Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disintegrins, the snake venom-derived arginine-glycine-aspartic acid-containing peptides, have been demonstrated to inhibit angiogenesis through induction of endothelial cell apoptosis. However, it is not clear how a disintegrin causes endothelial apoptosis. In this study, we elucidated the action mechanism of disintegrin in causing endothelial apoptosis by using rhodostomin as a tool. We showed that cell detachment was observed at the early stage of rhodostomin treatment. It was initiated through the blockade by integrin alphanubeta3 and was accelerated by a mechanical stretch from neighboring cells. Both rhodostomin and poly(HEME) induced a higher percentage of cells at G2-M phase, the cleavage of beta-catenin and poly(ADP-ribose) polymerase during apoptosis, indicating that cell detachment is a prerequisite for rhodostomin-induced apoptosis. Moreover, pp125(FAK) phosphorylation and actin cytoskeleton were affected upon rhodostomin treatment. The activation of caspase-3 but not that of caspase-9 was detected after rhodostomin treatment. In addition, general caspase inhibitors inhibited the cleavage of beta-catenin and poly(ADP-ribose) polymerase, and DNA fragmentation, whereas they did not prevent cell shape change or detachment. According to these results, we concluded that disintegrin-induced endothelial apoptosis is a complex process, not merely caused by a blockade of endothelial integrin alphanubeta3 but also by an accompanied shape change and mechanical stretches among cells.
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PMID:Disintegrin causes proteolysis of beta-catenin and apoptosis of endothelial cells. Involvement of cell-cell and cell-ECM interactions in regulating cell viability. 1272

This study shows a strong association between cell attachment to substratum and activation of beta 1-integrin-signaling with resistance to the camptothecin derivative topotecan (TPT) in breast cancer cells. We propose a mechanistic-driven approach to sensitize the cells to camptothecins. ZR-75-1 anchorage-dependent breast cancer cell line, its derivative 9D3S suspension cells (9D3S-S), and 9D3S cells attached to fibronectin-coated plates (9D3S-A) were treated with TPT (1 microM) or CPT-11 (40 microM) for 48 h. Programmed cell death (PCD), as shown by poly(ADP-ribose) polymerase (PARP), pro-caspase-3 and pro-caspase-9 cleavage, was observed in 9D3S-S cells but not in ZR-75-1 or 9D3S-A cells. Because p125 focal adhesion kinase (FAK) is a transducer in the beta 1-integrin signaling pathway, it is essential to cell adhesion and it is overexpressed in metastatic breast cancer, we hypothesized that attenuation of FAK might enhance the sensitivity of breast cancer cells to camptothecins. Moreover, inhibition of FAK gene expression by a phosphorothioated antisense oligodeoxynucleotide targeting the portion of the gene encoding amino acids 262-268, increased the sensitivity of ZR-75-1, MDA-MB-231 and MCF7 breast cancer cells to treatment with TPT or CPT-11.
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PMID:Inhibition of focal adhesion kinase by antisense oligonucleotides enhances the sensitivity of breast cancer cells to camptothecins. 1284 14

Sodium salicylate is known to induce apoptosis in a variety of cancer cells. However, the molecular mechanism for salicylate-induced apoptosis is yet unclear. Here we show that in HCT116 colon carcinoma cells, 10 mM sodium salicylate induces caspase-3 activation and degradation of its substrates, poly(ADP-ribose) polymerase (PARP), beta-catenin, and retinoblastoma (Rb). In contrast, sodium salicylate did not exert any significant effects on the expression of Fas L that is implicated in extrinsic apoptotic pathway and the levels of Bcl-2 family proteins, Bcl-2, Bcl-xsl, and Bad, which are involved in intrinsic apoptotic pathway, and anti-apoptotic molecules, c-IAP1 and HSP73. In addition, 10 mM salicylate induced p53 tumor suppressor protein that plays an important role in cell cycle arrest or apoptosis and the induction seemed to be linked to its phosphorylation at Set 15. To investigate the signal pathways for salicylate-induced apoptosis, we examined the effects of sodium salicylate on protein kinase activities. Sodium salicylate activated p38MAPK through phosphorylation at Thr 180/Tyr 182 and Akt/PKB at Ser 473, whereas it partially activated ERK1/2 through its phosphorylation at Thr 202/Tyr 204. We also show that SB203580 (a specific p38MAPK inhibitor), but not other protein kinase inhibitors (PD98059, LY294002, and wortmannin), significantly prevented salicylate-induced apoptosis. These results suggest that sodium salicylate-induced apoptosis in HCT116 colorectal cancer cells is mediated by p38MAPK.
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PMID:Sodium salicylate induces apoptosis in HCT116 colorectal cancer cells through activation of p38MAPK. 1285 2

