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

Wasting of skeletal muscle (cachexia) is associated with a variety of chronic or inflammatory disorders and has long been recognized as a poor prognostic sign. It is currently accepted that the cytokine tumor necrosis factor alpha (TNF-alpha; cachectin) plays a key role in the development of this condition. TNF-alpha-induced apoptotic cell death represents a potential mechanism by which muscle wasting can occur. Evidence has accumulated that the cytokine interferon gamma (IFN-gamma) may act as a modulator of TNF-alpha signalling. Thus, the present study was designed to elucidate if TNF-alpha can directly induce apoptosis in differentiated myotubes, to assess the potential anti-apoptotic properties of IFN-gamma and to get insight into the signalling pathways implicated in the modulatory effects of IFN-gamma. Myoblasts of the murine cell line C2C12 were allowed to differentiate in a low serum containing media and myogenesis assessed by muscle specific protein expression. Non-proliferating, polynucleated, fully differentiated myotubes were obtained after seven days in differentiation media. Exposure of C2C12 myotubes to TNF-alpha for 48 h induced apoptosis characterized by enhanced caspase-3 activity, which resulted in poly(ADP-ribose) polymerase (PARP) cleavage and increased histone-associated-DNA fragmentation. These effects were fully reverted in the presence of IFN-gamma. This cytokine induced down-regulation of the subtype 2 of TNF-alpha receptors (TNF-R2), enhanced TNF-alpha-induced NF-kappaB translocation to the nucleus and binding to DNA and increased the immunoreactivity of the protein c-IAP1, a member of the inhibitor of apoptosis (IAP) gene family whose synthesis is stimulated by NF-kappaB at the transcriptional level. Together, these results demonstrate that TNF-alpha directly induces apoptosis in differentiated myotubes and suggest that the cytokine IFN-gamma, might represent a new immunoadjuvant therapeutic tool for managing cachexia.
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PMID:IFN-gamma prevents TNF-alpha-induced apoptosis in C2C12 myotubes through down-regulation of TNF-R2 and increased NF-kappaB activity. 1612 53

We studied the expression of pro-apoptotic neurotrophin receptor p75 (p75(NTR)) in human and murine retinoblastoma, compared to normal retina, and examined changes in p75(NTR) expression with the onset of apoptosis in the course of murine retinoblastoma progression, using immunohistochemistry and quantitative real-time RT-PCR. The murine retinoblastoma is induced by retinal specific expression of SV40 T-antigen (TAg), which blocks the function of the retinoblastoma protein (pRB) and related proteins, and is a well-studied model that closely simulates human retinoblastoma. The majority of human retinoblastoma either lacked or expressed decreased levels of p75(NTR) mRNA, compared to human retina. Moreover, p75(NTR) protein was not detected in any tumor studied, unlike normal retina. Like human retinoblastoma, advanced murine retinoblastoma did not express p75(NTR). However, before tumors emerged, small clusters of TAg-positive cells coexpressed p75(NTR) and activated caspase-3, a marker of apoptosis. Furthermore, in three rare human eyes containing retinoblastoma adjacent to regions resembling the benign retinal tumor retinoma, both normal retina and retinoma-like tissue expressed p75(NTR) protein, while the retinoblastoma did not. We suggest that p75(NTR) loss accompanies progression from retinoma to retinoblastoma.
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PMID:Loss of p75 neurotrophin receptor expression accompanies malignant progression to human and murine retinoblastoma. 1655 52

