Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.
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PMID:Molecular characterization of mitochondrial apoptosis-inducing factor. 998 1

Anticancer treatment using cytotoxic drugs is considered to mediate cell death by activating key elements of the apoptosis program and the cellular stress response. While proteolytic enzymes (caspases) serve as main effectors of apoptosis, the mechanisms involved in activation of the caspase system are less clear. Two distinct pathways upstream of the caspase cascade have been identified. Death receptors, eg, CD95 (APO-1/Fas), trigger caspase-8, and mitochondria release apoptogenic factors (cytochrome c, Apaf-1, AIF), leading to the activation of caspase-9. The stressed endoplasmic reticulum (ER) contributes to apoptosis by the unfolded protein response pathway, which induces ER chaperones, and by the ER overload response pathway, which produces cytokines via nuclear factor-kappaB. Multiple other stress-inducible molecules, such as p53, JNK, AP-1, NF-kappaB, PKC/MAPK/ERK, and members of the sphingomyelin pathway have a profound influence on apoptosis. Understanding the complex interaction between different cellular programs provides insights into sensitivity or resistance of tumor cells and identifies molecular targets for rational therapeutic intervention strategies.
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PMID:Cellular stress response and apoptosis in cancer therapy. 1167 28

Caspase-2 is one of the earliest identified caspases, but the mechanism of caspase-2-induced apoptosis remains unknown. We show here that caspase-2 engages the mitochondria-dependent apoptotic pathway by inducing the release of cytochrome c (Cyt c) and other mitochondrial apoptogenic factors into the cell cytoplasm. In support of these observations we found that Bcl-2 and Bcl-xL can block caspase-2- and CRADD (caspase and RIP adaptor with death domain)-induced cell death. Unlike caspase-8, which can process all known caspase zymogens directly, caspase-2 is completely inactive toward other caspase zymogens. However, like caspase-8, physiological levels of purified caspase-2 can cleave cytosolic Bid protein, which in turn can trigger the release of Cyt c from isolated mitochondria. Interestingly, caspase-2 can also induce directly the release of Cyt c, AIF (apoptosis-inducing factor), and Smac (second mitochondria-derived activator of caspases protein) from isolated mitochondria independent of Bid or other cytosolic factors. The caspase-2-released Cyt c is sufficient to activate the Apaf-caspase-9 apoptosome in vitro. In combination, our data suggest that caspase-2 is a direct effector of the mitochondrial apoptotic pathway.
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PMID:Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. 1183 78

Effects of the tyrphostin tyrosine kinase inhibitor adaphostin (NSC 680410) have been examined in human leukemia cells (Jurkat, U937) in relation to mitochondrial events, apoptosis, and perturbations in signaling and cell cycle regulatory events. Exposure of cells to adaphostin concentrations > or =0.75 microM for intervals > or =6 h resulted in a pronounced release of cytochrome c and AIF, activation of caspase-9, -8, and -3, and apoptosis. These events were accompanied by the caspase-independent downregulation of Raf-1, inactivation of MEK1/2, ERK, Akt, p70S6K, dephosphorylation of GSK-3, and activation of c-Jun-N-terminal kinase (JNK) and p38 MAPK. Adaphostin also induced cleavage and dephosphorylation of pRb on CDK2- and CDK4-specific sites, as well as the caspase-dependent downregulation of cyclin D1. Inducible expression of a constitutively active MEK1 construct markedly diminished adaphostin-induced cytochrome c and AIF release, JNK activation, and apoptosis in Jurkat cells. Ectopic expression of Raf-1 or constitutively activated (myristolated) Akt also significantly attenuated adaphostin-induced apoptosis, but protection was less than that conferred by enforced activation of MEK. Lastly, antioxidants (e.g., L-N-acetylcysteine; L-NAC) opposed adaphostin-mediated mitochondrial dysfunction, Raf-1/MEK/ERK downregulation, JNK activation, and apoptosis. However, in contrast to L-NAC, enforced activation of MEK failed to block adaphostin-mediated ROS generation. Together, these findings demonstrate that the tyrphostin adaphostin induces multiple perturbations in signal transduction pathways in human leukemia cells, particularly inactivation of the cytoprotective Raf-1/MEK/ERK and Akt cascades, that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that adaphostin-related oxidative stress acts upstream of perturbations in these signaling pathways to trigger the cell death process.
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PMID:Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process. 1464 18

Methamphetamine (METH) is an illicit drug that causes neurodegenerative effects in humans. In rodents, METH induces apoptosis of striatal glutamic acid decarboxylase (GAD) -containing neurons. This paper provides evidence that METH-induced cell death occurs consequent to interactions of ER stress and mitochondrial death pathways. Specifically, injections of METH are followed by an almost immediate activation of proteases calpain and caspase-12, events consistent with drug-induced ER stress. Involvement of ER stress was further supported by observations of increases in the expression of GRP78/BiP and CHOP. Participation of the mitochondrial pathway was demonstrated by the transition of AIF, smac/DIABLO, and cytochrome c from mitochondrial into cytoplasmic fractions. These changes occur before the apoptosome-associated pro-caspase-9 cleavage. Effector caspases-3 and -6, but not -7, were cleaved with the initial time of caspase-3 activation occurring before caspase 9 cleavage; this suggests possible earlier cleavage of caspase-3 by caspase-12. These events preceded proteolysis of the caspase substrates DFF-45, lamin A, and PARP in nuclear fractions. These findings indicate that METH causes neuronal apoptosis in part via cross-talks between ER- and mitochondria-generated processes, which cause activation of both caspase-dependent and -independent pathways.
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PMID:Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades. 1476 18