The aim of this study was to investigate the cytotoxic activity of the third-generation nitrogen-containing bisphosphonate zoledronic acid (ZOL) as a single agent, and in combination with clinically relevant anticancer drugs, in a panel of human osteogenic sarcoma cell lines (HOS, BTK-143, MG-63, SJSA-1, G-292, and SAOS2). We found that ZOL, when used alone, reduced cell number in a dose- and time-dependent manner, due either to cell cycle arrest in S-phase or to the induction of apoptosis. In the sensitive HOS, BTK-143, and G-292 cell lines, genomic DNA fragmentation and morphological changes characteristic of apoptosis were evident, and cells became nonadherent. Induction of apoptosis in osteosarcoma cells by ZOL was associated with caspase activation. However, coaddition of the broad-spectrum caspase inhibitors, z-VAD-fmk, Boc-D-fmk, or the caspase-3-specific inhibitor z-DEVD fmk, failed to protect these cells from ZOL-induced apoptosis. Our data support a ZOL-specific induction of cell apoptosis that involves cell detachment (anoikis), and in which caspase activation occurs secondarily to, and is redundant as a mediator of cell death. The addition of geranylgeraniol, an intermediate of the mevalonate pathway, suppressed the ZOL-induced apoptosis, suggesting that the cytotoxic effects of ZOL in osteosarcoma cells were mediated by the mevalonate pathway. While treatment of osteosarcoma cells with the chemotherapeutic agents doxorubicin or etoposide decreased cell viability, combination of these agents with ZOL did not significantly augment apoptosis in any of the cell lines tested. These observations suggest that ZOL has direct effects on the proliferation and survival of osteosarcoma cells in vitro, which has implications for future therapy of osteosarcoma.
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PMID:Induction of cell death of human osteogenic sarcoma cells by zoledronic acid resembles anoikis. 1449 55

Here we describe a new approach to study apoptosis pathways using multiplex suspension arrays. Apoptosis was induced in Jurkat T cells using the protein synthesis inhibitor, anisomycin. Cells grown in 96-well plates were treated with anisomycin for up to 7 h, washed, and lysed in their respective wells. Samples of each lysate were analyzed using Beadlyte suspension arrays consisting of total Akt/PKB, phosphorylated Akt/PKB, active caspase-3, and single-stranded DNA (ssDNA)-specific Beadmate microspheres and quantified with the X-MAP system. We found that phosphorylated Akt levels dropped dramatically with 2 h or more of anisomycin treatment, whereas active caspase-3 levels rose sharply with 2 h of treatment, signifying the onset of apoptosis. Longer incubation with anisomycin showed increases in ssDNA, which is consistent with the characteristic degradation of DNA that occurs in late-stage apoptosis. This approach demonstrates how apoptosis pathways can be studied from a small amount of sample without the use of more lengthy techniques such as immunoprecipitation or Western blotting. The suspension array is being expanded to measure many other intracellular proteins including posttranslational modifications and should prove to be extremely useful for studying apoptosis and other important cellular pathways.
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PMID:Analysis of apoptotic cells using Beadlyte suspension arrays. 1451 68

We previously reported that the enterocytic differentiation of human colonic Caco-2 cells correlated with alterations in integrin signaling. We now investigated whether differentiation and apoptosis of Caco-2 cells induced by the short-chain fatty acid butyrate (NaBT) was associated with alterations in the integrin-mediated signaling pathway with special interest in the expression and activity of focal adhesion kinase (FAK), of the downstream phosphatidylinositol 3'-kinase (PI 3-kinase)-Akt pathway and in the role of the nuclear factor kappaB (NF-kappaB). NaBT increased the level of sucrase. It induced apoptosis as shown by: (1) decreased Bcl-2 and Bcl-X(L) proteins and increased Bax protein; (2) activation of caspase-3; and (3) increased shedding of apoptotic cells in the medium. This effect was associated with defective integrin-mediated signaling as shown by: (1) down-regulation of beta1 integrin expression; 2) decreased FAK expression and tyrosine phosphorylation; (3) concerted alterations in cytoskeletal and structural focal adhesions proteins (talin, ezrin); and (4) decreased FAK ability to associate with PI 3-kinase. However, in Caco-2 cells, beta1-mediated signaling failed to be activated downstream of FAK and PI 3-kinase at the level of Akt. Transfection studies show that NaBT treatment of Caco-2 cells promoted a significant activation of the NF-kappaB which was probably involved in the NaBT-induced apoptosis. Our results indicate that the prodifferentiating agent NaBT induced apoptosis of Caco-2 cells probably through NF-kappaB activation together with a defective beta1 integrin-FAK-PI 3-kinase pathways signaling.
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PMID:Butyrate-treated colonic Caco-2 cells exhibit defective integrin-mediated signaling together with increased apoptosis and differentiation. 1456 63