In our previous studies, we demonstrated the apoptotic cascades protein kinase C (PKC) delta/c-Jun NH2-terminal kinase (JNK)/Fas/caspases induced by penta-acetyl geniposide [(Ac)5GP]. However, the upstream signals mediating PKCdelta activation have not yet been clarified. Ceramide, mainly generated from the degradation of sphingomyelin, was hypothesized upstream above PKCdelta in (Ac)5GP-transduced apoptosis. Furthermore, nerve growth factor (NGF)/p75 is supposed to be involved because(Ac)5GP-induced apoptosis was demonstrated previously in glioma cells. In the present study, (Ac)5GP was shown to activate neutral sphingomyelinase (N-SMase) immediately, with its maximum at 15 min. The NGF and p75 enhanced by (Ac)5GP was inhibited when added with GW4869, the N-SMase inhibitor, indicating NGF/p75 as the downstream signals of N-SMase/ceramide. To investigate whether N-SMase is involved in (Ac)5GP-transduced apoptotic pathway, cells were treated with (Ac)5GP added with or without GW4869. It showed that N-SMase inhibition blocked FasL expression and caspase 3 activation. Likewise, p75 antagonist peptide attenuated the FasL/caspase 3 expression. The PKCdelta translocation induced by (Ac)5GP was also eliminated by GW4869 and p75 antagonist peptide. To further confirm whether N-SMase activation plays an important role in (Ac)5GP-induced apoptosis, cells were analyzed the apoptotic rate by 4', 6-diamidino-2-phenylindole (DAPI) staining. (Ac)5GP-induced apoptosis was reduced 40 and 80% by 10 and 20 microM GW4869, respectively. It indicated that N-SMase activation is pivotal in (Ac)5GP-mediated apoptosis. In conclusion, SMase and NGF/p75 are suggested to mediate upstream above PKCdelta, thus transducing FasL/caspase cascades in (Ac)5GP-induced apoptosis.
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PMID:Penta-acetyl geniposide induce apoptosis in C6 glioma cells by modulating the activation of neutral sphingomyelinase-induced p75 nerve growth factor receptor and protein kinase Cdelta pathway. 1676 91

Thyroid hormone insufficiency adversely affects cortical development; however, its effect on apoptosis modulation during cerebral cortex development is not understood. We investigated the effect of perinatal hypothyroidism on apoptosis and its mechanisms during rat cerebral cortex development. Primary hypothyroidism was induced by feeding methimazole (0.025% wt/vol) in the drinking water to pregnant and lactating rats and continued until the animals were killed (hypothyroid group). Cerebral cortices from pups were harvested at different postnatal ages (postnatal d 0, 8, 16, and 24 and adult), and apoptosis was quantitated by terminal deoxynucleotide transferase-mediated dUTP nick end labeling and cleaved caspase-3 immunoreactivity. Compared with the euthyroid, primary somatosensory cortex (S1) in the hypothyroid group exhibited enhanced apoptosis. In S1 of euthyroid rats, apoptotic cells were mostly found in cortical layers I-III and the proportion of apoptotic cells enhanced significantly in the hypothyroid group (P < 0.001). Most of the apoptotic cells were neurons, as assessed by double immunolabeling. A significantly increased activation of caspase-3 and -7, decreased levels of antiapoptotic proteins Bcl-2 and Bcl-x(L), and increased levels of proapoptotic protein Bax was observed in the developing cerebral cortex of hypothyroid rats, compared with the euthyroid (P < 0.001). In addition, hypothyroidism significantly elevated the levels of 53-kDa pro-nerve growth factor (P < 0.001) and p75 neurotrophin receptor (P < 0.001) and decreased TrkA expression. Taken together, we provide evidence for the possible contribution of pro-nerve growth factor/p75 neurotrophin receptor pathway in hypothyroidism-enhanced apoptosis during rat cortical development. Thus, the present study may help in explaining the mechanism of the deleterious effect of thyroid hormone deficiency on cerebral cortex development in children.
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PMID:Increased pro-nerve growth factor and p75 neurotrophin receptor levels in developing hypothyroid rat cerebral cortex are associated with enhanced apoptosis. 1679 16

The cyclic-AMP response element-binding (CREB) protein family of transcription factors plays a crucial role in supporting the survival of neurons. However, a cell-autonomous role has not been addressed in vivo. To investigate the cell-specific role of CREB, we used as a model developing sympathetic neurons, whose survival in vitro is dependent on CREB activity. We generated mice lacking CREB in noradrenergic (NA) and adrenergic neurons and compared them with the phenotype of the germline CREB mutant. Whereas the germline CREB mutant revealed increased apoptosis of NA neurons and misplacement of sympathetic precursors, the NA neuron-specific mutation unexpectedly led to reduced levels of caspase-3-dependent apoptosis in sympathetic ganglia during the period of naturally occurring neuronal death. A reduced level of p75 neurotrophin receptor expression in the absence of CREB was shown to be responsible. Thus, our analysis indicates that the activity of cell-autonomous pro-survival signalling is operative in developing sympathetic neurons in the absence of CREB.
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PMID:Specific ablation of the transcription factor CREB in sympathetic neurons surprisingly protects against developmentally regulated apoptosis. 1737 11

