Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of beta-adrenergic receptor normally results in signaling by the heterotrimeric G protein G(s), leading to the activation of adenylyl cyclase, production of cAMP, and activation of cAMP-dependent protein kinase (PKA). Here we report that cell death of thymocytes can be induced after stimulation of beta-adrenergic receptor, or by addition of exogenous cAMP. Apoptotic cell death in both cases was observed with the appearance of terminal deoxynucleotidyl transferase-mediated UTP end labeling reactivity and the activation of caspase-3 in S49 T cells. Using thymocytes deficient in either Galpha(s) or PKA, we find that engagement of beta-adrenergic receptors initiated a Galpha(s)-dependent, PKA-independent pathway leading to apoptosis. This alternative pathway involves Src family tyrosine kinase Lck. Furthermore, we show that Lck protein kinase activity can be directly stimulated by purified Galpha(s). Our data reveal a new signaling pathway for Galpha(s), distinct from the classical PKA pathway, that accounts for the apoptotic action of beta-adrenergic receptors.
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PMID:Apoptotic signaling through the beta -adrenergic receptor. A new Gs effector pathway. 1076 82

The unique N-terminal region of the cAMP-specific phosphodiesterase PDE4A5, which confers an ability to bind to certain protein SH3 domains, is cleaved during apoptosis in both Rat-1 fibroblasts and PC12 cells. Cleavage was abolished by the caspase-3-selective inhibitor, z-DEVD-CHO but not the caspase-1 selective inhibitor, z-YVAD-CHO. Caspase-3 treatment of PDE4A5, expressed either transiently in COS cells or generated in vitro by coupled transcription translation, generated a similar cleavage product of 100 kDa compared with the native 110-kDa PDE4A5. This product could be detected immunochemically with an antibody raised to a C-terminal PDE4A5 peptide but not an antibody raised to the N terminus of PDE4A5, indicating that caspase-3 caused N-terminal cleavage of PDE4A5. Deletion of the putative caspase-3 cleavage site, (69)DAVD(72), in PDE4A5, or generation of either the D72A or the D69A mutants, ablated the ability of caspase-3 to cause cleavage. The N-terminal truncate PDE4A5-DeltaP3 was engineered to mimic the caspase-cleaved product of PDE4A5. This showed altered catalytic activity and, unlike PDE4A5, was unable to interact with the SH3 domain of the tyrosyl kinase, LYN. Although both PDE4A5 and PDE4A5-DeltaP3 were localized at cell cortical regions (ruffles), the distinct perinuclear association noted for both PDE4A5 and LYN was not seen for PDE4A5-DeltaP3. Staurosporine-induced apoptosis caused a marked redistribution of PDE4A5 but not PDE4A8 in stably transfected Rat-1 cells. The PDE4-selective inhibitor, rolipram together with the adenylyl cyclase activator forskolin, caused a synergistic increase in the apoptosis of Rat-1 cells. Overexpression of PDE4A5 in Rat-1 cells protected against staurosporine-induced apoptosis in contrast to overexpression of PDE4A8, which potentiated apoptosis. PDE4A5 may be the sole PDE4 family member to provide a substrate for caspase-3 cleavage and this action serves to remove the SH3 binding domain that is unique to this isoform within the PDE4A family and to alter its intracellular targeting.
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PMID:The cAMP-specific phosphodiesterase PDE4A5 is cleaved downstream of its SH3 interaction domain by caspase-3. Consequences for altered intracellular distribution. 1082 34

The mechanisms that regulate cardiac myocyte apoptosis are not well understood. To study the role of protein phosphatase 1 (PP1) and 2A (PP2A) in apoptosis, we exposed cultured neonatal rat cardiac myocytes to the phosphatase inhibitor okadaic acid (OA). Exposure (18 h) to 100 nM OA (a concentration which inhibits both PP1 and PP2A) decreased the number of adherent cells, caused genomic DNA fragmentation, and increased the percentage of apoptotic cells. These effects did not occur at a lower concentration of OA (1 nM) which is relatively specific for PP2A. Stimulation of alpha1- or beta-adrenergic receptors with norepinephrine (NE) in the presence of propranolol or prazosin partially blocked OA-induced apoptosis as measured by flow cytometry. Likewise, stimulation of adenylyl cyclase with forskolin reduced OA-induced apoptosis. Conversely, inhibition of protein kinase A with H89 or protein kinase C with chelerethrine potentiated OA-induced apoptosis. OA increased caspase-3 activity, and this effect was reduced by NE. Thus, inhibition of PP1 stimulates apoptosis in NRVM and stimulation of adrenergic receptors protects against OA-induced apoptosis.
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PMID:Inhibition of protein phosphatase 1 induces apoptosis in neonatal rat cardiac myocytes: role of adrenergic receptor stimulation. 1109 66

