Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 binding protein 2 (53BP2) has been identified as the interacting protein to p53, Bcl-2, and p65 subunit of nuclear factor kappaB (NF-kappaB). The TP53BP2 gene encodes two splicing variants, 53BP2S and 53BP2L, previously known as apoptosis stimulating protein 2 of p53 (ASPP2). We found that these 53BP2 proteins are located predominantly in the cytoplasm and induce apoptosis as demonstrated by cleavage of poly ADP ribose polymerase (PARP) and annexin V staining. Furthermore, we demonstrate that 53BP2 is located in the mitochondria and induces apoptosis associated with depression of the mitochondrial trans-membrane potential (DeltaPsim) and activation of caspase-9. From these findings we conclude that 53BP2 induces apoptosis through the mitochondrial death pathway.
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PMID:53BP2 induces apoptosis through the mitochondrial death pathway. 1574 14

ATP or dATP is a required activator of Apaf-1 for formation of the Apoptosome and thereby activation of caspase-9 (Csp9) [Zou, H., Henzel, W. J., Liu, X., Lutschg, A., and Wang, X. (1997) Cell 90, 405-413]. Here we demonstrate that dATP or ATP may have an additional role in controlling Apaf-1-mediated Csp9 activation. In the presence of cytochrome c (CytC), dATP or ATP binds to Apaf-1 and triggers heptamerization of Apaf-1 leading to the activation of Csp9. At concentrations greater than 1 mM, dATP or ATP also functions as a negative regulator of apoptosis by binding to and inhibiting Csp9. The affinity labeling reagent, 3'-O-(5-fluoro-2,4-dinitrophenyl)-ATP (FDNP-ATP), was used to probe the binding of nucleotides to Csp9. Similar to ATP, but with a much more profound effect, FDNP-ATP binds to the full-length proCsp9 potently, with an IC(50) of approximately 5-11 nM. Neither ATP nor FDNP-ATP exhibits any effect on the prodomain-truncated enzyme DeltaproCsp9 or p18/p10. FDNP-ATP covalently labels proCsp9 with a stoichiometry of 1:1, resulting in DNP-ATP-proCsp9 that is incapable of forming a productive Apoptosome with Apaf-1. Activity assays show that ATP and dATP, but not ADP or AMP, bind to the processed Csp9 p35/p10. This nucleotide binding site might play an important and previously unrecognized role in regulating proCsp9 activation.
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PMID:A nucleotide binding site in caspase-9 regulates apoptosome activation. 1579 35

Apoptosis is executed by caspases, which undergo proteolytic activation in response to cell death stimuli. The apoptotic protease-activating factor 1 (Apaf-1) controls caspase activation downstream of mitochondria. During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 (ref. 2). The mechanisms underlying Apaf-1 function are largely unknown. Here we report the 2.2-A crystal structure of an ADP-bound, WD40-deleted Apaf-1, which reveals the molecular mechanism by which Apaf-1 exists in an inactive state before ATP binding. The amino-terminal caspase recruitment domain packs against a three-layered alpha/beta fold, a short helical motif and a winged-helix domain, resulting in the burial of the caspase-9-binding interface. The deeply buried ADP molecule serves as an organizing centre to strengthen interactions between these four adjoining domains, thus locking Apaf-1 in an inactive conformation. Apaf-1 binds to and hydrolyses ATP/dATP and their analogues. The binding and hydrolysis of nucleotides seem to drive conformational changes that are essential for the formation of the apoptosome and the activation of caspase-9.
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PMID:Structure of the apoptotic protease-activating factor 1 bound to ADP. 1582 69

The pathway of apoptosis is conserved in the three model species: mammals, Drosophila, and C. elegans. The apoptotic protease-activating factor 1, an essential protein conserved in all three species, is responsible for the activation of the initiator caspase-9 in mammalian cells. The structure of the auto-inhibited form of Apaf-1 reveals a critical role for ADP, which serves as an organizing center for four adjoining domains. The ADP-binding pocket contains features that are important for designing other nucleotide analogs. ATP binding is a prerequisite for the formation of the apoptosome. Despite strong sequence conservation between Apaf-1 and its orthologues in Drosophila and C. elegans, it is unclear whether they employ similar mechanisms for their own activation and for activating caspases. Much of the underlying mechanisms remain to be investigated by structural biology and biochemistry.
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PMID:Structure of Apaf-1 in the auto-inhibited form: a critical role for ADP. 1597 Jun 65

