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)

Insulin-like growth factor-I (IGF-I) protects neurons of the peripheral nervous system from apoptosis, but the underlying signaling pathways are not well understood. We studied IGF-I mediated signaling in embryonic dorsal root ganglia (DRG) neurons. DRG neurons express IGF-I receptors (IGF-IR), and IGF-I activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. High glucose exposure induces apoptosis, which is inhibited by IGF-I through the PI3K/Akt pathway. IGF-I stimulation of the PI3K/Akt pathway phosphorylates three known Akt effectors: the survival transcription factor cyclic AMP response element binding protein (CREB) and the pro-apoptotic effector proteins glycogen synthase kinase-3beta (GSK-3beta) and forkhead (FKHR). IGF-I regulates survival at the nuclear level through accumulation of phospho-Akt in DRG neuronal nuclei, increased CREB-mediated transcription, and nuclear exclusion of FKHR. High glucose increases expression of the pro-apoptotic Bcl protein Bim (a transcriptional target of FKHR). However, IGF-I does not regulate Bim or anti-apoptotic Bcl-xL protein expression levels, which suggests that IGF-I neuroprotection is not through regulation of their expression. High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage, effects blocked by IGF-I. These data suggest that IGF-I prevents apoptosis in DRG neurons by regulating PI3K/Akt pathway effectors, including GSK-3beta, CREB, and FKHR, and by blocking caspase activation.
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PMID:Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. 1531 68

The cyclic AMP signal transduction pathway modulates apoptosis in diverse cell types, although the mechanism is poorly understood. A critical component of the intrinsic apoptotic pathway is caspase-9, which is activated by Apaf-1 in the apoptosome, a large complex assembled in response to release of cytochrome c from mitochondria. Caspase-9 cleaves and activates effector caspases, predominantly caspase-3, resulting in the demise of the cell. Here we identified a distinct mechanism by which cyclic AMP regulates this apoptotic pathway through activation of protein kinase A. We show that protein kinase A inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in Xenopus egg extracts and in a human cell-free system. Protein kinase A directly phosphorylates human caspase-9 at serines 99, 183, and 195. However, mutational analysis demonstrated that phosphorylation at these sites is not required for the inhibitory effect of protein kinase A on caspase-9 activation. Importantly, protein kinase A inhibits cytochrome c-dependent recruitment of procaspase-9 to Apaf-1 but not activation of caspase-9 by a constitutively activated form of Apaf-1. These data indicate that extracellular signals that elevate cyclic AMP and activate protein kinase A may suppress apoptosis by inhibiting apoptosome formation downstream of cytochrome c release from mitochondria.
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PMID:Protein kinase A regulates caspase-9 activation by Apaf-1 downstream of cytochrome c. 1570 81

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

Extracellular adenosine reduced viability of RCR-1 rat astrocytoma cells in a dose (0.3-10mM)- and treatment time (24-72h)-dependent manner. In the apoptosis assay using propidium iodide (PI) and annexin V, treatment with adenosine (1mM) for 72h increased the population of PI-negative/annexin V-positive cells, that is related to early apoptosis, and that of PI-positive/annexin V-positive cells, that is related to late apoptosis/secondary necrosis. In addition, nuclei of cells treated with adenosine (1mM) for 72h were reactive to an antibody against single-stranded DNA. Adenosine activated caspase-3, -8 and -9, but mitochondrial membrane potentials were not affected. Adenosine-induced RCR-1 cell death was significantly inhibited by 8-CPT, an antagonist of A(1) adenosine receptors, and forskolin, an adenylate cyclase activator. SQ22536, an adenylate cyclase inhibitor, alternatively, exhibited an effect similar to adenosine. CHA, an agonist of A(1) adenosine receptors, activated caspase-3 and -9, but not caspase-8. Adenosine-induced cytotoxicity of RCR-1 cells was also significantly inhibited by dipyridamole, an inhibitor of adenosine transporter, and AMDA, an inhibitor of adenosine kinase. AICAR, an activator of AMP-activated protein kinase (AMPK), reduced RCR-1 cell viability, but synergistic effect was not obtained with co-treatment with adenosine and AICAR. AICAR activated caspase-3 and -9, but not caspase-8. An additive inhibition was found in the co-presence of 8-CPT and dipyridamole. Extracellular adenosine, thus, appears to activate caspase-9 followed by the effector caspase, caspase-3, at least via two independent pathways linked to A(1) adenosine receptor-mediated adenylate cyclase inhibition and adenosine uptake into cells/conversion to AMP/activation of AMPK, possibly regardless of mitochondrial damage, thereby leading to RCR-1 cell death, dominantly by apoptosis. Moreover, caspase-8 activation could again contribute to adenosine-induced cytotoxicity, although the underlying mechanism is currently unknown. Collectively, the results of the present study may represent a new pathway for caspase activation relevant to diverse adenosine signals in cell death.
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PMID:A(1) adenosine receptor signal and AMPK involving caspase-9/-3 activation are responsible for adenosine-induced RCR-1 astrocytoma cell death. 1646 85

