was no expression of cleaved/activated caspase 3 or 7 or cleaved lamin A/C. Our descriptive results support the idea that GISTs activate autophagy rather than apoptosis in response to imatinib treatment and that their molecular makeup includes fingerprints of autophagy.
 ...
PMID:Is autophagy rather than apoptosis the regression driver in imatinib-treated gastrointestinal stromal tumors? 1904 28

Infection with parvovirus B19 (B19) may induce apoptosis resulting in anemia, acute fulminant liver failure, placental insufficiency and myocarditis. Apoptosis has been attributed to proapoptotic activity of the non-structural viral protein NS1, which is known to trigger a signaling cascade eventually leading to activation of caspases. In several cell types apoptosis was found to be paralleled by profound cytosolic acidification, which may be secondary to inhibition of the Na+/H+ exchanger. The acidification has been considered to support the activation of pH sensitive caspases and endonucleases. However, nothing is known about the effect of NS1 on Na+/H+ exchanger activity and cytosolic pH. The present study thus explored whether NS1 expression affects cytosolic pH (pHi) and Na+-dependent realkalinization (DeltapHi) following acidification by an ammonium pulse. According to FACS analysis, overexpression of NS1 in RXR-10SW cells led within 72 hours to activation of caspase 3 and DNA fragmentation. NS1 overexpression resulted within 24 hours in a significant decline of pHi from 6.93 +/- 0.03 (n = 6) to 6.78 +/- 0.04 (n = 7), and to a significant decrease of DeltapHi from 0.159 +/- 0.017 (n = 6) to 0.039 +/- 0.004, (n = 7). The decrease of pHi and of DeltapHi following NS1 expression could be significantly blunted by inhibition of caspase 3 with zVAD. Western blot analysis revealed degradation of NHE1 following NS1 expression. In vitro, caspase 3, but not caspase 6, caspase 7 and caspase 8 degraded NHE1 protein of cell lysates. In conclusion, overexpression of NS1 triggers a signaling cascade eventually leading to activation of caspase 3 and subsequent degradation of NHE1. The effect contributes to cytosolic acidification which may in turn favor activation of caspases and endonucleases and thus participate in the pathophysiology of B19-infection.
 ...
PMID:Inhibition of Na+/H+ exchanger activity by parvovirus B19 protein NS1. 1925 16

Histone deacetylase (HDAC) inhibitors such as vorinostat (suberoylanilide hydroxamic acid), valproic acid, romidepsin (FK-228), and LBH589 comprise a relatively new class of potent anticancer agents. This study provides evidence for the potential of vorinostat to cause acquisition of multidrug resistance protein-independent resistance in HCT116 colon tumor cells. This acquired resistance is moderate (two-fold to three-fold), is nonreversible, and correlates with the loss of responses typically seen with HDAC inhibitors, that is the loss of acetylation of the histones H2A, H2B, H3, and H4, the loss of the G2/M checkpoint activation, and the loss of caspase 3-dependent and caspase 7-dependent apoptosis. This acquired resistance also associates with cross-resistance to the hydroxamate-class (LBH589 and JNJ26481585) and to the aliphatic acid-class (valproic acid) HDAC inhibitors but not to the benzamide-class (MGCD0103) and the cyclic peptide-class (romidepsin) HDAC inhibitors. The acquired HDAC inhibitor resistance described hereis not a result of altered HDAC and histone acetyltransferase activities and differs from that previously reported for romidepsin.
 ...
PMID:Acquired vorinostat resistance shows partial cross-resistance to 'second-generation' HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities. 1932 73

In order to explore the conservation/divergence of transcriptional regulation in the platyhelminth parasite Schistosoma mansoni, we are studying the structures and functions of transcriptional mediators and in particular histone-modifying enzymes. Reversible histone acetylation changes chromatin structure and modulates gene transcription. The removal of acetyl residues from histones and other proteins is catalyzed by histone deacetylases (HDACs) that are under increasing study as therapeutic targets, both in cancer and parasitic diseases. In order to determine the extent and importance of histone acetylation in S. mansoni, we tested the effects of three histone deacetylase inhibitors (HDACi) on both larval and adult worms in culture. Trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) inhibited global HDAC activity at all life-cycle stages. TSA and VPA, but not SAHA, caused mortality of schistosomula and adults, with TSA showing the most rapid effect. Moreover, TSA caused an increase in apoptosis in schistosomula shown by the TUNEL assay and an increase in caspase 3/7 activity. Both TSA and VPA were shown to cause an increase in general levels of protein acetylation in schistosomes; more particularly of histone 4 whereas histone 3 acetylation was less affected. In the case of TSA treatment this histone hyperacetylation was correlated with the increased expression of caspases 3 and 7 transcripts. Finally, quantitative chromatin immunoprecipitation showed that the proximal promoter region of the S. mansoni caspase 7 gene was hyperacetylated on histone H4 after TSA treatment.
 ...
PMID:Histone deacetylase inhibitors induce apoptosis, histone hyperacetylation and up-regulation of gene transcription in Schistosoma mansoni. 1953 92


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