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

Activation of protein kinase C (PKC) by TPA in human U937 myeloid leukemia cells is associated with induction of adherence, differentiation, and G0/G1 cell cycle arrest. In this study, we demonstrate that in addition to these differentiating cells about 25% of U937 cells accumulated in the subG1 phase after TPA treatment. This effect proved to be phorbol ester-specific, since other compounds such as retinoic acid or vitamin D3 failed to induce apoptosis in conjunction with differentiation. Only a specific inhibitor of PKC, GF109203X, but not the broad-spectrum kinase inhibitor staurosporine or a tyrosine kinase inhibitor genistein could reverse the induction of apoptosis. Bryostatin-1, another specific PKC activator with distinct biochemical activity failed to induce apoptosis. Moreover, bryostatin-1 completely abolished the induction of apoptosis in U937 cells even if added 8 hours after TPA treatment. Apart from apoptosis induced by various chemotherapeutic drugs, TPA-related cell death is not mediated by an autocrine Fas-FasL loop and could not be prevented by a blocking antibody to the Fas receptor. However, a 75% reduction in the number of apoptotic cells after TPA stimulation was achieved by preincubation with a blocking antibody to the TNFalpha receptor. Tetrapeptide cleavage assays revealed a four-fold increase in the DEVD-cleavage activity in U937 cells compared to a three-fold increase in TUR cells. Immunoblotting demonstrated that TUR cells did not activate significant levels of caspase-3 or -7, whereas in U937 cells a 20-kDa cleavage product corresponding to activated caspase-3 was detectable after 3 d TPA exposure. Moreover, immunoblots revealed a strongly reduced expression of the adaptor molecule APAF-1, which is required for cytochrome c-dependent activation of caspase-9 and subsequently caspase-3. APAF-1 proved to be inducible after PKC activation with phorbol ester in U937, but not in TUR cells. Thus, APAF-1 expression may, at least in part, be regulated by PKC activity and reduced APAF-1 levels are associated with resistance to various inducers of apoptosis. Furthermore, TPA exposure of U937 cells is associated with increased levels of the pro-apoptotic proteins Bak and Bcl-xs, whereas simultaneously a decline in the Bcl-2 expression was noticable.
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PMID:Protein kinase C activation modulates pro- and anti-apoptotic signaling pathways. 1113 46

Bcr-Abl tyrosine kinase inhibitor STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p190 Bcr-Abl) and K562 (with endogenous expression of p210 Bcr-Abl) cells (Blood, 96: 2246-2253, 2000). Cotreatment with STI-571 partially overcomes the resistance to antileukemic drug-induced apoptosis of HL-60/Bcr-Abl and K562 cells. Tumor necrosis factor (TNF) alpha-related apoptosis-inducing ligand (Apo-2L/TRAIL), after binding with its signaling death receptors (DR4 and DR5), triggers the intrinsic "mitochondrial" pathway of apoptosis more efficiently in the cancer than do normal cells. In the present studies, we compared the apoptotic effects of Apo-2L/TRAIL, with or without cotreatment with STI-571, in HL-60/neo, HL-60/Bcr-Abl, and K562 cells. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells are relatively resistant to Apo-2L/TRAIL-induced apoptosis. In HL-60/Bcr-Abl and K562 versus HL-60/neo cells, Apo-2L/TRAIL caused less cytosolic accumulation of cytochrome c and the processing of caspase-9 and -3. This was also associated with decreased processing of caspase-8, c-FLIP(L) and Bid. Reduced effects of Apo-2L/TRAIL in Bcr-Abl-positive leukemic cells were not attributable to diminished expression of DR4 and DR5, or higher expressions of the decoy receptors DcR1 and -2 or c-FLIP(L). Cotreatment with STI-571 significantly enhanced Apo-2L/TRAIL-induced apoptosis (P < 0.01) as well as increased the processing of caspase-9 and -3 and XIAP, without affecting the levels of DR4, DR5, decoy receptors, or c-FLIP(L). Cotreatment with STI-571 did not enhance Apo-2L/TRAIL-induced apoptosis of HL-60/neo cells. These studies suggest that a combined treatment with STI-571 may be an effective strategy to selectively sensitize Bcr-Abl-positive leukemic blasts to Apo-2L/TRAIL-induced apoptosis.
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PMID:Cotreatment with STI-571 enhances tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. 3126 34