Reportedly, beta-amyloid peptides (Abeta40 and Abeta42) induce the neurodegenerative changes of Alzheimer's disease (AD) both directly by interacting with components of the cell surface to trigger apoptogenic signaling and indirectly by activating astrocytes and microglia to produce excess amounts of inflammatory cytokines. A possible cell surface target for Abetas is the p75 neurotrophin receptor (p75(NTR)). By using SK-N-BE neuroblastoma cells without neurotrophin receptors or engineered to express the full-length p75(NTR) or various parts of it, we have proven that p75(NTR) does mediate the Abeta-induced cell killing via its intracellular death domain (DD). This signaling via the DD activates caspase-8, which then activates caspase-3 and apoptogenesis. We also found a strong cytocidal interaction of direct p75(NTR)-mediated and indirect pro-inflammatory cytokine-mediated neuronal damage induced by Abeta. In fact, pro-inflammatory cytokines such as TNF-alpha and IL-1beta from Abeta-activated microglia potentiated the neurotoxic action of Aalpha mediated by p75(NTR) signaling. The pro-inflammatory cytokines probably amplify neuronal damage and killing by causing astrocytes to flood their associated neurons with NO and its lethal oxidizing ONOO- derivative. Indeed, we have found that a combination of three major pro-inflammatory cytokines, IL-1beta+IFN-gamma+TNF-alpha, causes normal adult human astrocytes (NAHA) to express nitric oxide synthase-2 (NOS-2) and make dangerously large amounts of NO via mitogen-activated protein kinases (MAPKs). Soluble Abeta40, the major amyloid precursor protein cleavage product, by itself stimulates astrocytes to express NOS-2 and make NO, possibly by activating p75(NTR) receptors, which they share with neurons, and can considerably amplify NOS-2 expression by the pro-inflammatory cytokine trio. These observations have uncovered a deadly synergistic interaction of Abeta peptides with pro-inflammatory cytokines in the neuron-astrocyte functional units of the AD brain. Finally, we have found that p75(NTR) and its DD also mediate the killing of SK-N-BE human neuroblastoma cells by the prion protein fragment PrP106-126. Thus, neurons expressing p75(NTR) as well as pro-inflammatory cytokine receptors are likely the preferential targets of Abetas and prions and the neurodegenerative diseases they cause.
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PMID:The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. 1738 78

We have demonstrated the herbal derivative penta-acetyl geniposide ((Ac)(5)GP) induces C6 glioma cell apoptosis through the critical sphingomyelinase (SMase)/nerve growth factor (NGF)/p75 and its downstream signals. It has been reported mitogen-activated protein kinase (MAPK) mediates NGF synthesis induced by SMase activation. In this study, ERK, p38 and JNK are shown to mediate (Ac)(5)GP-induced glioma cell apoptosis and elevation of NGF and p75. Treatment of PD98059 (ERK-specific inhibitor), SB203580 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor) decreases the elevation of NGF and p75 mRNA induced by (Ac)(5)GP, indicating possible transcription regulation via MAPKs. The results of nuclear extract blotting and EMSA further confirm (Ac)(5)GP maximally increases AP-1 and NF-kappaB DNA binding at 6h. Inhibition of ERK, p38 and JNK block the activation of AP-1 and NF-kappaB, suggesting these MAPKs are involved in (Ac)(5)GP-induced transcription regulation. We thereby used RT-PCR to analyze cells treated with (Ac)(5)GP, with or without AP-1 or NF-kappaB inhibitors. AP-1 inhibitor NDGA decreases NGF/p75 and expression of FasL and caspase 3 induced by (Ac)(5)GP, suggesting the importance of AP-1 in mediating NGF/p75 and their downstream apoptotic signals. However, FasL and caspase 3 do not change with the NF-kappaB inhibitor PDTC; NF-kappaB might be linked to other cellular events. Overall, we demonstrate that MAPK mediates (Ac)(5)GP-induced activation of AP-1, promoting the transcription of NGF/p75 and downstream apoptotic signals. These results further highlight the potential therapeutic effects of (Ac)(5)GP in chemoprevention or as an anti-tumor agent.
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PMID:Penta-acetyl geniposide-induced apoptosis involving transcription of NGF/p75 via MAPK-mediated AP-1 activation in C6 glioma cells. 1765 87

