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)

Apoptosis, a cellular process critical to retinal neurogenesis, has been implicated in several neurodegenerative disorders. As the retina matures the suppression of apoptosis occurs and the emphasis shifts towards survival. To identify the cellular changes that bring about this critical shift in the balance, we performed an expression analysis of pro- and anti-apoptotic mediators in the immature, post-natal day 6 (P6) and the post-mitotic adult P60 mouse retina. Laser capture microdissection (LCM) of the P6 and the P60 retina, followed by reverse transcriptase-polymerase chain reaction (RT-PCR) was employed to elucidate changes in the mRNA expression of Apaf-1, caspase-3 and caspase-9 in the individual retinal layers in the young and mature tissue. RT-PCR and Western blotting of whole P6 and P60 retinal preparations was carried out to determine changes in other caspases and key survival mediators at the mRNA and protein level, respectively. Our results demonstrate that each neuronal cell layer in the adult retina down-regulates the gene expression of Apaf-1 and caspase-3, and to a lesser extent, caspase-9. The protein expression levels of other executioner and initiator caspases are also reduced in the adult tissue. Interestingly, XIAP, a potent caspase inhibitor, increases in expression in the adult retina. Additionally, we demonstrate age-dependent increased expression and activation status of the components of the MAPK transduction cascade. Conversely, we observe decreased PI3-K and AKT expression and decreased activity of AKT (pAKT) in the adult retina. Furthermore, results from RNAi experiments demonstrate an additional mechanism of PI3-K regulation in photoreceptor cells. Our findings suggest that a survival strategy adopted by the post-mitotic retina involves a down-regulation of key pro-apoptotic factors concomitant with changes in expression and activation status of certain pro-survival mediators.
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PMID:Analysis of apoptotic and survival mediators in the early post-natal and mature retina. 1701 50

We have previously shown that the HSV-2 anti-apoptotic protein ICP10PK is delivered by the replication incompetent virus mutant DeltaRR and prevents kainic acid (KA)-induced epileptiform seizures and neuronal cell loss in the mouse and rat models of temporal lobe epilepsy. The present studies used DeltaRR and the ICP10PK deleted virus mutant DeltaPK to examine the mechanism of neuroprotection. DeltaRR-infected neuronal cells expressed a chimeric protein in which ICP10PK is fused in frame to LacZ (p175) while retaining ICP10PK kinase activity. DeltaPK-infected neuronal cells expressed a mutant ICP10 protein that is deleted in the PK domain and is kinase negative (p95). p175 and p95 were expressed in CA3 (86+/-3%) and CA1 (69+/-7%) cells from DeltaRR or DeltaPK-infected organotypic hippocampal cultures (OHC) and 80-85% of the ICP10 positive cells co-stained with antibody to beta(III) Tubulin (neuronal marker). DeltaRR, but not DeltaPK, inhibited KA-induced cell death and caspase-3 activation in CA3 neurons, an inhibition seen whether DeltaRR was delivered 2 days before or 2 days after KA administration (95% neuroprotection). Neuroprotection was associated with ERK and Akt activation and was abrogated by simultaneous treatment with the MEK (U0126) and PI3-K (LY294002) inhibitors. DeltaRR-mediated neuroprotection was associated with increased expression of the anti-apoptotic protein Bag-1 and decreased expression of the pro-apoptotic protein Bad. The surviving neurons retained normal synaptic function potentially related to increased expression of the transcription factor CREB. The data indicate that DeltaRR is a promising platform for neuroprotection from excitotoxic injury.
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PMID:The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures. 1702 Jul 50

Advanced ovarian cancer (OC) is not curable by surgery alone and chemotherapy is essential for its treatment. Isothiocyanates have been shown to inhibit carcinogen-induced tumorigenesis in animal models, yet no efforts have been made to determine their therapeutic potential in OC. In the present study, we investigated the mechanism of the anti-proliferative and apoptotic activity of benzyl isothiocyanate (BITC) in OC. BITC inhibited the proliferation of OC cells and induced apoptosis in OC cells. Apoptosis was induced by a strong activation of caspase-3 and -9, and cleavage of PARP-1. However, caspase-8 was not activated by BITC. Cytotoxic effects of BITC were reversed by the inhibition caspase-3 and -9 specific inhibitors. BITC showed a concentration dependent decrease in the levels of Bcl-2 with a concomitant increase in Bax levels. In addition, BITC activated proapoptotic signaling by phosphorylation JNK1/2 and p38 while simultaneously inhibiting survival signaling mediated by ERK1/2 and Akt phosphorylation in a dose-dependent manner. While JNK inhibitor SP600125 and p38 inhibitor SB203580, abolished the cytotoxic effect of BITC, MEK inhibitor, PD98059 and PI3 kinase inhibitor, LY294002 failed to show such reversal indicating a critical role played by JNK1/2 and p38 signaling in apoptosis induced by BITC. In summary, our studies demonstrate that BITC inhibits proliferation of OC cells and induces apoptosis via caspase-9 and -3 pathways. BITC inhibits ERK1/2 and Akt survival signaling while simultaneously activating pro-apoptotic p38 and JNK1/2. Therefore, BITC can be potentially developed as a therapeutic agent to treat OC.
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PMID:Benzyl isothiocyanate (BITC) induces apoptosis in ovarian cancer cells in vitro. 1755 57