We have reported previously that among human prostate cancer cell lines LNCaP but not PC-3 cells undergo apoptosis after treatment with the protein kinase inhibitor staurosporine (STS). We have now further investigated this model to uncover the molecular mechanism causing resistance to STS-induced apoptosis in PC-3 cells. S-100 lysates of both cell lines showed biochemical changes typical of apoptosis after the addition of cytochrome c and dATP, suggesting that the postmitochondrial phase of apoptosis was intact. Upon addition of STS, the proapoptotic molecules Bax and Bad became predominantly mitochondrial in both cell lines. This, in turn, was followed by loss of mitochondrial transmembrane potential, translocation of cytochrome c to the cytosol, activation of caspase-9, -3, and -7, and cleavage of the apoptotic targets, DNA fragmentation factor and poly(ADP-ribose) polymerase, in LNCaP but not in PC-3 cells. Components of the mitochondrial permeability transition pore, adenine nucleotide transporter and voltage-dependent anion channel, were normally expressed in the correct subcellular fraction of both cell lines. Overexpression of the proapoptotic proteins Bax and Bad, fused to a green fluorescent protein but not of green fluorescent protein alone, induced apoptosis in >80% of PC-3 cells. These experiments suggested that a factor protecting the mitochondria of PC-3 cells mediates resistance to STS-induced apoptosis. A wide search among the antiapoptotic Bcl-2 family members was performed, and Bcl-X(L) was found to be overexpressed in PC-3 cells. Experiments down-regulating Bcl-X(L) expression by using the tyrosine kinase inhibitor genistein, sodium butyrate, or an antisense Bcl-X(L) oligonucleotide restored sensitivity to apoptosis in PC-3 cells. Thus, Bcl-X(L) overexpression is one of the mediators of resistance to STS-induced apoptosis in the prostate cancer cell line PC-3.
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PMID:Overexpression of BCL-X(L) underlies the molecular basis for resistance to staurosporine-induced apoptosis in PC-3 cells. 1124 86

HL-60/Bcr-Abl cells, with ectopic expression of p185 Bcr-Abl tyrosine kinase (TK), and K562 cells, with endogenous expression of p210 Bcr-Abl TK, display a high degree of resistance against antileukemic drug-induced apoptosis (G. Fang et al., Blood, 96: 2246-2256, 2000). Present studies demonstrate that treatment with ansamycin antibiotic geldanamycin (GA), or its less toxic analogue 17-allylamino-17-demethoxygeldanamycin (17-AAG), induces cytosolic accumulation of cytochrome c and cleavage and activities of caspase-9 and caspase-3, triggering apoptosis of HL-60/Bcr-Abl and K562 cells. GA or 17-AAG down-regulated intracellular Bcr-Abl and c-Raf protein levels, as well as reduced Akt kinase activity. Similar to Raf-1, v-Src, and Her-2-neu, Bcr-Abl TK has chaperone association with heat shock protein 90 (Hsp90). By binding and inhibiting Hsp90, GA or 17-AAG treatment shifted the binding of Bcr-Abl from Hsp90 to Hsp70 and induced the proteasomal degradation of Bcr-Abl, because cotreatment with proteasome inhibitor PSC341 reduced both GA (or 17-AAG)-mediated down-regulation of Bcr-Abl levels and inhibited apoptosis of HL-60/Bcr-Abl and K562 cells. These data establish the in vitro activity of GA and 17-AAG against Bcr-Abl-positive leukemic cells and support the in vivo investigation of 17-AAG against Bcr-Abl-positive leukemias.
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PMID:Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. 1128 Jul 26