The p53 binding protein 2 (53BP2) has been identified independently as the interacting protein to p53, Bcl-2, and p65 subunit of nuclear factor kappaB (NF-kappaB). It was demonstrated that over-expression of 53BP2 (renamed as 53BP2S) induces apoptotic cell death. In this study we explored the effect of NF-kappaB activation elicited by a physiological NF-kappaB inducer, interleukin-1beta (IL-1beta), and anti-apoptotic Bcl-2 family proteins on the 53BP2S-mediated apoptosis. We found that both NF-kappaB activation and Bcl-2 family proteins could prevent the 53BP2S-mediated depression of mitochondrial transmembrane potential, activation of caspase-9, cleavage of poly ADP ribose polymerase (PARP), and cell death. These observations suggested that 53BP2S/Bbp and its directly or indirectly interacting proteins might play crucial roles in the regulation of apoptosis and contribute to carcinogenesis. It is also suggested that 53BP2S/Bbp induces apoptosis through the mitochondrial death pathway presumably by counteracting the actions of anti-apoptotic Bcl-2 family proteins. The regulatory network of the 53BP2S-mediated apoptosis cascade including its interacting proteins is discussed.
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PMID:Inhibition of the 53BP2S-mediated apoptosis by nuclear factor kappaB and Bcl-2 family proteins. 1609 44

Poly(ADP-ribose) polymerase (PARP) activation has been implicated in the pathogenesis of acute and chronic myocardial dysfunction and heart failure. The goal of the present study was to investigate PARP activation in human heart failure, and to correlate PARP activation with various indices of apoptosis and oxidative and nitrosative stress in healthy (donor) and failing (NYHA class III-IV) human heart tissue samples. Higher levels of oxidized protein end-products were found in failing hearts compared with donor heart samples. On the other hand, no differences in tyrosine nitration (a marker of peroxynitrite generation) were detected. Activation of PARP was demonstrated in the failing hearts by an increased abundance of poly-ADP ribosylated proteins. Immunohistochemical analysis revealed that PARP activation was localized to the nucleus of the cardiomyocytes from the failing hearts. The expression of full-length PARP-1 was not significantly different in donor and failing hearts. The expression of caspase-9, in contrast, was significantly higher in the failing than in the donor hearts. Immunohistochemical analysis was used to detect the activation of mitochondrial apoptotic pathways. We found no significant translocation of apoptosis-inducing factor (AIF) into the nucleus. Overall, the current data provide evidence of oxidative stress and PARP activation in human heart failure. Interventional studies with antioxidants or PARP inhibitors are required to define the specific roles of these factors in the pathogenesis of human heart failure.
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PMID:Activation of the poly(ADP-ribose) polymerase pathway in human heart failure. 1708 46

Evaluation of apoptotic processes downstream of the mitochondrion reveals caspase-9- and low levels of caspase-3-like activities in partly purified extracts of Artemia franciscana embryos. However, in contrast to experiments with extracts of human hepatoma cells, cytochrome c fails to activate caspase-3 or -9 in extracts from A. franciscana. Furthermore, caspase-9 activity is sensitive to exogenous calcium. The addition of 5 mM calcium leads to a 4.86 +/- 0.19 fold (SD) (n = 3) increase in activity, which is fully prevented with 150 mM KCl. As with mammalian systems, high ATP (>1.25 mM) suppresses caspase activity in A. franciscana extracts. A strong inhibition of caspase-9 activity was also found by GTP. Comparison of GTP-induced inhibition of caspase-9 at 0 and 2.5 mM MgCl(2) indicates that free (nonchelated) GTP is likely to be the inhibitory form. The strongest inhibition among all nucleotides tested was with ADP. Inhibition by ADP in the presence of Mg(2+) is 60-fold greater in diapause embryos than in postdiapause embryos. Because ADP does not change appreciably in concentration between the two physiological states, it is likely that this differential sensitivity to Mg(2+)-ADP is important in avoiding caspase activation during diapause. Finally, mixtures of nucleotides that mimic physiological concentrations in postdiapause and diapause states underscore the depressive action of these regulators on caspase-9 during diapause. Our biochemical characterization of caspase-like activity in A. franciscana extracts reveals that multiple mechanisms are in place to reduce the probability of apoptosis under conditions of energy limitation in this embryo.
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PMID:Caspase activity during cell stasis: avoidance of apoptosis in an invertebrate extremophile, Artemia franciscana. 1725 12

