Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many agents, such as the endoplasmic reticulum Ca(2+) ATPase inhibitor, thapsigargin, or the ionophore, ionomycin, induce apoptosis by transiently elevating [Ca(2+)](i). The role of [Ca(2+)](i) in apoptosis induced by agents that do not immediately increase [Ca(2+)](i), such as 5-FdUr, TGF beta-1, doxorubicin, or radiation, is far more controversial. In the present paper, [Ca(2+)](i) was measured continuously for 120 h. in prostate and bladder cancer cell lines exposed to these four agents: 5-FdUR, TGF beta-1, doxorubicin, or radiation. Each of them consistently induced a delayed [Ca(2+)](i) rise associated with the morphological changes that characterize the execution phase of apoptosis (i.e. rounding, blebbing). This [Ca(2+)](i) rise occurred in two consecutive steps (< or = 10 microM and >10 microM) and resulted from a Ca(2+) influx from the extracellular medium. This delayed supramicromolar [Ca(2+)](i) rise was also observed previously in breast, prostate and bladder cancer cell lines exposed to thapsigargin. This influx regulated transcriptional reprogramming of Gadd153 and is required to activate cytochrome c release, caspase-3 activation, loss of clonal survival and DNA fragmentation. When cells were maintained in low extracellular Ca(2+) media, these phenomena were temporarily delayed but occurred on return to normal Ca(2+) medium. Similarly, apoptosis could be delayed by overexpressing the Ca(2+)-binding proteins, Calbindin-D(28K) and parvalbumin. As this delayed >or = 10 microM [Ca(2+)](i) elevation was observed in a number of cell lines exposed to a variety of different agents, we conclude that such elevation constitutes a key and general event of apoptosis in these malignant cells.
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PMID:A supramicromolar elevation of intracellular free calcium ([Ca(2+)](i)) is consistently required to induce the execution phase of apoptosis. 1197 14

Amphetamine (AMPH) is a psychostimulant whose chronic abuse may cause impairments in attention and memory in humans. These cognitive deficits might be related to neurotoxic effects of the drug. One such toxic effect is the well-described destruction of striatal dopaminergic terminals in mammals. In the present study, we investigated the possibility that AMPH might also cause neuronal apoptosis in the rodent striatum. Administration of a dose of the drug (10 mg/kg, 4 times, every 2 h) that is toxic to dopaminergic terminals resulted in the appearance of striatal cells that were positive for cleaved caspase-3 and for terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling (TUNEL), observations that are indicative of an ongoing apoptotic process. Dual immunofluorescence staining revealed that cleaved caspase-3-positive cells express calbindin and DARPP-32, but not somatostatin, parvalbumin, or cholinergic markers. In addition, AMPH also caused increased expression of p53 and Bax at both transcript and protein levels; in contrast, Bcl-2 levels were decreased after the AMPH injections. Moreover, Bax knockout mice showed resistance to AMPH-induced apoptotic cell death but not to AMPH-induced destruction of dopaminergic terminals. When taken together, these observations indicate that injections of doses of AMPH that are known to destroy striatal dopamine terminals can also cause apoptotic death of postsynaptic medium spiny projection neurons via mitochondria-dependent mechanisms.
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PMID:Amphetamine induces apoptosis of medium spiny striatal projection neurons via the mitochondria-dependent pathway. 1573 Dec 93

Age-dependent, neuronal apoptosis following N-methyl-D-aspartate receptor blockade has been linked to loss of calcium. To further explore this relationship, we examined expression of activated caspase-3, as well as the calcium binding proteins, calbindin-D 28K, calretinin and parvalbumin, following injection of vehicle or the N-methyl-D-aspartate receptor blocker, MK801, in postnatal day 7 or 21 rats. At postnatal day 7, MK801-induced activated caspase-3 expression was most frequently found in mutually exclusive cell populations to those expressing any of the three calcium binding proteins. For example, in the somatosensory cortex, most immunoreactivity for activated caspase-3 was found in layers IV/V, layered between areas of high calbindin or calretinin expression. Further, in the caudate putamen, activated caspase-3 rarely invaded zones of intense calbindin immunoreactivity. Suggesting expression patterns of these proteins were inversely related, these same brain regions no longer displayed MK801-induced activated caspase-3 at postnatal day 21, but instead robustly expressed calcium binding proteins. This later surge in expression was especially true for parvalbumin in regions such as the somatosensory and retrosplenial cortex, as well as the subicular complex. Calbindin-D 28K was also found to increase in the same regions though not as impressively as parvalbumin. Thus, developmental regulation of calcium binding protein expression may be a critical factor in age-dependent sensitivity to agents that disrupt calcium homeostasis in maturing neurons, providing a possible mechanistic explanation for age-dependent MK801 toxicity.
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PMID:MK801-induced caspase-3 in the postnatal brain: inverse relationship with calcium binding proteins. 1678 80

