Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The caspase-activated DNase (CAD) is the primary nuclease responsible for oligonucleosomal DNA fragmentation during apoptosis. The DNA fragmentation factor (DFF) is composed of the 40-kDa CAD (DFF40) in complex with its cognate 45-kDa inhibitor (inhibitor of CAD: ICAD or DFF45). The association of ICAD with CAD not only inhibits the DNase activity but is also essential for the co-translational folding of CAD. Activation of CAD requires caspase-3-dependent proteolysis of ICAD. The tertiary structures of neither the inactive nor the activated DFF have been conclusively established. Whereas the inactive DFF is thought to consist of the CAD/ICAD heterodimer, activated CAD has been isolated as a large (>MDa) multimer, as well as a monomer. To establish the subunit stoichiometry of DFF and some of its structural determinants in normal and apoptotic cells, we utilized size-exclusion chromatography in combination with co-immunoprecipitation and mutagenesis techniques. Both endogenous and heterologously expressed DFF have an apparent molecular mass of 160-190 kDa and contain 2 CAD and 2 ICAD molecules (CAD/ICAD)2 in HeLa cells. Although the N-terminal (CIDE-N) domain of CAD is not required for ICAD binding, it is necessary but not sufficient for ICAD homodimerization in the DFF. In contrast, the CIDE-N domain of ICAD is required for CAD/ICAD association. Using bioluminescence resonance energy transfer (BRET), dimerization of ICAD in DFF was confirmed in live cells. In apoptotic cells, endogenous and exogenous CAD forms limited oligomers, representing the active nuclease. A model is proposed for the rearrangement of the DFF subunit stoichiometry in cells undergoing programmed cell death.
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PMID:Oligomerization state of the DNA fragmentation factor in normal and apoptotic cells. 1620 57

For nucleosomal DNA fragmentation, one of the hallmarks of apoptosis, activated caspase, an apoptosis specific cysteine protease, is required to cleave ICAD/DFF45 that releases its complexed DNase, CAD/DFF40. The protein complex is located predominantly in the nuclei. Inconsistently, caspase alone cannot induce DNA fragmentation in the isolated nuclei without the addition of a cell extract or purified CAD/DFF40. In this study, however, it is demonstrated that under selected conditions with 50-75 mM: KCl or NaCl, caspase-3 and-7 can induce DNA fragmentation without the additional factor(s).
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PMID:Salt is necessary for nucleosomal DNA fragmentation induced by caspase. 1632 93

The involvement of caspase-3 and its failure in the induction of DNA fragmentation during erythropoiesis were investigated with TF-1 cells. During erythroid differentiation, caspase-3 activation and cleavage of caspase-3 substrates such as ICAD (inhibitor of caspase-activated DNase) were detected without concomitant phosphatidyl-serine (PS) externalization and DNA fragmentation. These observations are in contrast to our understanding that DNA is degraded by CAD (caspase-activated DNase) when ICAD is cleaved by caspase-3. Our study demonstrates that CAD is downregulated at the mRNA and protein level during the erythroid differentiation in TF-1 cells. This provides a mechanism for the first time how cells avoid DNA fragmentation with activated caspase-3.
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PMID:Erythropoietin activates caspase-3 and downregulates CAD during erythroid differentiation in TF-1 cells - a protection mechanism against DNA fragmentation. 1652 48

The anti-cancer effects and possible mechanisms of the freshwater clam (Corbicula fluminea Muller) and its active compounds (FME) on cell viability in human leukemia HL-60 cells were investigated. This study demonstrated that FME was able to inhibit cell proliferation in a concentration- and time-dependent manner. Treatment with FME caused induction of caspase-2, caspase-3, caspase-6, caspase-8, and caspase-9 activity in a time-dependent manner, but not affect caspase-1 activity; it induced the proteolysis of DNA fragmentation factor (DFF-45) and poly(ADP-ribose) polymerase (PARP). Induction of cell death by FME was completely prevented by a pan-caspase inhibitor, Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and a caspase-2 inhibitor, Z-Val-Asp-Val-Ala-Asp-FMK (Z-VDVAD-FMK). Furthermore, treatment with FME caused a rapid loss of mitochondrial transmembrane potential, stimulation of generation of reactive oxygen species (ROS), release of mitochondrial cytochrome c into cytosol, and GSH depletion. Anti-oxidants such as N-acetylcysteine, catalase, superoxide dismutase, allopurinol, and pyrrolidine dithiocarbamate, but not diphenylene iodonium, significantly inhibited FME-induced cell death. In addition, the results showed that FME-induced apoptosis was accompanied by up-regulation of Bax and Bad, and down-regulation of Bcl-2 and Bcl-XL. Taken together, induction of apoptosis on HL-60 cells by FME was mainly associated with ROS production, GSH depletion, mitochondrial dysfunction, and caspase activation.
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PMID:Apoptosis-inducing active components from Corbicula fluminea through activation of caspase-2 and production of reactive oxygen species in human leukemia HL-60 cells. 1654 98

