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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Widespread use of MCF-7 human breast carcinoma cells as a model system for breast cancer has led to variations in these cells between different laboratories. Although several reports have addressed these differences in terms of proliferation and estrogenic response, variations in sensitivity to apoptosis have not yet been described. Tumor necrosis factor alpha (TNF-alpha) has been shown to both induce apoptosis and inhibit proliferation in MCF-7 cells. We observed that TNF-alpha inhibited proliferation in MCF-7 cell variants from three different laboratories (designated M, L, and N). MCF-7 M cells were resistant to TNF-alpha-induced apoptosis, whereas MCF-7 L cells were moderately resistant to the effect of TNF-alpha. A third variant, MCF-7 N, underwent apoptosis when exposed to TNF-alpha. Analysis of the p55 TNF-alpha receptor (TNFR) 1 expression revealed the greatest expression in MCF-7 N cells, whereas the MCF-7 L and M cells expressed 89 and 67% of MCF-7 N cell TNFR1 levels, respectively. Ceramide generation occurred in all three variants in response to TNF-alpha treatment, with MCF-7 N cells expressing the greatest increase. Cleavage of the CPP32/caspase 3 substrate poly(ADP-ribose) was observed in MCF-7 N and L cells as early as 3 and 6 h, respectively, but poly(ADP-ribose) cleavage was not observed in MCF-7 M cells. The delayed protease activation in the L variant may represent the mechanism by which these cells display delayed sensitivity to TNF-a-induced apoptosis. Expression of the Bcl-2, Mcl-1, Bcl-X, Bax, and Bak proteins was analyzed to determine whether the differences in MCF-7 cell sensitivity to apoptosis could be correlated to the differential expression of these proteins. Whereas Bak, Bcl-X, and Mcl-1 levels were identical between variants, the levels of Bcl-2 were 3.5-3.8-fold higher and the levels of Bax were 1.5-1.7-fold lower in the resistant variants (M and L) as compared with those of the sensitive variant (N). Taken together, these results suggest that differences in susceptibility to TNF-alpha-induced apoptosis among MCF-7 breast cancer cell variants may be explained by differences in TNFR expression, ceramide generation, differential expression of the Bcl-2 family of proteins, and protease activation.
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PMID:Differences in susceptibility to tumor necrosis factor alpha-induced apoptosis among MCF-7 breast cancer cell variants. 981 3

Injection of mouse recombinant TNF to mice induced apoptosis and detachment of the enterocytes of the tip of the villi, evident after 30 to 90 minutes, which resulted in a shrinkage of the villi. Injection of TNF increased the expression of caspase 1, 2, 3, and 6 as well as of cathepsin D in the mucosal wall, which was maximal 30 minutes after TNF injection. Caspase 1 and 3 were not induced in TNFR1-deficient mice in which TNF does not induce apoptosis and detachment. The administration of a caspase inhibitor (ZVAD-fmk, 300 microg) decreased enterocyte detachment and apoptosis, as well as villus atrophy, whereas a caspase 3 inhibitor (Z-DEVD-cmk) had no effect. The results indicate that the induction of caspases by TNF is the cause of their detachment in the lumen and of the resulting villus atrophy.
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PMID:TNF-induced enterocyte apoptosis and detachment in mice: induction of caspases and prevention by a caspase inhibitor, ZVAD-fmk. 1021 2

Tumor necrosis factor alpha (TNFalpha) generates a potent cytotoxic effect, however many cancer cells are resistant to TNFalpha-mediated killing and the cause of the differential sensitivity remains to be elucidated. In this study, we demonstrated that TNFalpha induced cell death in four different human colon cancer cell lines. The degree of cytotoxic effect was different in each cell line, in that HCT-15 was relatively sensitive, while DLD-1, HT-29 and WiDr were relatively resistant. TNFalpha induced apoptotic changes such as morphological changes, DNA fragmentation and activation of caspase-3 in HCT-15, but to a lesser degree in the others. Transcriptional expression of TNFR1(p55), as well as that of FLICE, Fas, FADD, DR3, FAF, TRADD, and RIP was similar in these cell lines, indicating that the susceptibility to TNFalpha-induced apoptosis may not be determined by the constitutive expression level of these factors. Interestingly, the cytotoxic effect of TNFalpha was well correlated with the DNA binding activity of NF-kappaB in the colon cancer cell lines. Further, the overexpression of a non-phosphorylated mutant form of IkappaBalpha enhanced the cytotoxicity of TNFalpha in the resistant cell line, DLD-1, indicating that NF-kappaB activity may determine the sensitivity of colon cancer cells to TNFalpha-induced apoptosis. Thus, our results indicate that modulation of NF-kappaB activity may provide a useful tool to sensitize colon cancer cells to TNFalpha treatment.
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PMID:Activation of NF-kappaB determines the sensitivity of human colon cancer cells to TNFalpha-induced apoptosis. 1078 20