Loss of neuronal calcium is associated with later apoptotic injury but observing reduced calcium and increased apoptosis in the same cell would provide more definitive proof of this apparent correlation. Thus, following exposure to vehicle or the calcium chelator, BAPTA (1-20 microM), primary cortical neurons were labeled with Calcium Green-1 which was then cross-linked with EDAC, prior to immuno-staining for various proteins. We found that BAPTA-induced changes in calcium were highly correlated with changes in expression of activated caspase-3 as well as the calcium binding proteins calbindin, calretinin, and parvalbumin. Additionally, in brain slices from P7 neonatal rats, BAPTA induced significant loss of calcium in a brain region we have previously shown to express only moderate levels of calcium binding proteins as well as display robust apoptosis following calcium entry blockade. In contrast, BAPTA had little influence on calcium levels in a brain region we have previously shown to express robust calcium binding proteins as well as display far less apoptosis following calcium entry blockade. These data suggest that the ability of developing neurons to buffer changes in calcium may be critical to their long-term survival.
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PMID:Loss of calcium and increased apoptosis within the same neuron. 1712 51

Transient postnatal NMDA receptor blockade by phencyclidine (PCP), ketamine, or MK-801 induces developmental neuroapoptosis and adult behavioral deficits, which resemble abnormal human behaviors typically present in schizophrenia. This study tested the hypothesis that PCP-induced developmental apoptosis causes a specific deficit of GABAergic interneurons containing parvalbumin (PV), calretinin (CR), or calbindin (CB). Young adult (PND56) rats that were given a single dose of PCP (10 mg/kg) on PND7 exhibited no densitometric change of either CR or CB neurons in any brain region studied, but demonstrated a selective deficit of PV-containing neurons in the superficial layers (II-IV) of the primary somatosensory (S1), motor (M), and retrosplenial cortices, but not in the striatum (CPu) or hippocampus. Further, CR and CB neurons, which were expressed at the time of PCP administration, showed no colocalization with cellular markers of apoptosis (terminal dUTP nick-end labeling (TUNEL) of broken DNA or cleaved caspase-3), indicating that CR- and CB-containing neurons were protected from the toxic effect of PCP and survived into adulthood. This suggests that the deletion of PV neurons occurred during development, but cleaved caspase-3 showed no colocalization with BrdU, a specific marker of S-phase proliferation. These data suggest that the loss of PV-containing neurons was not due to an effect of PCP on proliferating neurons, but rather an effect on post-mitotic neurons. The developmental dependence and neuronal specificity of this effect of PCP provides further evidence that this model may be valuable in exploring the pathophysiology of schizophrenia.
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PMID:Postnatal phencyclidine administration selectively reduces adult cortical parvalbumin-containing interneurons. 1805 37

MK801-induced activation of caspase-3 is developmentally regulated, peaking at postnatal day (P) 7 and decreasing with increasing postnatal age thereafter. Further, at P7, cells displaying activation of caspase-3 lack expression of calcium binding proteins (CaBPs). To further explore this relationship, we investigated postnatal expression of calbindin (CB), calretinin (CR) and parvalbumin (PV) in two brain regions susceptible to MK801-induced injury, the somatosensory cortex (S1) and layer II/III of motor cortex (M1/M2). Expression of CB and especially PV was low to absent prior to P7 but substantially increased from P7 through to P21 and adulthood. In contrast, CR expression was more variable at early developmental ages, stabilized to lower levels after P7 and showed a marked decline by P21. The results suggest that not only does calcium buffering capacity increase developmentally but also acquisition of enhanced buffering may be one mechanism by which neurons survive agent-induced alterations in calcium homeostasis.
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PMID:Decline in age-dependent, MK801-induced injury coincides with developmental switch in parvalbumin expression: somatosensory and motor cortex. 1868 10

The prefrontal cortex (PFC) is associated with higher cognitive functions including attention and working memory and has been implicated in the regulation of impulsivity as well as the pathology of complex mental illnesses. N-methyl D-aspartate (NMDA) antagonist treatment with dizocilpine induces cell death which is greatest in the frontal cortex on post-natal day seven (P7), however the long-term structural and behavioral effects of this treatment are unknown. This study investigates both the acute neurotoxicity of P7 dizocilpine and the persistent effects of this treatment on pyramidal cells and parvalbumin interneurons in the adult PFC, a brain region involved in the regulation of impulsivity. Dizocilpine treatment on P7 increased cleaved caspase-3 immunoreactivity (IR) in the PFC on P8. In adult mice (P82), P7 dizocilpine treatment resulted in 50% fewer parvalbumin-positive interneurons (p<0.01) and 42% fewer layer V pyramidal neurons (p<0.01) in the PFC. Double immunohistochemistry revealed cleaved caspase-3 IR in both GAD67 IR interneurons and GAD67 (-) neurons. Following dizocilpine treatment at P7, adults showed reduced time in the center of the open field suggesting increased anxiety-like behavior. These findings indicate that early brain insults affecting glutamatergic neurotransmission lead to persistent brain pathology that could contribute to impulsivity and cognitive dysfunction.
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PMID:Deficits in adult prefrontal cortex neurons and behavior following early post-natal NMDA antagonist treatment. 1940 20