Thyroid-stimulating hormone (TSH) action in adipose tissue remains largely unknown. Our previous work indicates that human preadipocytes express functional TSH receptor (TSHR) protein, demonstrated by TSH activation of p70 S6 kinase (p70 S6K). We have now studied murine 3T3-L1 preadipocytes to further characterize TSH signaling and cellular action. Western blot analysis of 3T3-L1 preadipocyte lysate revealed the 100-kDa mature processed form of TSHR. TSH activated p70 S6K and protein kinase B (PKB/Akt), as measured by immunoblot analysis. Preincubation with wortmannin or LY-294002 completely blocked TSH activation of p70 S6K and PKB/Akt, implicating phosphoinositide 3-kinase (PI3K) in their regulation. TSH increased phosphotyrosine protein(s) in the 125-kDa region and augmented the associated PI3K activity fourfold. TSH had no effect on cAMP levels in 3T3-L1 preadipocytes, suggesting that adenylyl cyclase is not involved in TSH activation of the PI3K-PKB/Akt-p70 S6K pathway. 3T3-L1 preadipocyte cell death was reduced by 29-76% in serum-deprived (6 h) preadipocytes treated with 1-20 microM TSH. In the presence of 20 microM TSH, an 88% reduction in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive cells was observed in serum-starved (3 h) 3T3-L1 preadipocytes as well as a 93% reduction in the level of cleaved activated caspase 3. In summary, TSH acts as a survival factor in 3T3-L1 preadipocytes. TSH does not stimulate cAMP accumulation in these cells but instead activates a PI3K-PKB/Akt-p70 S6K pathway.
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PMID:TSH signaling and cell survival in 3T3-L1 preadipocytes. 1222 69

Abstract Activation of potassium (K(+)) currents plays a critical role in the control of programmed cell death. Because pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to inhibit the apoptotic cascade in the cerebellar cortex during development, we have investigated the effect of PACAP on K(+) currents in cultured cerebellar granule cells using the patch-clamp technique in the whole-cell configuration. Two types of outward K(+) currents, a transient K(+) current (I(A)) and a delayed rectifier K(+) current (I(K)) were characterized using two different voltage protocols and specific inhibitors of K(+) channels. Application of PACAP induced a reversible reduction of the I(K) amplitude, but did not affect I(A), while the PACAP-related peptide vasoactive intestinal polypeptide had no effect on either types of K(+) currents. Repeated applications of PACAP induced gradual attenuation of the electrophysiological response. In the presence of guanosine 5'-[gammathio]triphosphate (GTPgammaS), PACAP provoked a marked and irreversible I(K) depression, whereas cell dialysis with guanosine 5'-[betathio]diphosphate GDPbetaS totally abolished the effect of PACAP. Pre-treatment of the cells with pertussis toxin did not modify the effect of PACAP on I(K). In contrast, cholera toxin suppressed the PACAP-induced inhibition of I(K). Exposure of granule cells to dibutyryl cyclic adenosine monophosphate (dbcAMP) mimicked the inhibitory effect of PACAP on I(K). Addition of the specific protein kinase A inhibitor H89 in the patch pipette solution prevented the reduction of I(K) induced by both PACAP and dbcAMP. PACAP provoked a sustained increase of the resting membrane potential in cerebellar granule cells cultured either in high or low KCl-containing medium, and this long-term depolarizing effect of PACAP was mimicked by the I(K) specific blocker tetraethylammonium chloride (TEA). In addition, pre-incubation of granule cells with TEA suppressed the effect of PACAP on resting membrane potential. TEA mimicked the neuroprotective effect of PACAP against ethanol-induced apoptotic cell death, and the increase of caspase-3 activity observed after exposure of granule cells to ethanol was also significantly inhibited by TEA. Taken together, the present results demonstrate that, in rat cerebellar granule cells, PACAP reduces the delayed outward rectifier K(+) current by activating a type 1 PACAP (PAC1) receptor coupled to the adenylyl cyclase/protein kinase A pathway through a cholera toxin-sensitive Gs protein. Our data also show that PACAP and TEA induce long-term depolarization of the resting membrane potential, promote cell survival and inhibit caspase-3 activity, suggesting that PACAP-evoked inhibition of I(K) contributes to the anti-apoptotic effect of the peptide on cerebellar granule cells.
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PMID:PACAP inhibits delayed rectifier potassium current via a cAMP/PKA transduction pathway: evidence for the involvement of I k in the anti-apoptotic action of PACAP. 1506 41