A RIP-like protein, RIP3, has recently been reported that contains an N-terminal kinase domain and a novel C-terminal domain that promotes apoptosis. These experiments further characterize RIP3-mediated apoptosis and NF-kappaB activation. Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system. The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia. RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-x(L), dominant-negative FADD, as well as the general caspase inhibitor Z-VAD. Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2). However, caspase-1, -6, -8 and -9 inhibitors had little or no effect on RIP3-mediated apoptosis. Mutational analysis of RIP3 revealed that the C-terminus of RIP3 contributed to its apoptotic activity. This region is similar, but distinct, to the death domain found in many pro-apoptotic receptors and adapter proteins, including FAS, FADD, TNFR1, and RIP. Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity. RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis.
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PMID:The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. 1081 27

CD40, a tumor necrosis factor (TNF) receptor (TNFR) family member, conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. The ability of CD40 to mediate apoptosis in carcinoma cells is intriguing given the fact that the CD40 cytoplasmic C terminus lacks a death domain homology with the cytotoxic members of the TNFR superfamily, such as Fas, TNFR1, and TNF-related apoptosis-inducing ligand (TRAIL) receptors. In this study, we have probed the mechanism by which CD40 transduces death signals. Using a trimeric recombinant soluble CD40 ligand to activate CD40, we have found that this phenomenon critically depends on the membrane proximal domain (amino acids 216 to 239) but not the TNFR-associated factor-interacting PXQXT motif in the CD40 cytoplasmic tail. CD40-mediated cytotoxicity is blocked by caspase inhibitors, such as zVAD-fmk and crmA, and involves activation of caspase 8 and caspase 3. Interestingly, CD40 ligation was found to induce functional Fas ligand, TRAIL (Apo-2L) and TNF in apoptosis-susceptible carcinoma cells and to up-regulate expression of Fas. These findings identify a novel proapoptotic mechanism which is induced by CD40 in carcinoma cells and depends on the endogenous production of cytotoxic cytokines and autocrine or paracrine induction of cell death.
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PMID:CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily. 1089 90

The effect of tumor necrosis factor-alpha (TNF-alpha) on neuronal viability has been investigated in the SK-N-BE neuroblastoma cell line. These cells undergo differentiation upon chronic treatment with retinoic acid. Exposure of SK-N-BE cells to TNF-alpha produced a proliferative response in undifferentiated cells, whereas a reduced cell number was observed in retinoic acid (RA)-differentiated cultures. This biphasic response may be related to the different expression of TNF-alpha receptors (TNFRs); a significant increase in the density of TNFR1 was in fact observed following RA-induced differentiation. Under these conditions, a pronounced increase in the formation of ceramide-1-phosphate (which was prevented by the selective inhibitor of phosphatidylcholine-specific phospholipase C, D609) and an activation of caspase-3 upon TNF-alpha challenge were evident. Selective blockade of each TNFR subtype allowed a more detailed analysis of the effect observed. Preincubation with an anti-TNFR1 antibody prevented the cytotoxic effect of TNF-alpha in RA-differentiated SK-N-BE cells, whereas the anti-TNFR2 antibody blocked the proliferative activity of the cytokine in undifferentiated cultures.
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PMID:Relative contribution of different receptor subtypes in the response of neuroblastoma cells to tumor necrosis factor-alpha. 1093

Tumor necrosis factor-alpha (TNF-alpha) expression has been documented extensively in animal models of traumatic spinal cord injury (SCI). However, the pathophysiological significance of TNF-alpha expression in the injured cord remains to be delineated. The TNF receptor (TNFR)-nuclear factor-kappaB (NF-kappaB) signal transduction pathway is important for maintaining cell viability. NF-kappaB exerts anti-apoptotic effects via an endogenous caspase inhibitory system mediated by cellular inhibitor of apoptosis protein 2 (c-IAP2). NF-kappaB transactivates c-IAP2 to inhibit caspase-3 activation. Progressive cell death, including morphological and biochemical features suggestive of apoptosis, has been noted after SCI. We explored the effects of TNFR1 or TNFR2 deletion on the apoptotic events downstream of NF-kappaB in relation to SCI pathology and functional recovery. Nuclear proteins from the injured cords of the TNFR1(-/-) mice had a reduced NF-kappaB binding activity compared with the wild-type controls. This decrease in NF-kappaB activation was accompanied by a reduction in c-IAP2 expression and an increase in the active form of caspase-3 protein. After SCI the TNFR1(-/-) mice had greater numbers of apoptotic cells, a larger lesion size, and worse functional recovery than wild-type mice. TNFR2-deficient mice had a similar, although not as pronounced, consequence as the TNFR1(-/-) mice. These findings support the argument that the TNFR-NF-kappaB pathway is beneficial for limiting apoptotic cell death after SCI and that a defective TNFR-NF-kappaB pathway results in a poorer neurological outcome. A worse functional outcome in TNFR(-/-) mice suggests that an endogenous apoptosis inhibitory mechanism mediated by TNFR activation, NF-kappaB, and c-IAP2 may be of pathophysiological importance.
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PMID:Tumor necrosis factor receptor deletion reduces nuclear factor-kappaB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. 1151 51