Thapsigargin is a specific inhibitor of the sarco/endoplasmic reticulum Ca(2+) ATPase of the endoplasmic reticulum. Here, we show that stimulation of human HaCaT keratinocytes with nanomolar concentrations of thapsigargin triggers expression of activating transcription factor (ATF) 3, a basic-region leucin zipper transcription factor. ATF3 expression was also up-regulated in thapsigargin-stimulated glioma cells, hepatoma cells, retinal pigment epithelial cells, and airway epithelial cells. Thapsigargin-induced up-regulation of ATF3 expression in keratinocytes was attenuated by BAPTA-acetoxymethyl ester or by expression of the Ca(2+)-binding protein parvalbumin in the cytosol of HaCaT cells but not by a panel of pharmacological agents that chelate extracellular Ca(2+) (EGTA) or inhibit either ryanodine receptors (dantrolene) or voltage-gated Ca(2+) channels (nifedipine). Hence, elevated levels of intracellular Ca(2+), released from intracellular stores, are essential for the effect of thapsigargin on the biosynthesis of ATF3. The thapsigargin-induced signaling pathway was blocked by expression of either mitogen-activated protein kinase phosphatase-1 or -5. Experiments involving pharmacological and genetic tools revealed the importance of c-Jun N-terminal protein kinase (JNK) within the signaling cascade, whereas inhibition of extracellular signal-regulated protein kinase or p38 protein kinase did not attenuate thapsigargin-induced expression of ATF3. Functional studies showed that treatment of HaCaT keratinocytes with thapsigargin led to a 2-fold induction of caspase-3/7 activity. The up-regulation of caspase-3/7 activity in thapsigargin-stimulated HaCaT cells was attenuated by inhibition of JNK. Together, these data show that stimulation of HaCaT cells with thapsigargin induces a specific signaling pathway in keratinocytes involving activation of JNK, biosynthesis of ATF3, and up-regulation of caspase-3/7 activity.
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PMID:Thapsigargin induces expression of activating transcription factor 3 in human keratinocytes involving Ca2+ ions and c-Jun N-terminal protein kinase. 2071 50

In this study, the neuropathological changes induced by chronic unpredictable stress (CUS) and chronic mild stress (CMS) in calbindin D-28K (CB) and parvalbumin (PV) immunoreactive neurons in the rat hippocampus were demonstrated. We used immunohistochemical techniques to quantify the numerical density and morphological changes of PV immunoreactive and CB immunoreactive neurons in the dentate gyrus (DG) and the CA1 and CA3 regions of the hippocampus. We also assessed cell proliferation (Ki-67) and apoptotic processes (active caspase-3) in the DG. We found a significant decrease (16.6% for CUS and 13.3% for CMS) in the numerical density of granule cells (GC), alterations in the CB immunoreactive cells of the GC in the DG and an impairment of mossy fiber CB immunolabelling in the CA3. These changes were not accompanied by a decrease in Ki-67 labeling or the level of caspase-3 in the DG. These data indicate a stress-induced reduction of calcium binding neuron parameters, which may be related to the behavioral paradigms exhibited in these models.
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PMID:Alterations in hippocampal calcium-binding neurons induced by stress models of depression: a preliminary assessment. 2127 79

Reductions in the number and size of neurons in the medial prefrontal cortex (mPFC) have been documented in many post-mortem studies of depressed patients and animals exposed to stress. Here, we examined the effect of chronic unpredictable stress (CUS) and chronic mild stress (CMS) on specific populations of neurons in the rat mPFC. Antibodies directed against parvalbumin (PV), calbindin D-28K (CB) and active caspase-3 have been used to quantify the numerical density of PV-immunoreactive (PV-ir), CB-ir and active caspase-3-ir cells, and to measure the relative optical density of neuropil. CUS decreased the density of CB-ir neurons and the optical density of CB-ir neuropil. In turn, CMS increased the densities of both CB-ir neurons and neuropil, while PV-ir neurons and PV-ir neuropil were not changed. The frequency distribution of neuronal surface areas was significantly different only for PV-ir neurons, and only between the control and CUS group. CMS reduced the density of active caspase-3-ir cells while CUS did not. We concluded that the mPFC reveals a different pattern of changes in neurons containing calcium binding proteins and active caspase-3 immunoreactivity in response to CUS and CMS.
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PMID:Different pattern of changes in calcium binding proteins immunoreactivity in the medial prefrontal cortex of rats exposed to stress models of depression. 2235 2


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