1 We have previously demonstrated that nitric oxide (NO) triggers CD34(+)-derived megakaryocyte apoptosis. We here show that prostacyclin (PGI(2)) inhibits PAPA/NO-induced megakaryocyte death detected by fluorescent microscopy and flow cytometry. 2 The cAMP-specific phosphodiesterase inhibitor, Ro 20-1724, and the permeable analog dibutyryl-cAMP also delayed apoptosis. PGI(2) effect was fully prevented when adenylyl cyclase activity was suppressed by SQ 22536, and partially reversed by the permeable protein kinase A inhibitor PKI 14-22 amide. ELISA showed that while both PGI(2) and NO alone or synergistically raised cAMP, only NO was able to increase intracellular cGMP levels. 3 Treatment of megakaryocytes with PGI(2) abolished both basal and NO-raised cGMP levels. Addition of 8-pCPT-cGMP or activation of soluble guanylyl cyclase by BAY 41-2272 induced cell death in a concentration-dependent manner, and ODQ, an inhibitor of guanylyl cyclase, prevented both PAPA/NO- or BAY 41-2272-induced apoptosis. Specific cGMP phosphodiesterase inhibition by Zaprinast or suppression of adenylyl cyclase by SQ 22536 enhanced the PAPA/NO proapoptotic effect. 4 PGI(2) completely inhibited NO-mediated generation and the increased activity of the cleaved form of caspase-3. 5 In conclusion, our results demonstrate that contrary to their well-known direct and synergistic inhibitory effects on platelets, PGI(2) and NO regulate opposite megakaryocyte survival responses through a delicate balance between intracellular cyclic nucleotide levels and caspase-3 activity control.
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PMID:Prostacyclin prevents nitric oxide-induced megakaryocyte apoptosis. 1577 35

Pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and peptide histidine-isoleucine (PHI), are structurally related endogenous peptides widely expressed in the central and peripheral nervous system and showing rich profile of biological activities. They act as neurotransmitters, neuromodulators and neurotrophic factors. Recently, their neuroprotective potential has been revealed in numerous in vitro and in vivo models. Thus, PACAP and VIP protected the cells from neurotoxic effects of ethanol, hydrogen peroxide (H2O2, beta-amyloid and glycoprotein 120 (gp120). Moreover, PACAP showed neuroprotection against glutamate, human prion protein fragment 106-126 [PrP(106-126)] and C2-ceramide. Both peptides reduced brain damage after ischemia and ameliorated neurological deficits in a model of Parkinson's disease. Neuroprotective potential of PHI has not been thoroughly investigated yet, but several results obtained in the last years do not exclude it. The mechanism underlying neuroprotective properties of PACAP seems to involve activation of adenylyl cyclase (AC) --> cyclic adenosine 3',5'-mono-phosphate (cAMP) --> protein kinase A (PKA) and mitogen-activated protein (MAP) kinase pathways, and inhibition of caspase-3. PACAP can also, yet indirectly, stimulate astrocytes to release neuroprotective factors, such as regulated upon activation normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein 1 (MIP-1) chemokines. Neuroprotective activity of VIP seems to involve an indirect mechanism requiring astrocytes. VIP-stimulated astrocytes secrete neuroprotective proteins, including activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP), as well as a number of cytokines. However, in the activated microglia, VIP and PACAP are capable of inhibiting the production of inflammatory mediators which can lead to neurodegenerative processes within the brain. In conclusion, studies carried out on the central nervous system have shown that PACAP, VIP, and likely PHI, are endowed with a neuroprotective potential, which renders them (or their derivatives) promising therapeutic agents in several psychoneurological disorders linked to neurodegeneration.
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PMID:Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. 1598 13