AG957 (NSC 654705) is a tyrphostin tyrosine kinase inhibitor that has been demonstrated previously to induce growth arrest in chronic myelogenous leukemia cells by inhibiting p210(bcr-abl) kinase activity and by stabilizing the association of p210(bcr-abl) kinase with its signaling adaptor molecules, Shc and Grb2. In previous studies, it has been demonstrated that AG957-associated down-regulation of bcr-abl activates the cytochrome c/Apaf-1/caspase-9 pathway and induces apoptosis in chronic myelogenous leukemia blasts and progenitor cells. While AG957 has been purported to have specificity for the p210(bcr-abl) kinase, antiproliferative effects of AG957 in normal T-lymphocytes and bcr-abl negative leukemia cells suggest that other targets, such as c-CBL, may be substrates. In this study, we explored the mechanisms of AG957-mediated growth inhibition and apoptosis in the p210(bcr-abl) negative leukemia cell lines Nalm-6 and Jurkat, and demonstrate that AG957-mediated apoptosis is associated with altered phosphorylation of Akt and BAD, which destabilizes the Bcl-xL/BAD complex and releases the block to apoptosis. We, therefore, propose that AG957 induces apoptosis in bcr-abl negative hematopoietic cells by affecting the phosphorylation state of phosphatidylinositol-3 kinase/Akt.
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PMID:Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells. 1199 36

The induction of apoptosis requires the activation of a highly coordinated signaling network ultimately leading to the activation of caspases. In previous experiments we and others have shown that the tyrosine kinase Lck is required for adequate apoptosis induction in response to ionizing radiation, ceramide incubation and overexpression of the HIV-TAT protein. However, the position of Lck within given apoptotic signaling cascades remains unclear. We therefore aimed to define the role of Lck during radiation-induced apoptosis. Apoptosis induction in response to ionizing radiation, CD95 or TRAIL receptor stimulation was determined in Jurkat T-cells, the Lck-deficient Jurkat clone JCaM1.6- and Lck-retransfected JCaM1.6/Lck. No apoptosis, release of cytochrome c, breakdown of the mitochondrial potential were detectable during the first 48 h after irradiation of JCaM1.6 cells. In parallel, no activation of caspase-9, -8 and -3 was detectable. Since mitochondrial apoptosis pathways act within a feedback mechanism during death-receptor-mediated apoptosis, the influence of the Lck defect on CD95/Fas/Apo-1-L or TRAIL-induced apoptosis was also tested. Both stimuli induced apoptosis in Lck-deficient cells. However, the kinetics of apoptosis induction determined by caspase-8, -9 and -3 activation as well as deltapsi(m) breakdown was slowed. We conclude that the Lck deficiency influences early steps during radiation-induced mitochondrial alterations.
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PMID:The tyrosine kinase Lck is involved in regulation of mitochondrial apoptosis pathways. 1252 87

The Ret finger protein (RFP) is a member of the tripartite motif family, which is characterized by a conserved RING finger, a B-box, and a coiled-coil domain (together called RBCC). Although RFP is known to become oncogenic when its RBCC moiety is connected to a tyrosine kinase domain by DNA rearrangement, its biological function is not well defined. Here we show that ectopic expression of RFP in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria. RFP expression activates Jun N-terminal kinase and p38 kinase and also increases caspase-3-like activity. However, RFP failed to release cytochrome c and, therefore, to increase caspase-9-like activity. RFP-induced apoptosis could be blocked by the caspase-8 inhibitor crmA and dominant negative ASK1 but not by Bcl-2. These results reveal a novel RFP death pathway that recruits mitogen-activated protein kinase and caspases independently of mitochondrial events. Domain mapping showed that the intact RBCC moiety is necessary for the pro-apoptotic function of RFP. Moreover, expression of the RBCC moiety further potentiated the pro-apoptotic activity and resulted in a 7-fold increase of caspase activation compared with that induced by full-length RFP. This suggests that a large number of tripartite motif family members sharing the RBCC moiety may participate in the control of cell survival.
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PMID:The Ret finger protein induces apoptosis via its RING finger-B box-coiled-coil motif. 1280 81

