UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antitumor activity of a synthetic chenodeoxycholic acid derivative, HS-1200, on the p815 mastocytoma cell line was investigated. We present several lines of evidence indicating that HS-1200 at 35 microM induced apoptosis of p815 cells. Reduction of mitochondrial membrane potential, the release of cytochrome to cytosol, activation of caspase-3, nuclear condensation, production of poly(ADP-ribose) polymerase cleavage, generation of DNA fragmentation and nuclear condensation were demonstrated. Importantly, HS-1200 inhibited proteasome activity. Next, the combination treatment of HS-1200 or a proteasome inhibitor lactacystin was undertaken. Although the single treatment of 20 microM HS-1200 or 1 microM lactacystin induced apoptosis slightly, the combination treatment of them augmented prominently the extent of apoptosis. The combination therapy of HS-1200 and lactacystin could be potentially a therapeutic strategy reducing the extent and severity of treatment-related toxicity.
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PMID:Synthetic chenodeoxycholic acid derivative HS-1200-induced apoptosis of p815 mastocytoma cells is augmented by co-treatment with lactacystin. 1263 16

Constitutive activation of the NF-kappaB has been documented to be involved in the pathogenesis of many human malignancies, including hemopoietic neoplasms. In this study, we examined the status of NF-kappaB in two non-Hodgkin's lymphoma cell lines derived from mantle cell lymphoma (MCL) samples and in patient MCL biopsy specimens by EMSA and confocal microscopic analysis. We observed that NF-kappaB is constitutively activated in both the MCL cell lines and in the MCL patient biopsy cells. Since NF-kappaB has been shown to play an important role in a variety of cellular processes, including cell cycle regulation and apoptosis, targeting the NF-kappaB pathways for therapy may represent a rational approach in this malignancy. In the MCL cell lines, inhibition of constitutive NF-kappaB by the proteasome inhibitor PS-341 or a specific pIkappaBalpha inhibitor, BAY 11-7082, led to cell cycle arrest in G(1) and rapid induction of apoptosis. Apoptosis was associated with the down-regulation of bcl-2 family members bcl-x(L) and bfl/A1, and the activation of caspase 3, that mediates bcl-2 cleavage, resulting in the release of cytochrome c from the mitochondria. PS-341or BAY 11-induced G(1) cell cycle arrest was associated with the inhibition of cyclin D1 expression, a molecular genetic marker of MCL. These studies suggest that constitutive NF-kappaB expression plays a key role in the growth and survival of MCL cells, and that PS-341 and BAY 11 may be useful therapeutic agents for MCL, a lymphoma that is refractory to most current chemotherapy regimens.
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PMID:Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. 1281 86

Procaspase-3 (p32) is processed by upstream caspases to p12 and p20 subunits, which heterodimerize. Concomitant with formation of the active heterotetramer, p20 is autoprocessed to p17. Treatment of HL-60 cells with lactacystin, a selective inhibitor of the proteasome, exponentially increased caspase-3-like hydrolytic activity and induced apoptosis but had little or no effect on the activity of upstream caspase-8, caspase-9, or granzyme B. Lactacystin treatment decreased the p32 zymogen and evoked the accumulation of the p17 and p12 subunits. Treatment of transfected human retinoblast 911 cells with a proteasome inhibitor evoked the accumulation of epitope-tagged p12, p17, and p20 but had no effect on p32 zymogen. This result suggests that caspase-3 subunits, in contrast to the zymogen, are unstable because of degradation by the ubiquitin-proteasome system. Ubiquitin conjugates of p12 and p17 accumulated in cells that were cotransfected with p12 and a caspase inactive mutant of p17. Substitution of arginine for all eight lysines of p12 almost abolished its ubiquitination. Any single lysine or lysine pair was sufficient for p12 ubiquitination. Lactacystin treatment of HL-60 cells induced proteolytic processing of the X-linked inhibitor of apoptosis (XIAP) and decreased full-length XIAP, which is known to have ubiquitin-protein ligase activity for active caspase-3. These findings indicate that caspase-3 subunits can be degraded by the ubiquitin-proteasome system and suggest that lactacystin induces apoptosis in part by disabling the ubiquitin-protein ligase function of XIAP and by stabilizing active caspase-3 subunits.
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PMID:Preservation of caspase-3 subunits from degradation contributes to apoptosis evoked by lactacystin: any single lysine or lysine pair of the small subunit is sufficient for ubiquitination. 1286 38