The effect of exercise on apoptosis in postmitotic tissues is not known. In this study, we investigated the effect of regular moderate physical activity (i.e., exercise training) on the extent of apoptosis in rat skeletal and cardiac muscles. Adult Sprague Dawley rats were trained (TR) 5 days weekly for 8 wk on treadmill. Sedentary rats served as controls (CON). An ELISA was used to detect mono- and oligonucleosome fragmentation as an indicator of apoptosis. Bcl-2, Bax, Apaf-1, AIF, cleaved PARP, cleaved caspase-3, cleaved/active caspase-9, heat shock protein (HSP)70, Cu/Zn-SOD, and Mn-SOD protein levels were determined by Western analyses. Bcl-2 and Bax transcript contents were estimated by RT-PCR. A spectrofluorometric assay was used to determine caspase-3 activity. DNA fragmentation in ventricles of the TR group decreased by 15% whereas that in soleus of the TR group tended to decrease (P=0.058) when compared with CON group. Protein contents of Bcl-2, HSP70, and Mn-SOD increased in both soleus and ventricle muscles of TR animals when compared with CON animals. Apaf-1 protein content in the soleus of TR animals was lower than that of CON animals. Bcl-2 mRNA levels increased in both ventricle and soleus muscles of TR animals, and Bax mRNA levels decreased in the soleus of TR animals when compared with CON animals. Furthermore, HSP70 protein content was negatively correlated to Bax mRNA content and was positively correlated to Bcl-2 protein and mRNA contents. Mn-SOD protein content was negatively correlated to the apoptotic index, and caspase-3 activity and was positively correlated to Bcl-2 transcript content and HSP70 protein content. These data suggest that exercise training attenuates the extent of apoptosis in cardiac and skeletal muscles.
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PMID:Apoptotic adaptations from exercise training in skeletal and cardiac muscles. 1513 82

Our previous study has shown that alpha-mangostin, a xanthone from the pericarps of mangosteen, induces caspase-3-dependent apoptosis in HL60 cells. In the current study, we investigated the mechanism of apoptosis induced by alpha-mangostin in HL60 cells. Alpha-mangostin-treated HL60 cells demonstrated caspase-9 and -3 activation but not -8, which leads us to assume that alpha-mangostin may mediate the mitochondrial pathway in the apoptosis. Parameters of mitochondrial dysfunction including swelling, loss of membrane potential (deltapsim), decrease in intracellular ATP, ROS accumulation, and cytochrome c/AIF release, were observed within 1 or 2 h after the treatment. On the other hand, alpha-mangostin-treatment did not affect expression of bcl-2 family proteins and activation of MAP kinases. These findings indicate that alpha-mangostin preferentially targets mitochondria in the early phase, resulting in indication of apoptosis in HL60 cells. Furthermore, we examined the structure-activity relationship between xanthone derivatives including alpha-mangostin and the potency of deltapsim-loss in HL60 cells. Interestingly, replacement of hydroxyl group by methoxy group remarkably decreased its potency. It was also shown that the cytotoxicity substantially correlated with deltapsim decrease. These results indicate that alpha-mangostin and its analogs would be candidates for preventive and therapeutic application for cancer treatment.
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PMID:Preferential target is mitochondria in alpha-mangostin-induced apoptosis in human leukemia HL60 cells. 1549 56