The protein factor beta2-microglobulin (beta2M), purified from the conditioned medium of human prostate cancer cell lines, stimulated growth and enhanced osteocalcin (OC) and bone sialoprotein (BSP) gene expression in human prostate cancer cells by activating a cyclic AMP (cAMP)-dependent protein kinase A signaling pathway. When beta2M was overexpressed in prostate cancer cells, it induced explosive tumor growth in mouse bone through increased phosphorylated cAMP-responsive element binding protein (CREB) and activated CREB target gene expression, including OC, BSP, cyclin A, cyclin D1, and vascular endothelial growth factor. Interrupting the beta2M downstream signaling pathway by injection of the beta2M small interfering RNA liposome complex produced an effective regression of previously established prostate tumors in mouse bone through increased apoptosis as shown by immunohistochemistry and activation of caspase-9, caspase-3, and cleavage of poly(ADP-ribose) polymerase. These results suggest that beta2M signaling is an attractive new therapeutic target for the treatment of lethal prostate cancer bone metastasis.
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PMID:beta2-microglobulin is a signaling and growth-promoting factor for human prostate cancer bone metastasis. 1698 53

By transfection of Coxsackievirus B3 (CVB3) individual protease gene into HeLa cells, we demonstrated that 2A(pro) and 3C(pro) induced apoptosis through multiple converging pathways. Firstly, both 2A(pro) and 3C(pro) induced caspase-8-mediated activation of caspase-3 and dramatically reduced cell viability. Secondly, they both activated the intrinsic mitochondria-mediated apoptosis pathway leading to cytochrome c release from mitochondria and activation of caspase-9. However, 3C(pro) induced these events via both up-regulation of Bax and cleavage of Bid, and 2A(pro) induced these events via cleavage of Bid only. Nevertheless, neither altered Bcl-2 expression. Thirdly, both proteases induced cell death through cleavage or down regulation of cellular factors for translation and transcription: both 2A(pro) and 3C(pro) cleaved eukaryotic translation initiation factor 4GI but their cleavage products are different, indicating different cleavage sites; further, both 2A(pro) and 3C(pro) down-regulated cyclic AMP responsive element binding protein, a transcription factor, with 2A(pro) exhibiting a stronger effect than 3C(pro). Surprisingly, neither could cleave DAP5/p97/NAT1, a translation regulator, although this cleavage was observed during CVB3 infection and could not be blocked by caspase inhibitor z-VAD-fmk. Taken together, these data suggest that 2A(pro) and 3C(pro) induce apoptosis through both activation of proapoptotic mediators and suppression of translation and transcription.
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PMID:Coxsackievirus B3 proteases 2A and 3C induce apoptotic cell death through mitochondrial injury and cleavage of eIF4GI but not DAP5/p97/NAT1. 1719 95

Extracellular adenosine induced apoptosis of HuH-7 cells, a Fas-deficient human hepatoma cell line. The adenosine action was inhibited by dipyridamole, an adenosine transporter inhibitor, or 5'-amino-5'-deoxyadenosine, an inhibitor of adenosine kinase to convert from adenosine to AMP, but it was not affected by inhibitors for adenosine A(1), A(2a), A(2b), and A(3) adenosine receptors. Adenosine activated caspase-3 and -8, but not caspase-9, in HuH-7 cells, and the activation was abolished by dipyridamole. In the real-time RT-PCR and Western blot analysis, extracellular adenosine downregulated mRNA and protein levels for c-FLIP, and the effect was suppressed by dipyridamole. Furthermore, overexpression of c-FLIP short in HuH-7 cells inhibited adenosine-induced caspase-8 activity. Taken together, these results suggest that intracellularly transported adenosine, perhaps converted AMP as the ensuing event, activates caspase-8 and the downstream effector caspase caspase-3 by neutralizing caspase-8 inhibition due to c-FLIP as a consequence of decreased c-FLIP expression, leading to apoptosis. This extends our understanding of adenosine-induced molecular apoptotic pathways.
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PMID:Intracellularly transported adenosine induces apoptosis in HuH-7 human hepatoma cells by downregulating c-FLIP expression causing caspase-3/-8 activation. 1730 86