Curcumin is a natural pigment that has been shown to induce cell death in many cancer cells; however, the death mode depends on the cell type and curcumin concentration. Here we show that, in Jurkat cells, 50 micromol/L curcumin severely lowers cell survival and induces initial stage of chromatin condensation. It also induces caspase-3, which is sufficient to cleave DNA fragmentation factor 45 [DFF45/inhibitor of caspase-activated DNase (ICAD)], the inhibitor of DFF40/CAD endonuclease. However, the release of DFF40/CAD from its inhibitor does not lead to oligonucleosomal DNA degradation in curcumin-treated cells. Moreover, curcumin treatment protects cells from UVC-induced oligonucleosomal DNA degradation. In biochemical experiments using recombinant DFF activated with caspase-3, we show that curcumin inhibits plasmid DNA and chromatin degradation although it does not prevent activation of DFF40/CAD endonuclease after its release from the inhibitor. Using DNA-binding assay, we show that curcumin does not disrupt the DNA-DFF40/CAD interaction. Instead, molecular modeling indicates that the inhibitory effect of curcumin on DFF40/CAD activity results from curcumin binding to the active center of DFF40/CAD endonuclease.
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PMID:Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells. 1664 63

We have demonstrated that S179D prolactin (PRL) is potently antiangiogenic in vivo. Here, we examined apoptosis in human endothelial cells, using procaspase-8 and cytochrome c release as markers of the extrinsic and intrinsic pathways, respectively. Both pathways converge at caspase-3, which is responsible for cleavage of DNA fragmentation factor (DFF45). A 3-d incubation in 50 ng/ml S179D PRL quadrupled the number of early apoptotic cells; this effect was doubled at 100 ng/ml and became maximal at 500 ng/ml. DFF45 and procaspase 8 cleavage were detectable at 100 ng/ml. Cytochrome c, however, was unaffected until 500 ng/ml. The p21 increased at 24 h, whereas a change in p53 required both triple the time and higher doses. The p21 promoter activity was maximal at 50 ng/ml, whereas 500 ng/ml were required to see a significant change in the Bax promoter (a measure of p53 activity). Because S179D PRL and basic fibroblast growth factor (bFGF) have both been shown to activate ERK, the effect of S179D PRL on bFGF-induced ERK signaling was examined. S179D PRL blocked ERK phosphorylation in response to bFGF, whereas continued coincubation caused a delayed and prolonged activation of ERK. PD98059 inhibited this delayed activation of ERK and effects of S179D PRL on all measures except p53 levels or activity of the Bax promoter. We conclude that S179D PRL blocks bFGF-induced ERK signaling and yet uses ERK in a different time frame to elevate p21 and activate the extrinsic pathway. Prolonged incubations and high concentrations additionally activate the intrinsic pathway using an alternate intracellular signal.
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PMID:S179D prolactin primarily uses the extrinsic pathway and mitogen-activated protein kinase signaling to induce apoptosis in human endothelial cells. 1684 May 47

The julibroside J8 was isolated from the Albizia julibrissin and evaluated for antiproliferatived on six cancer cell lines (BGC-823, Bel-7402, HeLa, PC-3MIE8, MDA-MB-435 and LH-60) in vitro. Julibroside J8 at 100 microg mL- 1 (46.08 micromol.L- 1) significantly inhibited growth in the first three cell lines. In addition, in HeLa cells typical apoptotic changes in morphology were observed, and further, nuclear damage was observed by Giemsa staining and DNA fragmentation was exhibited. Effects of julibrosideJ8 on induction of DNA fragmentation, caspase-3 activation and downregulation of ICAD expression were effectively inhibited by a caspase-3 inhibitor, z-DEVD-fmk. In addition, apoptosis induced with julibroside J8 was associated with an increase in expression of the apoptosis inducer Bax, and a significant reduction in expression of the apoptosis suppressor Bcl-2 in mitochondria. These results suggest that julibroside J8 induces HeLa death through caspase pathway.
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PMID:Julibroside J8-induced HeLa cell apoptosis through caspase pathway. 1686 63