The effects of a number of substances on neointima formation following angioplasty have been investigated in animal models. It was suggested that delivering of proteasome inhibitor to the site of vascular injury would be a potential therapeutic approach in prevention of vascular restenosis. But the mechanisms underlying biologic activities of proteasome inhibition in vascular smooth muscle cells (VSMCs) are largely unknown. We have investigated effects of proteasome inhibition on VSMCs using proteasome inhibitor MG115. MG115 induced apoptotic death in VSMCs as determined by viability, morphology, and DNA fragmentation. Proteasome inhibition was accompanied by up-regulation of p53, p21, and p27. In contrast, there were no appreciable alterations in the levels of Bcl-2 and Bax. Proteasome inhibition was followed by activation of caspase-3 but not of -8. The induction of apoptosis was suppressed by treatment with a selective inhibitor of the caspase-3 family, z-DEVD-fmk but not by NG-monomethyl-L-arginine. These results indicate that proteasome inhibition induces apoptosis in VSMCs by activation of caspase-3.
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PMID:Caspase-3-dependent apoptosis in vascular smooth muscle cell by proteasome inhibition. 1450 42

This study addresses mechanisms by which interleukin-1beta (IL-1beta) regulates human chondrocyte apoptosis induced by a combination of the anti-CD95 antibody CH-11 and the proteasome inhibitor (PSI). The effect of IL-1beta on apoptosis varied among tissue samples. IL-1beta either enhanced (16/22 samples) or inhibited (6/22 samples) DNA fragmentation and caspase-3 processing. The protective effect of IL-1beta was abrogated by the nitric oxide (NO) synthesis inhibitor N-monomethyl-l-arginine (L-NMMA) while apoptosis stimulation was not affected. The NO-donors sodium nitroprusside (SNP) and S-nitroso-N-acetyl penicillamine (SNAP) blocked DNA fragmentation, and this was associated with partial inhibition of caspase-3 processing. Pyrrolidine dithiocarbamate (PDTC), a scavenger of reactive oxygen species (ROS) blocked apoptosis induction by CH-11/PSI as well as the enhancement by IL-1beta. The pro-apoptotic effects of IL-1beta were also abrogated by the p38 inhibitor SB 202190. In conclusion, IL-1beta augments CH-11/PSI induced apoptosis in the majority of chondrocyte samples. The pro-apoptotic effect of IL-1beta is not dependent on NO. In contrast, the anti-apoptotic effect of IL-1beta observed in a minority of samples is partially NO-dependent.
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PMID:Role of nitric oxide, reactive oxygen species, and p38 MAP kinase in the regulation of human chondrocyte apoptosis. 1456 67

In this study, we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid to phosphatidic acid, on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176, CT-32458, and CT-32615 induced >95% growth inhibition (P < 0.01) in MM.1S, U266, and RPMI8226 MM cell lines, as well as MM cells from patients (IC(50), 50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615, the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8, caspase-3, caspase-7, and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely, JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly, CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally, although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis, CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM.
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PMID:Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. 1467 6

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a constitutively active fusion tyrosine kinase involved in lymphomagenesis of human anaplastic large cell lymphomas (ALCL), the maturation and activity of which depend on the association with the heat shock protein (hsp) 90 protein chaperone. Targeting hsp90 by the ansamycins geldanamycin and 17-allyl-amino-demethoxygeldanamycin (17-AAG) promotes degradation of several proteins through the ubiquitin-proteasome pathway, including oncogenic Raf, v-Src, erbB2, and BCR-ABL. We have previously shown that 17-AAG prevents hsp90/NPM-ALK complex formation and fosters NPM-ALK turnover, perhaps through its association with the hsp70 chaperone. Here, we show that inhibition of the proteasome activity by the potent and specific compound pyrazylcarbonyl-Phe-Leu-boronate (PS-341) blocks 17-AAG-induced down-regulation of NPM-ALK, which becomes detergent-insoluble and relocates into ubiquitin-rich perinuclear vesicles that represent aggregated polyubiquitinated forms of the protein. Kinase activity was not mandatory for proteasomal degradation of NPM-ALK, because kinase-defective NPM-ALK was even more rapidly degraded upon 17-AAG treatment. Prolonged exposure to the proteasome inhibitor was shown to trigger caspase-3-mediated apoptosis in proliferating ALCL cells at nanomolar concentrations. However, we verified that the accumulation of detergent-insoluble NPM-ALK in ALCL cells was not a spurious consequence of PS341-committed apoptosis, because caspase inhibitors prevented poly(ADP-ribose) polymerase cleavage whereas they did not affect partitioning of aggregated NPM-ALK. In line with these observations, the carboxyl hsp70-interacting ubiquitin ligase (CHIP), was shown to increase basal ubiquitination and turnover of NPM-ALK kinase, supporting a mechanism whereby NPM-ALK proceeds rapidly toward hsp70-assisted ubiquitin-dependent proteasomal degradation, when chaperoning activity of hsp90 is prohibited by 17-AAG.
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PMID:Ubiquitination and proteasomal degradation of nucleophosmin-anaplastic lymphoma kinase induced by 17-allylamino-demethoxygeldanamycin: role of the co-chaperone carboxyl heat shock protein 70-interacting protein. 1512 67