The mechanisms initiating post-spinal cord injury (SCI) apoptotic cell death remain incompletely understood. The p75 neurotrophin receptor (p75(NTR)) has been shown to exert both pro-survival and pro-apoptotic effects on neural cells in vitro. While a previous study had shown that there is decreased oligodendrocyte apoptosis distal to a clean partial transection injury of the cord in mice with nonfunctional p75(NTR), most human spinal cord injuries do not involve partial transections but are rather due to compression/contusion injuries with significant perilesional ischemia. Therefore, we sought to examine the role of the p75(NTR) in a clinically relevant clip compression model of SCI in p75 null mice with an exon III mutation. Mice with a functional p75(NTR) had increased caspase-9 activation at 3 days after SCI in comparison to the functionally deficient p75(NTR) mice. However, at 7 days following SCI there was no difference in the activation of the effector caspases (caspase-3 and caspase-6) at the spinal cord lesion. Moreover, at 7 days after injury, there was increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end (TUNEL) positive cell death at the injury site in the functionally deficient p75(NTR) mice. Using double labeling with TUNEL and cell specific markers we showed that the absence of p75(NTR) function increased the extent of neuronal but not oligodendroglial cell death at the injury site. This selective loss of neuronal cells after SCI was confirmed with a decrease in levels of microtubule-associated protein 2 in the p75 null mice. Furthermore, the wild-type animals had dramatically improved survival and enhanced locomotor recovery at 8 weeks after SCI when compared with the p75(NTR) null mice. Also at 8 weeks, there were significantly more neurons present at the injury site of wild-type mice when compared with p75 null mice. We conclude that the p75(NTR) receptor is integral to neuronal cell survival and endogenous reparative mechanisms after compressive/contusive SCI.
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PMID:The p75 neurotrophin receptor is essential for neuronal cell survival and improvement of functional recovery after spinal cord injury. 1770 65

Oligodendrocyte (OLG) damage leads to demyelination, which is frequently observed in ischemic cerebrovascular diseases. In this study, we investigated the effect of bone marrow stromal cells (BMSCs) on OLGs subjected to oxygen-glucose deprivation (OGD). N20.1 cells (mouse OLG cell line) were transferred into an anaerobic chamber for 3 hr in glucose-free and serum-free medium. After OGD incubation, OLG cultures were divided into the following groups: 1) OGD alone, 2) OLG cocultured with BMSCs, 3) treatment with the phosphoinostide 3-kinase (PI3k) inhibitor LY294002, 4) LY294002-treated OLGs with BMSC cocultured, and 5) anti-p75 antibody-treated OLGs. After an additional 3 hr of reoxygenation incubation, OLG viability and apoptosis were measured. The mRNA expression in the BMSCs and OLGs was analyzed using quantitative real-time PCR (RT-PCR). Serine/threonine-specific protein kinase (Akt), phosphorylated Akt (p-Akt), p75, and caspase 3 protein expressions in OLGs were measured by Western blot. Our results suggest that BMSCs produce growth factors, activate the Akt pathway, and increase the survival of OLGs. BMSCs also reduce p75 and caspase 3 expressions in the OGD-OLGs, which leads to decreased OLG apoptosis. BMSCs participate in OLG protection that may occur with promoting growth factors/PI3K/Akt and inhibiting the p75/caspase pathways. Our study provides insight into white matter damage and the therapeutic benefits of BMSC-based remyelinating therapy after stroke and demyelinating diseases.
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PMID:Bone marrow stromal cells protect oligodendrocytes from oxygen-glucose deprivation injury. 1821 88

There is increasing evidence that an augmented state of cellular oxidative stress modulates the expression of stress genes implicated in diseases associated with health disparities such as certain cancers and diabetes. Lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 autoantigen, is emerging as a survival oncoprotein that promotes resistance to oxidative stress-induced cell death and chemotherapy. We previously showed that LEDGF/p75 is targeted by autoantibodies in prostate cancer patients and is overexpressed in prostate tumors, and that its stress survival activity is abrogated during apoptosis. LEDGF/p75 has a COOH-terminally truncated splice variant, p52, whose role in stress survival and apoptosis has not been thoroughly investigated. We observed unbalanced expression of these proteins in a panel of tumor cell lines, with LEDGF/p75 generally expressed at higher levels. During apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the NH(2)-terminal PWWP domain and failed to transactivate the Hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of LEDGF/p75. Overexpression of p52 or its variants with truncated PWWP domains in several tumor cell lines induced apoptosis, an activity that was linked to the presence of an intron-derived COOH-terminal sequence. These results implicate the PWWP domain of p52 in transcription function but not in chromatin association and proapoptotic activities. Consistent with their unbalanced expression in tumor cells, LEDGF/p75 and p52 seem to play antagonistic roles in the cellular stress response and could serve as targets for novel antitumor therapies.
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PMID:Alternative splicing and caspase-mediated cleavage generate antagonistic variants of the stress oncoprotein LEDGF/p75. 1870 62


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