Apoptotic endonuclease is a key enzyme that mediates regulated DNA fragmentation and chromatin condensation in response to apoptotic signals such as the Fas ligand, ionizing radiation, and anticancer agents. An endonuclease that is activated specifically by caspase-3 has been identified in humans and mice. The human gene for this protein has been termed DFF40 (DNA fragmentation factor, 40-kd subunit) or caspase-activated nuclease (CPAN), whereas the mouse homologue has been named caspase-activated deoxyribonuclease (CAD). Although CAD/DFF40 is known as a major apoptotic nuclease, mice lacking inhibitor of CAD (ICAD) (also known as DFF45) are viable and still show DNA fragmentation, suggesting that alternative endonucleases play an important role during apoptosis. Endonuclease G has been reported to possibly be responsible for DNA fragmentation in various cells during apoptosis. Furthermore, we also have found that apurinic/apyrimidinic endonuclease 1 (Ape1) and its N-terminal-truncated form (AN34) are involved in DNA fragmentation during apoptosis in leukemia cells. In this review, we describe the features of several endonucleases that are involved in the apoptosis of human leukemia cells. Apoptotic endonuclease may vary among different leukemia cell types.
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PMID:Endonuclease activation and chromosomal DNA fragmentation during apoptosis in leukemia cells. 1686 99

DNA fragmentation factors (DFF) form protein complexes consisting of nuclease DFF40/CAD and inhibitory chaperon DFF45/ICAD. Although activated caspase-3 has been shown to cleave DFF complexes with the release of active DFF40 and DNA fragmentation, the organ-specific mechanisms of DFF turnover during liver injury accompanied by massive apoptosis are unclear. In this study, we investigated hepatic profile of DFF40-immunopositive proteins in two models of liver injury in rats: acute ischemia/reperfusion (I/R) and chronic alcohol administration. We show that DFF40-like proteins occur in intact rat liver mainly as a 52kDa protein. Hepatic I/R-induced caspase-3 activation and a time-dependent accumulation of DFF40-positive protein fragments (40 and 20kDa), most likely via specific caspase-3 cleavage as evidenced by in vitro digestion of intact liver tissue with recombinant caspase-3. In addition, immunoprecipitation with DFF40 followed by Western blot with active caspase-3 antibody revealed the presence of active caspase-3 in DFF40-immunopositive 20kDa proteins. Chronic alcohol administration in rats also resulted in a dose-dependent fragmentation of DFF40 proteins similar to I/R injury. Collectively, these data demonstrate that DFF40 immunopositive proteins exist in the liver as distinct, tissue-specific molecular forms that may be processed by caspase-3 during both acute and chronic liver injury.
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PMID:Generation of aberrant forms of DFF40 concurrent with caspase-3 activation during acute and chronic liver injury in rats. 1701 20

The wide variation in sensitivity of cancer cells to TRAIL- or histone deacetylase (HDAC) inhibitor - induced apoptosis precludes successful treatment of cancer with these agents. We report here that TRAIL and SBHA synergistically induce apoptosis of melanoma cells as revealed by quantitative analysis using the normalized isobologram method. This is supported by enhanced activation of caspase-3 and cleavage of its substrates, PARP and ICAD. Co-treatment with SBHA and TRAIL did not enhance formation of the death-inducing signaling complex (DISC) and processing of caspase-8 and Bid, but potentiated activation of Bax and release of Cytochrome C and Smac/DIABLO from mitochondria into the cytosol. SBHA down-regulated Bcl-X(L), Mcl-1 and XIAP, but up-regulated Bax, Bak, and the BH3-only protein Bim(EL). Up-regulation of the latter by SBHA was attenuated by the presence of TRAIL, which was inhibitable by the pan-caspase inhibitor z-VAD-fmk. Inhibition of Bim by siRNA attenuated conformational changes of Bax, mitochondrial apoptotic events, and activation of caspase-3, leading to marked inhibition of the synergy between SBHA and TRAIL. Thus, Bim plays an essential role in synergistic induction of apoptosis by SBHA and TRAIL in melanoma.
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PMID:Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. 1705 34


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