Our previous study has shown that chronic morphine exposure induces neuronal apoptosis within the spinal cord dorsal horn; however, the mechanisms of morphine-induced apoptosis remain unclear. Here we examined whether adenylyl cyclase (AC) and protein kinase A (PKA) would play a role in this process. Intrathecal morphine regimen (10 microg, twice daily x 7 days) that resulted in antinociceptive tolerance induced spinal apoptosis as revealed by in situ terminal deoxynucleotidyl transferase (TdT)-UTP-biotin nick end labeling (TUNEL). The TUNEL-positive cells were detected primarily in the superficial laminae of the spinal cord dorsal horn, which was associated with an increase in the expression of activated caspase-3 and mitogen-activated protein kinase (MAPK) within the same spinal region. Co-administration of morphine with a broad AC inhibitor (ddA), a PKA inhibitor (H89), or a MAPK inhibitor (PD98059) substantially reduced the number of TUNEL-positive cells, as compared with the morphine alone group. The results indicate that the spinal AC and PKA pathway through intracellular MAPK may be contributory to the cellular mechanisms of morphine-induced apoptosis.
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PMID:Activity of adenylyl cyclase and protein kinase A contributes to morphine-induced spinal apoptosis. 1610 99

The programmed cell death plays a crucial role in the regulation of numerous physiological and pathological phenomena. In this study, we show that interleukin-1 beta (IL-1beta) induces an early production of endogenous ceramides via N-sphingomyelinase (N-Smase) as well as an inhibition of adenylyl cyclase activity in pig thyroid cells. This effect is followed by a down-regulation of the extracellular signal-regulated protein kinase (ERK1/2) phosphorylation, an activation of caspase-3, and ends by setting up the programmed cell death. The permeable exogenous C(2)-ceramide reproduces IL-1beta effects on: (i) inhibition of adenylyl cyclase activity, (ii) down-regulation of ERK1/2 phosphorylation, (iii) activation of caspase-3, and (iv) apoptosis in pig thyroid cells. Cell treatment with a PKA inhibitor down-regulates ERK1/2 phosphorylation. Furthermore, inhibition of ERK1/2 signaling pathway by U-0126 enhances caspase-3 activity and sets up programmed cell death. Both IL-1beta and exogenous C(2)-ceramide effects are reproduced by U-0126 so illustrating the implication of ERK1/2 down-regulation in both caspase-3 activation and apoptosis induction. Our study shows for the first time that endogenous ceramides are important second messengers in IL-1beta-induced apoptosis in pig thyroid cells through inhibition of adenylyl cyclase and ERK1/2 activities.
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PMID:Interleukin-1beta-induced apoptosis through adenylyl cyclase and ERK1/2 inhibition in primary cultured thyroid cells. 1631 Jan 70

The mechanism by which ethanol induces beta-endorphin (beta-EP) neuronal death during the developmental period was determined using fetal rat hypothalamic cells in primary cultures. The addition of ethanol to hypothalamic cell cultures stimulated apoptotic cell death of beta-EP neurons by increasing caspase-3 activity. Ethanol lowered the levels of adenylyl cyclase (AC)7 mRNA, AC8 mRNA, and/or cAMP in hypothalamic cells, whereas a cAMP analog blocked the apoptotic action of ethanol on beta-EP neurons. The AC inhibitor dideoxyadenosine (DDA) increased cell apoptosis and reduced the number of beta-EP neurons, and it potentiated the apoptotic action of ethanol on these neurons. beta-EP neurons in hypothalamic cultures showed immunoreactivity to transforming growth factor-beta1 (TGF-beta1) protein. Ethanol and DDA increased TGF-beta1 production and/or release from hypothalamic cells. A cAMP analog blocked the activation by ethanol of TGF-beta1 in these cells. TGF-beta1 increased apoptosis of beta-EP neurons, but it did not potentiate the action of ethanol or DDA actions on these neurons. TGF-beta1 neutralizing antibody blocked the apoptotic action of ethanol on beta-EP neurons. Determination of TGF-beta1-controlled cell apoptosis regulatory gene levels in hypothalamic cell cultures and in isolated beta-EP neurons indicated that ethanol, TGF-beta1, and DDA similarly alter the expression of these genes in these cells. These data suggest that ethanol increases beta-EP neuronal death during the developmental period by cellular mechanisms involving, at least partly, the suppression of cAMP production and activation of TGF-beta1-linked apoptotic signaling.
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PMID:Ethanol induces apoptotic death of developing beta-endorphin neurons via suppression of cyclic adenosine monophosphate production and activation of transforming growth factor-beta1-linked apoptotic signaling. 1632 33


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