It has been shown that noscapine, an opium-derived phthalideisoquinoline alkaloid that is currently being used as an oral antitussive drug, induces apoptosis in myeloid leukemia cells. The molecular mechanism responsible for the anticancer effects of noscapine is poorly understood. In the current study, the apoptotic effects of noscapine on two myeloid cell lines, apoptosis-proficient HL60 cells and apoptosis-resistant K562 cells, were analyzed. An increase in the activity of caspase-2, -3, -6, -8 and -9, poly(ADP ribose) polymerase cleavage, detection of phosphatidylserine on the outer layer of the cell membrane, nucleation of chromatin, and DNA fragmentation suggested the induction of apoptosis. Noscapine increased the Bax/Bcl-2 ratio with a significant decrease of Bcl-2 expression accompanied with Bcl-2 phosphorylation. Using an inhibitory approach, the activation of the caspase cascade involved in the noscapine-induced apoptosis was analyzed. We observed no inhibitory effect of the caspase-8 inhibitor on caspase-9 activity. In view of these results and taking into consideration that K562 cells are Fas-null, we suggested that caspase-8 is activated in a Fas-independent manner downstream of caspase-9. In conclusion, noscapine can induce apoptosis in both apoptosis-proficient and apoptosis-resistant leukemic cells, and it can be a novel candidate in the treatment of hematological malignancies.
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PMID:Apoptotic pathway induced by noscapine in human myelogenous leukemic cells. 1789 14

Polyalthia longifolia is a lofty evergreen tree found in India and Sri Lanka. We are reporting first time the anticancer potential of P. longifolia leaves extract (A001) and its chloroform fraction (F002). Both inhibited cell proliferation of various human cancer cell lines in which colon cancer cells SW-620 showed maximum inhibition with IC(50) value 6.1 microg/ml. Furthermore, F002 induce apoptosis in human leukemia HL-60 cells as measured by several biological end points. F002 induce apoptotic bodies formation, DNA ladder, enhanced annexin-V-FITC binding of the cells, increased sub-G(0) DNA fraction, loss of mitochondrial membrane potential (DeltaPsi(mt)), release of cytochrome c, activation of caspase-9, caspase-3, and cleavage of poly ADP ribose polymerase (PARP) in HL-60 cells. All the above parameters revealed that F002-induced apoptosis through the mitochondrial-dependent pathway in HL-60 cells.
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PMID:In vitro cytotoxic potential of Polyalthia longifolia on human cancer cell lines and induction of apoptosis through mitochondrial-dependent pathway in HL-60 cells. 1793 6

Sonodynamic therapy employs a combination of ultrasound and a sonosensitizer to enhance the cytotoxic effect of ultrasound and promote apoptosis. However, the mechanism underlying the synergistic effect of ultrasound and hematoporphyrin is still unclear. In this study, we investigated mechanism of the induction of apoptosis by sonodynamic therapy in Sarcoma 180 cells. The cell suspension was treated by 1.75-MHz focused continuous ultrasound at an acoustic power (I(SATA)) of 1.4+/-0.07 W/cm(2) for 3 min in the absence or presence of 20 microg/ml hematoporphyrin. The proportion of apoptotic cells was determined by flow cytometry. We then analyzed the reactive oxygen species generation and localization by confocal microscopy. Western blotting and reverse transcriptase-polymerase chain reaction were used to analyze the expression of caspase-8, caspase-9, poly(ADP)-ribose polymerase, and nuclear factor-kappaB. The findings of our study indicate that ultrasound treatment induced the activation of nuclear factor-kappaB as an early stress response. When cells were pretreated with hematoporphyrin, the initial response to the therapy was the formation of (1)O(2) in the mitochondria. Our results primarily demonstrate that the mechanisms of induction of apoptosis by ultrasound and hematoporphyrin-sonodynamic therapies are very different. Our findings can provide a basis for explaining the synergistic effect of ultrasound and hematoporphyrin.
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PMID:Potential mechanism in sonodynamic therapy and focused ultrasound induced apoptosis in sarcoma 180 cells in vitro. 1964 May 55


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