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)

CD4 cross-linking by HIV gp120 triggers CD4+ T cell death. Several authors have suggested that this effect is mediated by CD95, but this possibility is debated by other authors. In a previous work, we found by co-capping that gp120(451) and gp120MN, but not gp120(IIIB), induce lateral association of CD4 with CD95 on the T cell surface. In this work, we used fluorescence resonance energy transfer to confirm that CD4/CD95 lateral association is induced by gp120(451), but not gp120(IIIB). Moreover, we found that gp120 ability to induce the CD4/CD95 association correlates with ability to induce cell death, since gp120(451) and gp120MN induced higher levels of cell death than did gp120(IIIB) in PHA-derived CD4+ T cell lines. CD95 involvement in gp120-induced cell death was confirmed by showing that gp120(451) and gp120MN did not induce death in CD4+ T cells derived from patients with autoimmune/lymphoproliferative disease (ALD) and decreased CD95 function. Cell death induced by gp120MN was inhibited by a recombinant CD95/IgG.Fc molecule blocking the CD95/CD95L interaction. However, inhibition was late and only partial. These data suggest that the gp120-induced CD4/CD95 association exerts a dual effect: an early effect that is independent of CD95L and may be due to direct triggering of CD95 by gp120, and a late effect that may be due to sensitization of CD95 to triggering by CD95L. In line with the former effect, cell treatment with gp120MN activated caspase 3 in the presence of Fas/IgG.Fc, which shows that cell death induced by gp120MN independently of CD95L uses the same pathway as CD95.
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PMID:The cell death-inducing ability of glycoprotein 120 from different HIV strains correlates with their ability to induce CD4 lateral association with CD95 on CD4+ T cells. 1050 74

It is commonly believed that the age-related decrease in the ratio CD28(+)/CD28(-) among CD8(+) T cells reflects replicative senescence of the lymphocytes. To verify this claim we measured the proliferation of CD8(+)CD28(+) and CD8(+)CD28(-) subsets by flow cytometry after PHA treatment of mononuclear lymphocytes from donors of different age, including centenarians. The fraction of CD28(+) cells decreases from ca. 80 to 40% (young to centenarians, respectively) with increasing age of the donors. Stimulation by PHA results in an increase in the ratio of CD28(+) relative to CD28(-) in all age groups. We found that not only CD8(+)CD28(+) but also CD8(+)CD28(-) cells were capable of proliferation. Moreover, the fraction of proliferation-competent CD28(-) cells was higher in the older donors compared with the younger ones. While PHA treatment led to apoptosis (as measured by DNA content and caspase-3 activation) of more than 20% of all lymphocytes, in the CD8(+) subset only ca. 10% died, irrespective of their CD28 status. Altogether, we showed over-representation of proliferating CD8(+)CD28(-) cells in aged people, which might not be particularly prone to undergo apoptosis.
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PMID:Proliferation and apoptosis of human CD8(+)CD28(+) and CD8(+)CD28(-) lymphocytes during aging. 1505 Feb 88

High doses of Ag can paradoxically suppress immune responses in vivo. This Ag-specific unresponsiveness (termed high dose tolerance) involves extrathymic mechanisms in mature T lymphocytes. To investigate these mechanisms, we used the in vitro model of PBL activated with anti-CD3 or PHA. In these conditions, increasing mitogen concentrations resulted in a reduction of the proliferative response, associated with an increased percentage of apoptotic cells. Apoptosis did not require prior exposure to IL-2, it was not the consequence of CD178/CD95 or TNF/TNFR interactions, and was therefore clearly distinct from activation-induced cell death. Although the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) decreased DNA fragmentation, cytochrome c release and caspase-9 and caspase-3 activation were not implicated, suggesting that this apoptosis did not primarily involve the intrinsic mitochondrial pathway. E64d, a cysteine protease inhibitor, as well as specific inhibitors of cathepsin B and cathepsin L conferred protection. We further demonstrated that cathepsin B and cathepsin L were released from the lysosomes and catalytically active in the cytosol. Release of cathepsin B and cathepsin L was the consequence of lysosomal membrane permeabilization without complete disruption of the cytosol-lysosome pH gradient. These results demonstrate a role for cathepsins in supraoptimal activation-induced apoptosis in vitro and suggest their possible participation in high dose tolerance in vivo.
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PMID:Cathepsin-dependent apoptosis triggered by supraoptimal activation of T lymphocytes: a possible mechanism of high dose tolerance. 1510 Feb 81

In this study, we investigated whether alterations in the pattern of caspase activation could be found at the level of peripheral blood mononuclear cells (PBMCs) in patients with Alzheimer's disease (AD). The results showed that in experimental conditions resembling a physiological stimulation, there was a statistically significant increase in the enzymatic activity of caspase-3, caspase-8, and caspase-9 in PBMCs from a small, but well-characterized, cohort of sporadic AD patients compared to those from a comparable control group of aged adults (AA). This was accompanied by a parallel, early increase in the cleavage activity of the same caspases. The higher level of caspase activity in PBMCs from AD compared to AA was not associated with quantitative differences in cell subset profiles. Moreover, no increase in apoptosis level, in the same experimental conditions, was found in PBMCs from this cohort of AD patients compared to those from AA. Conversely, the higher proneness to caspase activation in PBMCs from AD patients in comparison with that from AA was associated with a higher proliferative response to PHA or CD3. These data show a new dysfunction in AD patients at the PBMCs level and suggest that increased proneness to caspase activation in lymphocytes could reflect an ongoing systemic response in neurodegenerative disease with pathogenetic implications.
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PMID:Increased caspase activation in peripheral blood mononuclear cells of patients with Alzheimer's disease. 1547 98

Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G(1) arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G(1) arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors.
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PMID:Identification of c-Src as a potential therapeutic target for gastric cancer and of MET activation as a cause of resistance to c-Src inhibition. 2040 49

Apoptosis is a major mechanism regulating immune tolerance by the elimination of autoreactive T lymphocytes. A failure of activation induced cell-death (AICD) has been described in T lymphocytes from patients with multiple sclerosis (MS). The aims of this study were to evaluate AICD in T lymphocytes from patients with MS and healthy controls, and to explore the molecular mechanisms underlying the deregulation observed in apoptosis induction. PHA-induced AICD was reduced in T lymphocytes from patients with relapsing-remitting MS compared with controls. This finding was associated with a diminished expression of Fas and a failure in caspase 3 activation.
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PMID:Activation-induced cell death in T lymphocytes from multiple sclerosis patients. 2479 98

Activation of checkpoint kinase 1 (Chk1) is essential in chemoresistance of hepatocarcinoma (HCC) to 5-fluorouracil (5-FU) and other antimetabolite family of drugs. In this study, we demonstrated that PHA-767491, a dual inhibitor of two cell cycle checkpoint kinases, cell division cycle kinase 7 (Cdc7) and cyclin-dependent kinase 9 (Cdk9), has synergistic antitumor effect with 5-FU to suppress human HCC cells both in vitro and in vivo. Compared with the sole use of each agent, PHA-767491 in combination with 5-FU exhibited much stronger cytotoxicity and induced significant apoptosis manifested by remarkably increased caspase 3 activation and poly(ADP-Ribose) polymerase fragmentation in HCC cells. PHA-767491 directly counteracted the 5-FU-induced phosphorylation of Chk1, a substrate of Cdc7; and decreased the expression of the anti-apoptotic protein myeloid leukemia cell 1, a downstream target of Cdk9. In tumor tissues sectioned from nude mice HCC xenografts, administration of PHA-767491 also decreased Chk1 phosphorylation and increased in situ cell apoptosis. Our study suggests that PHA- 767491 could enhance the efficacy of 5-FU by inhibiting Chk1 phosphorylation and down-regulating Mcl1 expression through inhibition of Cdc7 and Cdk9, thus combinational administration of PHA-767491 with 5-FU could be potentially beneficial to patients with advanced and resistant HCC.
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PMID:Dual Inhibition of Cdc7 and Cdk9 by PHA-767491 Suppresses Hepatocarcinoma Synergistically with 5-Fluorouracil. 2564 58

Leukoagglutinin is one of the phytohemagglutinin isolectins isolated from Phaseolus vulgaris. In our recent study, we showed that this lectin is able to influence the growth of human cancer cells in vitro. In addition, using the acridine orange and ethidium bromide staining, we found that leukoagglutinin can induce apoptosis. In order to understand the molecular mechanisms of induction of apoptosis, we performed computational modeling with subsequent experimental verification of theoretical data in vitro. We developed computational models of leukoagglutinin interaction with pro- (FasR and TNFR) and anti-apoptotic (IGF-1 and EGFR) receptors, and confirmed that leukoagglutinin may specifically interact with these receptors. Furthermore, we proved that leukoagglutinin can induce apoptosis in cancer (HEp-2) and non-cancer (4BL) cells, and observed that PHA-L is able to induce apoptosis through the up-regulation of Bax protein and activation of the effector caspase-3 and initiator caspase-8. However, these proteins have no effect on the Bcl-2 expression level.
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PMID:Possible mechanisms of Leukoagglutinin induced apoptosis in human cells in vitro. 2762 32

Gelatin is an efficient drug delivery vehicle for attaching targeting molecules like phytohemagglutinin erythroagglutinating (PHA-E) and carrying the chemotherapeutic agent gemcitabine (GEM). Fluorescent gelatin nanoparticles (GNPs) conjugated with PHA-E and carrying gemcitabine (GNP-(PHA-E)-GEM) were synthesized by nanoprecipitation for guiding gemcitabine-loaded gelatin nanoparticles to NSCLC by PHA-E targeting. GNPs have a uniform narrow size distribution and spherical shape, and their particle size is about 290 nm. The release rate of gemcitabine from nanoparticles reached the plateau of the curve at approximately 30% within 72 hours. PHA-E conjugated nanoparticles could enhance the cellular accumulation of nanoparticles. The results showed that GNP-(PHA-E)-GEM treatment caused an increase of cell growth inhibition and cytotoxicity on NSCLC cells A-549 and H292. In an Annexin V/PI assay, treatment with GNP-(PHA-E)-GEM could induce apoptosis of cancer cells. Treatment of NSCLC cells with GNP-(PHA-E)-GEM firstly resulted in time-dependent inhibition of epidermal growth factor receptor (EGFR) and Akt phosphorylation. And it also could increase p53 phosphorylation. And then it could decrease Bad phosphorylation and increase Bax. Finally, it could result in enhancing the release of cytochrome c, which thus increases caspase-9 and caspase-3. In conclusion, GNP-(PHA-E)-GEM could induce growth inhibition and cytotoxicity, which was mediated through inhibition of EGFR phosphorylation and the switching on of p53 that causes cell apoptosis of NSCLC cells A-549 and H292. It's significant to conjugate PHA-E for targeting cancer and inhibiting EGFR phosphorylation as it could decrease the dosage of gemcitabine, which reduces side effects on normal tissue. GNP-(PHA-E)-GEM has great potential for NSCLC treatment.
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PMID:Development of gelatin nanoparticles conjugated with phytohemagglutinin erythroagglutinating loaded with gemcitabine for inducing apoptosis in non-small cell lung cancer cells. 3226 94