To clarify the mechanisms of osteoblastic cell death, we examined whether serum deprivation would cause activation of the apoptotic signal cascade and arrest of the cell cycle in mouse osteoblastic MC3T3-E1 cells. Serum withdrawal from osteoblastic cell cultures resulted in growth arrest and cell-cycle arrest at G0/G1, which actions were accompanied by transient and potent activation of NF-kappaB, caspase-8, caspase-2, caspase-3, and caspase-9 in this order. Apoptosis, but not necrosis, in serum-deprived cells could be detected by FACS using Annexin-V/propidium iodine double staining. Serum deprivation also resulted in transient activation of the 20S proteasome, which is an important component for regulation of the cell cycle by the ubiquitin-proteasome system. The 20S proteasome inhibitor (PSI) but not NF-kappaB inhibitor SN50 suppressed the activation of proteasomes in serum-deprived cells. Although caspase inhibitors could not prevent the G0/G1 arrest in the serum-deprived cells, SN50 and the 20S proteasome inhibitor could block it. Since SN50, 20S proteasome inhibitor and caspase inhibitor could rescue cells from serum deprivation-induced apoptosis, the pathway for NF-kappaB/caspase activation is independent of the NF-kappaB/cell-cycle pathway, and the events downstream of the NF-kappaB/caspase-9 cascade lead to apoptosis. Taken together, our present results identify a novel role for NF-kappaB in cell-cycle and apoptosis regulation and underscore the significance of each independent signal cascade in serum-deprived osteoblastic cells.
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PMID:Dual roles for NF-kappaB activation in osteoblastic cells by serum deprivation: osteoblastic apoptosis and cell-cycle arrest. 1526 3

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins related to signal transduction. Cytokine and growth factor-dependent aberrant proliferation has been implicated in renal cell carcinoma (RCC). We hypothesized that inhibiting the proteasome function might activate a proapoptotic signal transduction by modulating the cytokine and growth factor related signal transduction pathway. We therefore investigated the effectiveness of a proteasome inhibitor in the treatment of RCC regarding the involvement of Mitogen-activated protein kinases (MAP kinases), because MAP kinases are major signal transduction molecules that are known to play a pivotal role in cancer cell proliferation or apoptosis triggered by extra-cellular cytokines and growth factors. A proteasome inhibitor, MG132 inhibited the proliferation of RCC cell lines, 786-O and KU20-01 in a time and dose-dependent manner. 786-O cells have truncated von-Hippel Lindau (VHL) tumor suppressor gene protein due to a one base pair deletion at exon 1, whereas KU20-01 cells have a wild-type VHL protein. MG132 induced apoptosis in both cell lines. The inhibition of the ubiquitin-proteasome pathways was confirmed by the accumulation of ubiquitin-tagged proteins. MG132 induced the phosphorylation of ERK at 4 h and thereafter persisted for 8 to 16 h. In contrast, JNK and p38 activation persisted for longer periods and remained enhanced until 24 h. The concomitant activation of effector caspases, caspase-3 and caspase-7 was observed in 786-O cells. The inhibition of the proteasome function can induce apoptosis in RCC irrespective of the VHL protein status. The persistence of JNK and p38 activation may therefore be a unique mechanism underlying MG132 induced apoptosis.
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PMID:Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. 1528 72

The tumor suppressor function of PTEN is attributed to its phospholipid phosphatase activity that dephosphorylates the plasma membrane phosphatidylinositol-(3,4,5)-triphosphate [PtdIns(3,4,5)P3]. Implicit in this notion is that PTEN needs to be targeted to the plasma membrane to dephosphorylate PtdIns(3,4,5)P3. However, the recruitment of PTEN to the plasma membrane is not fully understood. Here, we demonstrate PTEN accumulation in the detergent-insoluble fraction of neuronal cells in response to treatment by the proteasome inhibitor lactacystin. First, lactacystin induces apoptosis and the activation of caspase-3 in cultured cortical neurons. Second, PTEN undergoes proteolysis to form a truncated 50-kDa form that lacks parts of its C-terminal tail. Third, the truncated PTEN is stably associated with the detergent-insoluble fraction in which the plasma membrane marker protein flotillin-1 resides. Taken together, our results suggest that truncation and accumulation of PTEN to the detergent-insoluble membrane fraction are two events associated with the apoptotic signals of the proteasome inhibitor in cortical neurons.
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PMID:Lactacystin-induced apoptosis of cultured mouse cortical neurons is associated with accumulation of PTEN in the detergent-resistant membrane fraction. 1528 34

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