t-Darpp is a cancer-related truncated isoform of Darpp-32 (dopamine and cyclic-AMP-regulated phosphoprotein of M(r) 32,000). We detected overexpression of t-Darpp mRNA in two thirds of gastric cancers compared with normal samples (P = 0.004). Using 20 micromol/L ceramide treatment as a model for induction of apoptosis in AGS cancer cells, we found that expression of t-Darpp led to an increase in Bcl2 protein levels and blocked the activation of caspase-3 and caspase-9. The MitoCapture mitochondrial apoptosis and cytochrome c release assays indicated that t-Darpp expression enforces the mitochondrial transmembrane potential and protects against ceramide-induced apoptosis. Interestingly, the expression of t-Darpp in AGS cells led to >or=2-fold increase in Akt kinase activity with an increase in protein levels of p-Ser(473) Akt and p-Ser(9) GSK3 beta. These findings were further confirmed using tetracycline-inducible AGS cells stably expressing t-Darpp. We also showed transcriptional up-regulation of Bcl2 using the luciferase assay with Bcl2 reporter containing P1 full promoter, quantitative reverse transcription-PCR, and t-Darpp small interfering RNA. The Bcl2 promoter contains binding sites for cyclic AMP-responsive element binding protein CREB/ATF1 transcription factors and using the electrophoretic mobility shift assay with a CREB response element, we detected a stronger binding in t-Darpp-expressing cells. The t-Darpp expression led to an increase in expression and phosphorylation of CREB and ATF-1 transcription factors that were required for up-regulating Bcl2 levels. Indeed, knockdown of Akt, CREB, or ATF1 in t-Darpp-expressing cells reduced Bcl2 protein levels. In conclusion, the t-Darpp/Akt axis underscores a novel oncogenic potential of t-Darpp in gastric carcinogenesis and resistance to drug-induced apoptosis.
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PMID:t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism. 1819 33

Hippocampal dentate gyrus possesses an exceptional capacity of adaptation to ischemic insults. Recently, using a transient global ischemic model in the adult rat, we identified a neuroprotective signalling cascade in the dentate gyrus involving calcium/calmodulin-dependent protein kinase IV (CaMKIV), cyclic AMP response element (CRE)-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), a major regulator of survival. We have shown that intracerebroventricular injections of anti-BDNF and anti-CREB are sufficient to cause substantial tissular damages and apoptotic deaths in late periods (48-72 h) after ischemia. Herein, we provide immunohistochemical and biochemical evidence that antibody-induced impairment of the protective CaMKIV/CREB/BDNF pathway induces an apparent duality of response in the dentate gyrus. The experimental protocol is performed as follows: (a) rats are anesthetized and vertebral arteries are occluded by electrocauterization; (b) on the following day, transient global ischemia is produced by occlusion of carotid arteries for 25 min; (c) finally, rats are infused with the pharmacologic agents into the left cerebral ventricle and then perfusion-fixed at different time points after ischemia for immunohistochemical and immunoblotting analyses. After infusion with anti-CaMKIV, phosphorylation of mitogen-activated protein kinases (MAPK) MKK3, MKK6 and p38 and phospho-acetylation of histone H3 occur at 6 h after ischemia without presence of any caspase-9 activation and cellular injuries. In contrast, infusion of anti-BDNF or anti-CREB surprisingly results in a remarkable stimulation of casein kinase 2 (CK2) and caspase-9 activities at 48-72 h post-insult. This is accompanied by the disappearance of phosphorylation of MKK(3/6) and p38 and phospho-acetylation of histone H3. These results suggest that: (1) activation of a MKK(3/6)/p38/H3 cascade at early periods post-ischemia may be capable of causing a short transient protective effect in the dentate gyrus; (2) CK2 might be implicated in inhibition of activity of molecules such as MKK(3/6), p38 and deacetylases at late periods post-insult, thereby promoting injuries and cell deaths in the dentate cell layer.
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PMID:Temporal assessment of histone H3 phospho-acetylation and casein kinase 2 activation in dentate gyrus from ischemic rats. 1976 64

Gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, is under clinical testing and use in cancer patients, including glioma. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma remain largely uncharacterized. Gefitinib inhibits cell growth and induces apoptosis in human glioma cells. Gefitinib also induces death of H4 cells with characteristics of the intrinsic apoptotic pathway, including Bax mitochondrial translocation, mitochondrial outer membrane permeabilization, cytochrome c cytosolic release, and caspase-9/caspase-3 activation. The importance of Bax in mediating gefitinib-induced apoptosis was confirmed by the attenuation of apoptosis by Bax siRNA and Bax channel blocker. Gefitinib caused Bad dephosphorylation, particularly in serine-112, and increased its binding preference to Bcl-2 and Bcl-xL. The dephosphorylation of Bad in gefitinib-treated cells was accompanied by reduced intracellular cyclic AMP content and protein kinase A (PKA) activity. Adenylyl cyclase activator forskolin attenuated, but PKA inhibitor H89 augmented, gefitinib-induced Bad dephosphorylation, Bax mitochondrial translocation, caspase-9/caspase-3 activation, and viability loss. Intriguingly, a nonselective protein phosphatase inhibitor okadaic acid alleviated gefitinib-induced alterations, except Bad dephosphorylation. In parallel with the higher basal PKA activity, response of U87 cells to gefitinib treatment was delayed and relatively resistant compared with that of H4 and T98G cells. Inactivation of PKA sensitized H4, T98G, and U87 cells to gefitinib cytotoxicity, Bad dephosphorylation in serine-112, and caspase-9/caspase-3 activation. Our findings suggest the involvement of the Bad/Bax signaling pathway in gefitinib-induced glioma apoptosis. Furthermore, the inactivation of PKA was shown to play a role in triggering the proapoptotic function of Bad.
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PMID:Gefitinib induces apoptosis in human glioma cells by targeting Bad phosphorylation. 2174 78


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