The aim of this study was to investigate the effects of apelin on proliferation and apoptosis of mouse osteoblastic MC3T3-E1 cells. APJ was expressed in MC3T3-E1 cells. Apelin did not affect Runx2 expression, alkaline phosphatase (ALP) activity, osteocalcin and type I collagen secretion, suggesting that it has no effect on osteoblastic differentiation of MC3T3-E1 cells. However, apelin stimulated MC3T3-E1 cell proliferation and inhibited cell apoptosis induced by serum deprivation. Our study also shows that apelin decreased cytochrome c release and caspase-3, capase-8 and caspase-9 activation in serum-deprived MC3T3-E1 cells. Apelin activated c-Jun N-terminal kinase (JNK) and Akt (phosphatidylinositol 3-kinase downstream effector), and the JNK inhibitor SP600125, the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 or the Akt inhibitor 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate (HIMO) inhibited its effects on proliferation and serum deprivation-induced apoptosis. Furthermore, apelin protected against apoptosis induced by the glucocorticoid dexamethasone or TNF-alpha. Apelin stimulates proliferation and suppresses serum deprivation-induced apoptosis of MC3T3-E1 cells and these actions are mediated via JNK and PI3-K/Akt signaling pathways.
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PMID:Apelin stimulates proliferation and suppresses apoptosis of mouse osteoblastic cell line MC3T3-E1 via JNK and PI3-K/Akt signaling pathways. 1710 97

The anti-apoptotic effect of PGE(2) was examined in Jurkat cells (human T-cell leukemia) by incubation with PGE(2) (5 nM) prior to treatment with the cancer chemotherapeutic agent camptothecin. Apoptosis was evaluated by caspase-3 activity in cell extracts and flow cytometry of propidium iodide-labeled cells. Pre-incubation with PGE(2) reduced camptothecin-induced caspase activity by 30% and apoptosis by 35%, respectively. Pharmacological data demonstrate that the EP4 receptor is responsible for mediating the protection from camptothecin-induced apoptosis. Pre-treatment of the cells with the EP4 antagonist (EP4A) prior to PGE(2) and camptothecin abolished the increased survival effect of PGE(2). Specific inhibition of the downstream of PI3 kinase or AKT/protein kinase but not protein kinase A prevents the observed increase in cell survival elicited by PGE(2). These findings have critical implications regarding the mechanism and potential application of PGE(2) receptor specific inhibition in cancer therapy.
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PMID:EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway. 1725 77

The objective of this study was to assess the anti-tumor efficacy of rapamycin alone or in combination with herceptin in breast cancer. A total of 20 human breast cancer lines were examined for expression of various receptor tyrosine kinases and activation of their down stream signaling molecules, as well as for their invasion and colony forming ability. The ErbB2 and PI3 kinase pathway inhibitors were tested for the inhibition on breast cancer cell growth and tumor development. Seven of the 20 lines displayed an elevated level of ErbB2, others had varying level of EGF, IGF-1 or insulin receptor. Over 30% of the lines also had constitutive activation of Akt and MAP kinase. The lines displayed a wide range of colony forming and invasion ability. The PI3 kinase pathway inhibitors LY294002 and rapamycin inhibited the colony forming ability of all of the lines with the ErbB2 overexpressing lines having a higher sensitivity. A similar trend was observed for inhibition of invasion by LY294002. Rapamycin alone and additively together with herceptin inhibited the breast cancer cell growth especially in ErbB2 overexpressing cells. Rapamycin and herceptin synergistically inhibited tumor growth and endpoint tumor load in a xenograft model using a MCF-7 subline and in a MMTV-ErbB2 transgenic model. Rapamycin and herceptin significantly reduced the level of cyclin D1 and D3 and increased the cleavage of caspase 3 suggesting an increased apoptosis. Our results suggest that rapamycin together with herceptin has an enhanced anti-cancer effect and could be developed as an improved therapeutic regimen for breast cancer.
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PMID:Rapamycin together with herceptin significantly increased anti-tumor efficacy compared to either alone in ErbB2 over expressing breast cancer cells. 1730 6

HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. Roles of HMGA1 in mediating the malignant phenotype of this cancer are poorly understood. We tested the hypothesis that overexpression of HMGA1 promotes resistance to anoikis (apoptosis induced by anchorage deprivation) in pancreatic cancer cells. HMGA1 cDNA was stably transfected into MiaPaCa2 human pancreatic adenocarcinoma cells (which have low baseline expression levels of HMGA1). Cells were grown in suspension on PolyHEMA-coated plates and their susceptibility to anoikis was assayed using flow cytometry. Overexpression of HMGA1 was associated with marked reductions in susceptibility to anoikis in concert with increases in Akt phosphorylation (Ser473) and in Akt kinase activity and with reductions in caspase 3 activation. Inhibition of phosphoinositidyl-3 (PI3-K)/Akt pathway with either the small molecule inhibitor LY294002 or dominant-negative Akt resulted in reversal of anoikis resistance induced by HMGA1 overexpression. Further, RNA interference-mediated HMGA1 silencing in MiaPaCa2 and BxPC3 (a human pancreatic adenocarcinoma cell line with high baseline levels of HMGA1 expression) cells resulted in significant increases in susceptibility to anoikis. Our findings suggest HMGA1 promotes anoikis resistance through a PI3-K/Akt-dependent mechanism. Given the putative associations between anoikis resistance and metastatic potential, HMGA1 represents a potential therapeutic target in pancreatic adenocarcinoma.
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PMID:Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells. 1734 93

The role of glucocorticoids in the regulation of apoptosis remains incongruous. Here, we demonstrate that corticosterone protects neurons from apoptosis by a mechanism involving the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21(Waf1/Cip1) at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21(Waf1/Cip1) preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21(Waf1/Cip1) and neuroprotection are completely abolished by glucocorticoid and mineralocorticoid receptor antagonists as well as inhibitors of PI3- and Akt-kinase. Both germline and somatically induced p21(Waf1/Cip1) deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21(Waf1/Cip1) suffices to protect neurons from apoptosis. We identify p21(Waf1/Cip1) as a novel antiapoptotic factor for postmitotic neurons and implicate p21(Waf1/Cip1) as the molecular target of neuroprotection by high-dose glucocorticoids.
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PMID:Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21(Waf1/Cip1) as a novel mechanism of neuroprotection by glucocorticoids. 1746 69

Our previous studies demonstrated that a significant fraction of interleukin-8 (IL-8) in lung fluids from patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 immune complexes). Neutrophils have been implicated in the pathogenesis of ALI/ARDS, and moreover, it is well-established that apoptosis of neutrophils is delayed in patients with ALI/ARDS. The aim of this study was, therefore, to examine the role of anti-IL-8:IL-8 immune complexes in modulating spontaneous apoptosis of normal human neutrophils. Apoptosis was assessed by evaluating morphological changes, measuring enzymatic activity of caspase-3, and determining the extent of DNA degradation. We found that samples containing anti-IL-8:IL-8 immune complexes but not samples from which these complexes were removed inhibited neutrophil apoptosis. Furthermore, the former samples or effectively anti-IL-8:IL-8 complexes induced an increase in the level of antiapoptotic protein, Bcl-X(L). In contrast, levels of proapoptotic proteins Bax and Bak were decreased in the same conditions. Activity of both caspase-3 and caspase-9 was also suppressed by anti-IL-8:IL-8 complex-containing samples. Finally, we established that IgG receptor, FcgammaRIIa, mediates antiapoptotic activity of anti-IL-8:IL-8 complexes and that the key components of the FcgammaRIIa signaling pathway, Src, Syk, PI3 kinase, and ERK, may be involved in regulation of neutrophil apoptosis by the complexes. These studies demonstrate for the first time that anti-IL-8:IL-8 immune complexes have the ability to prolong neutrophil life.
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PMID:Anti-IL-8 autoantibody:IL-8 immune complexes suppress spontaneous apoptosis of neutrophils. 1751 55

We recently demonstrated the activation of phosphatidylinositol 3-kinase (PI3-K/Akt) survival pathway in Jurkat T leukemia cells known for their sensitivity to the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/Apo2L cytotoxic action. The present investigation was done to elucidate the role of cAMP-response element-binding (CREB) protein in this system. Jurkat T cells were treated with 100-1,000 ng/ml TRAIL for time intervals up to 24 h in the presence or absence of selective pharmacologic inhibitors of PI3-K/Akt (LY294002) or p38 MAPK (SB253580) pathways. Upon TRAIL treatment, a dose-dependent increase in the percentage of apoptotic cells as well as in caspase-3 activity was observed. A further enhancement of apoptotic cell death was obtained with the use of CREB1 siRNA technology, as demonstrated by flow cytometry. Western blot analysis showed a high constitutive level of CREB phosphorylation at Ser(133) in Jurkat T cells under normal serum culture conditions. Under low serum culture conditions, an early (within 1 h) and transient increase in CREB phosphorylation was detected in response to both TRAIL doses and reduced upon pre-treatment with LY294002 or SB253580, demonstrating the PI3-K/Akt- and p38 MAPK-dependency of this effect. The parallel analysis in immune fluorescence demonstrated the nuclear translocation of the phosphorylated form upon treatment with 100 ng/ml TRAIL, whereas the immune labeling was mainly detectable in the cytoplasm compartment upon the higher more cytotoxic dose. These results let us hypothesize that CREB activation can be an important player in the complex cross-talk among pro- and anti-apoptotic pathways in this peculiar cell model.
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PMID:PI3-K/Akt-dependent activation of cAMP-response element-binding (CREB) protein in Jurkat T leukemia cells treated with TRAIL. 1757 44


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