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

Tannins are a group of widely distributed plant polyphenols, some of which are beneficial to health because of their chemopreventive activities. In the present study, we investigated the effects and action mechanisms of woodfordin I, a macrocyclic ellagitannin dimer, on human chronic myelogenous leukemia (CML) K562 cells. The results showed that woodfordin I was able to suppress the proliferation and induce apoptosis in K562 cells. Apoptosis was evaluated by cytomorphology, internucleosomal DNA fragmentation, and externalization of phosphatidylserine. Woodfordin I treatment caused a rapid and sustained loss of mitochondrial transmembrane potential (MMP), transient generation of reactive oxygen species (ROS), transient elevation of intracellular Ca2+ concentration, and cytosolic accumulation of cytochrome c. The activation of caspase-9 and 3, but not caspase-8, was also demonstrated, indicating that the apoptotic signaling triggered by woodfordin I was mediated through the intrinsic mitochondria-dependent pathway. Western blot and immunofluorescence analysis revealed that the anti-apoptotic Bcl-2 and Bcl-xL levels were downregulated, together with the pro-apoptotic Bax protein. Significantly, woodfordin I-induced apoptosis was associated with a decline in the levels of c-Abl, Bcr-Abl, and cellular protein tyrosine phosphorylation. Considering the consequence of all the events in the process of woodfordin I-induced apoptosis, the mitochondrial dysfunction is directly responsible for the pro-apoptotic effects on K562 cells. Furthermore, because CML is a malignancy of pleuripotent hematopoietic cells caused by the dysregulated tyrosine kinase activity of Bcr-Abl, these findings suggest that woodfordin I may be a potential lead compound against CML.
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PMID:Mitochondrial dysfunction as an early event in the process of apoptosis induced by woodfordin I in human leukemia K562 cells. 1473 95

In vascular smooth muscle cells, Jak2 tyrosine kinase becomes activated in response to oxidative stress in the form of hydrogen peroxide. Although it has been postulated that hydrogen peroxide-induced Jak2 activation promotes cell survival, this has never been tested. We therefore examined the role that Jak2 plays in vascular smooth muscle cell apoptosis following hydrogen peroxide treatment. Here, we report that Jak2 tyrosine kinase activation by hydrogen peroxide is required for apoptosis of vascular smooth muscle cells. Upon treatment of primary rat aortic smooth muscle cells with hydrogen peroxide, we observed laddering of genomic DNA and nuclear condensation, both hallmarks of apoptotic cells. However, apoptosis was prevented by either the expression of a dominant negative Jak2 protein or by the Jak2 pharmacological inhibitor AG490. Moreover, expression of the proapoptotic Bax protein was induced following hydrogen peroxide treatment. Again, expression of a dominant negative Jak2 protein or treatment of cells with AG490 prevented this Bax induction. Following Bax induction by hydrogen peroxide, mitochondrial membrane integrity was compromised, and caspase-9 became activated. In contrast, in cells expressing a Jak2 dominant negative we observed that mitochondrial membrane integrity was preserved, and no caspase-9 activation occurred. These data demonstrate that the activation of Jak2 tyrosine kinase by hydrogen peroxide is essential for apoptosis of vascular smooth muscle cells. Furthermore, this report identifies Jak2 as a potential therapeutic target in vascular diseases in which vascular smooth muscle cell apoptosis contributes to pathological progression.
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PMID:Jak2 tyrosine kinase mediates oxidative stress-induced apoptosis in vascular smooth muscle cells. 1515 94


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