One of the cellular responses to DNA damaging events is the activation of programmed cell death, also known as apoptosis. Apoptosis is an important process in limiting tumorigenesis by eliminating cells with damaged DNA. This view is reinforced by the finding that many genes with pro-apoptotic function are absent or altered in cancer cells. The tumor suppressor p53 performs a significant role in apoptotic signaling by controlling expression of a host of genes that have pro-apoptotic or pro-survival function. The S(N)1 DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) triggers apoptosis and the upregulation/phosphorylation of p53; however, the mechanism(s) governing MNNG-induced cell death remain unresolved. We observed that the human lymphoblastoid cell line WTK-1, which expresses mutant p53, shows far less sensitivity to the cytotoxic effects of MNNG than the closely related, p53-normal line TK-6. Exposure to 15 muM MNNG (LD50 at 24 h in TK-6) leads to a kinetically slower rate of apoptotic onset in WTK-1 cells compared to TK-6 as judged by viability assays and approaches that directly examine apoptotic onset. Similar results were obtained using an unrelated human lymphoblastoid line B310 expressing reduced levels of p53 due to E6 oncoprotein expression, indicating that MNNG activates both p53-dependent and -independent apoptotic mechanisms and that these two mechanisms are discernable by the rates which they trigger apoptotic onset. We document, during time points corresponding to peak apoptotic response in TK6, WTK-1, B310, and B310-E6, that these cell lines show marked decreases in mitochondrial transmembrane potential and increases in cytochrome c within the cytosolic fraction of MNNG-treated cells. Consistent with these events, we observed that both caspase-9 and -3 are activated in our panel of lymphoblastoid cells after MNNG exposure. We also found, using both broad spectrum and specific inhibitors, that blocking caspase activity in TK-6 and B310 cells had a significant effect on apoptotic advance, but that this treatment had no effect on entry of WTK-1 or B310-E6 cells into apoptosis. Finally, the PARP inhibitors benzamide and 6(5H)-phenanthridinone exerted notable inhibition of PARP activity and the nuclear translocation of the mitochondrial protein AIF (apoptosis-inducing factor) in MNNG-treated cells; however, these compounds exhibited no detectable inhibitory effects on MNNG-induced death in human lymphoblastoid cells. These observations suggest that PARP activity is not required during MNNG-triggered apoptosis in this cell type. Taken together, our observations support the conclusion that MNNG activates multiple apoptogenic pathways that contain both common and unique mechanisms.
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PMID:The monofunctional alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine triggers apoptosis through p53-dependent and -independent pathways. 1558 79

BAY 43-9006 is a kinase inhibitor that induces apoptosis in a variety of tumor cells. Here we report that treatment with BAY 43-9006 results in marked cytochrome c and AIF release into the cytosol, caspase-9, -8, -7, and -3 activation, and apoptosis in human leukemia cells (U937, Jurkat, and K562). Pronounced apoptosis was also observed in blasts from patients with acute myeloid leukemia. These events were accompanied by ERK1/2 inactivation and caspase-independent down-regulation of Mcl-1. Inducible expression of a constitutively active MEK1 construct did not prevent Mcl-1 down-regulation, suggesting that this event is not related to MEK/ERK pathway inactivation. Furthermore, BAY 43-9006 did not induce major changes in Mcl-1 mRNA levels monitored by real-time PCR or Mcl-1 promoter activity demonstrated by luciferase reporter assays, but it did enhance Mcl-1 down-regulation in actinomycin D-treated cells. Inhibition of protein synthesis by cycloheximide or proteasome function with MG132 and pulse-chase studies with [35S]methionine demonstrated that BAY 43-9006 did not diminish Mcl-1 protein stability, nor did it enhance Mcl-1 ubiquitination, but instead markedly attenuated Mcl-1 translation in association with the rapid and potent dephosphorylation of the eIF4E translation initiation factor. Finally, ectopic expression of Mcl-1 in leukemic cells markedly inhibited BAY 43-9006-mediated cytochrome c cytosolic release, caspase-9, -7, and -3 activation, as well as cell death, indicating that Mcl-1 operates upstream of cytochrome c release and caspase activation. Together, these findings demonstrate that BAY 43-9006 mediates cell death in human leukemia cells, at least in part, through down-regulation of Mcl-1 via inhibition of translation.
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PMID:Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. 1610 13

Aging of skeletal muscle is often accompanied by muscle atrophy and it appears that apoptosis plays an important role in this process. The detailed mechanism(s) is not completely understood, however. In this study, we examined expression of the apoptosis regulatory proteins as well as the heat shock proteins, which have been shown to modulate the apoptotic process in certain cell types, in order to more completely elucidate apoptotic signaling in aged skeletal muscle. To more specifically identify alterations that are likely to be the result of aging, we compared 16-month-old middle-aged (MD) and 29-month-old senescent (SE) male Fischer 344 x Brown Norway rats in our study. Our results show that the degree of DNA laddering was higher in SE compared to MD rats. Using total tissue homogenates we examined the level of expression of several apoptosis-related proteins in two categories: mitochondria-associated proteins and caspases. Of the mitochondria-associated proteins, the levels of p53 showed a significant increase in SE compared to MD rats. There was also a significant increase in the expression of Bax, Bcl-2 and Apaf-1 in SE rats over that of MD rats; cytochrome c and AIF levels remained unchanged, however. Regarding the caspases, there were increases in the levels of pro-caspases-12 and -7 and cleaved caspase-9, although the levels of pro- and cleaved caspase-3 as well as cleaved caspase-12 remained unchanged. Furthermore, our results showed significant increases in HSP27, HSP60, and the inducible HSP70. These data show that in rat skeletal muscle increased apoptosis occurs between middle-age and senescence, indicating an aging-related increase in apoptosis in skeletal muscle. The involvement of different apoptotic pathways in the aging process is suggested by the selective alterations in the apoptosis regulatory proteins. The increased expression of the HSPs suggests a relationship between HSPs and the aging-related apoptotic process.
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PMID:Age-related alterations in expression of apoptosis regulatory proteins and heat shock proteins in rat skeletal muscle. 1613 96


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