We demonstrated that 4 mM butyrate induces apoptosis in murine peritoneal macrophages in a dose- and time-dependent manner as indicated by studies of cell viability, flow cytometric analysis of annexin-V binding, DNA ladder pattern and the determination of hypodiploid DNA content. The activity of caspase-3 was enhanced during macrophage apoptosis induced by butyrate and the caspase inhibitor z-VAD-FMK (100 microM) inhibited the butyrate effect, indicating the major role of the caspase cascade in the process. The levels of butyrate-induced apoptosis in macrophages were enhanced by co-treatment with 1 microg/ml bacterial lipopolysaccharide (LPS). However, our data indicate that apoptosis induced by butyrate and LPS involves different mechanisms. Thus, LPS-induced apoptosis was only observed when macrophages were primed with IFN-gamma and was partially dependent on iNOS, TNFR1 and IRF-1 functions as determined in experiments employing macrophages from various knockout mice. In contrast, butyrate-induced macrophage apoptosis was highly independent of IFN-gamma priming and of iNOS, TNFR1 and IRF-1 functions.
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PMID:Butyrate induces apoptosis in murine macrophages via caspase-3, but independent of autocrine synthesis of tumor necrosis factor and nitric oxide. 1184 19

The destruction of CD4 T cells in human immunodeficiency virus (HIV) infection is associated with activation of apoptotic programs, partly mediated by death receptors. The role of CD95L/CD95 in depletion of patients' CD4 T cells is well documented, but the possible contribution of the tumor necrosis factor/tumor necrosis factor receptor (TNF/TNFR) pathway has not been examined. In this study, we found that both TNFR1 and TNFR2 induced marked apoptosis in peripheral T cells from HIV-infected persons, involving both CD4 and CD8 T cells. Longitudinal follow-up of HIV(+) patients suggests an association between the in vivo evolution of CD4 T-cell numbers and variations in susceptibility to TNFR-induced apoptosis. Analysis of molecular mechanisms involved showed that it was not related to altered ex vivo expression of TNFR1-associated death domain, receptor interacting protein, or TNFR-associated factor 2. Susceptibility to TNFR-mediated apoptosis was rather related to Bcl-2 expression, because patients' T cells expressing high levels of Bcl-2 were completely protected from TNFR1- and TNFR2-induced cell death, whereas T cells expressing normal levels of Bcl-2 were not protected in patients in contrast to controls. Early recruitment of caspase-8 and caspase-3 is needed to transduce the apoptotic signals, and expression of both caspases in their active form was detected in blood T cells from HIV(+) patients, whereas it was hardly detected in controls. Moreover, ligation of TNFRs induced increased activation of both caspases in patients' T cells. Together these data demonstrate that exacerbated TNFR-mediated cell death of T cells from HIV-infected individuals is associated with both alteration of Bcl-2 expression and activation of caspase-8 and caspase-3 and may contribute to the pathogenesis of acquired immunodeficiency syndrome.
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PMID:Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3. 1186 Dec 82

The activation of the extracellular signal-regulated kinases (ERKs) by tumour necrosis factor-alpha (TNF) receptors (TNFRs) is an integral part of the cytokine's pleiotropic cellular responses. Here we report differences in the caspase sensitivity and TNFR subtype activation of members of the ERK family. Inhibition in HeLa cells of caspase function by pharmacological inhibitors or the expression of CrmA (cytokine response modifier A), a viral modifier protein, blocks TNF-induced apoptosis or caspase-dependent protein kinase Cdelta and poly(ADP-ribose) polymerase protein degradation. TNFR1- or TNFR2-stimulated c-Jun N-terminal kinase (JNK) activity was attenuated in cells in which caspase activity was inhibited either by pharmacological blockers or CrmA expression. Both TNFR1- and TNFR2-stimulated JNK activity was caspase-sensitive; however, only TNFR1 was capable of stimulating p42/44 mitogen-activated protein kinase (MAPK) and p38 MAPK activities. TNFR1-stimulated p42/44 MAPK and p38 MAPK activities were insensitive to pharmacological caspase inhibition or CrmA. These findings were supported when measuring TNF-induced cytosolic phospholipase A(2) activation, which is a downstream target for MAPK and p38 MAPK. Profiling caspase enzymes activated by TNF in HeLa cells showed sequential caspase-8, -3, -7, -6 and -9 activation, with their inhibition characteristics suggesting a role for caspase-3 and/or caspase-6 in modulating JNK activity. Taken together these results show delineated ERK-activation pathways employed by TNFR subtypes.
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PMID:Tumour necrosis factor-induced activation of c-Jun N-terminal kinase is sensitive to caspase-dependent modulation while activation of mitogen-activated protein kinase (MAPK) or p38 MAPK is not. 1199 67


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