Ochratoxin A (OTA), a metabolite produced by strains of Aspergillus and Penicillium, has nephritogenic, carcinogenic, and teratogenic activity in animals and humans. Nanomolar concentrations of OTA promote apoptosis in a cell-type specific fashion. In this study, we have analyzed the molecular mechanism by which OTA affects COS cell adhesion and signaling resulting in an apoptotic response. OTA, at noncytotoxic doses, was able to detach collagen- and fibronectin-adherent cells from immobilized substratum. However, prior to inducing detachment of adherent cells, OTA caused apoptosis as measured by caspase-3 activation. The treatment of adherent cells by OTA caused a reduction of tyrosine phosphorylation levels of FAK and of the adapter protein paxillin. The down-regulation of FAK preceded apoptosis and cell detachment induced by OTA. The mycotoxin was also able to cause a decrease of the phosphorylation levels of the two Shc isoforms, P66 and P52, in adherent cells. Since these Shc isoforms have been implicated in the activation of protein kinase c-Src, which is required for FAK tyrosine phosphorylation, the observed dephosphorylation of FAK and of the FAK substrate paxillin by OTA could be ascribed to the early down-regulation of Shc isoforms. However, whether FAK and Shc phosphorylation contribute both to the same pathway leading to the induction of apoptosis by OTA or are involved in two parallel signaling pathways remains to be investigated.
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PMID:Ochratoxin A affects COS cell adhesion and signaling. 1457 39

Glycogen synthase kinase-3beta (GSK-3beta) is implicated in regulating apoptosis and tau protein hyperphosphorylation in Alzheimer's disease (AD). We investigated the effects of two key AD molecules, namely apoE (E3 and E4 isoforms) and beta-amyloid (Abeta) 1-42 on GSK-3beta and its major upstream regulators, intracellular calcium and protein kinases C and B (PKC and PKB) in human SH-SY5Y neuroblastoma cells. ApoE3 induced a mild, transient, Ca2+-independent and early activation of GSK-3beta. ApoE4 effects were biphasic, with an early strong GSK-3beta activation that was partially dependent on extracellular Ca2+, followed by a GSK-3beta inactivation. ApoE4 also activated PKC-alpha and PKB possibly giving the subsequent GSK-3beta inhibition. Abeta(1-42) effects were also biphasic with a strong activation dependent partially on extracellular Ca2+ followed by an inactivation. Abeta(1-42) induced an early and potent activation of PKC-alpha and a late decrease of PKB activity. ApoE4 and Abeta(1-42) were more toxic than apoE3 as shown by MTT reduction assays and generation of activated caspase-3. ApoE4 and Abeta(1-42)-induced early activation of GSK-3beta could lead to apoptosis and tau hyperphosphorylation. A late inhibition of GSK-3beta through activation of upstream kinases likely compensates the effects of apoE4 and Abeta(1-42) on GSK-3beta, the unbalanced regulation of which may contribute to AD pathology.
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PMID:Apolipoprotein E and beta-amyloid (1-42) regulation of glycogen synthase kinase-3beta. 1462 95

We have found that neuregulin-1beta (NRG-1beta) is expressed in the cardiac microvascular endothelium, and promotes the growth and survival of cardiac myocytes in culture through the activation of erbB2 and erbB4 receptor tyrosine kinases. In this study, we examined the role of NRG-1/erbB signaling in protection of cardiac myocytes from anthracycline-induced apoptosis in vitro to determine the coupling between erbB receptor subtypes and cytoprotective signaling. Treatment of neonatal rat ventricular myocytes with NRG-1beta inhibited daunorubicin-induced apoptosis as shown by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling staining for DNA fragmentation as well as flow cytometric quantification of apoptotic myocytes. Daunorubicin-induced activation of caspase-3 in cardiomyocytes was similarly inhibited by NRG-1beta. The phosphoinositol-3-kinase (PI3-kinase) inhibitor wortmannin prevented the effects of NRG-1beta on daunorubicin-induced apoptosis and activation of caspase-3. NRG-1beta treatment induced rapid activation of Akt/PKB that was inhibited by wortmannin, and adenoviral-mediated overexpression of a dominant-negative Akt prevented the protective effect of NRG-1beta. Akt activation by NRG-1beta was prevented by the tyrphostin AG1478, which we show inhibits erbB4 activation by NRG-1beta. In contrast, the erbB2-specific tyrphostin AG879 had no effect on NRG-1beta activation of Akt. Myocyte treatment with an activating antibody to erbB2 caused phosphorylation of erbB2, and led to activation of Erk but not Akt. Treatment with the erbB2 antibody had no effect on anthracycline-induced apoptosis. Thus, NRG-1beta protects against anthracycline-induced apoptosis via erbB4-dependent activation of the PI3-kinase/Akt pathway.
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PMID:Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt. 1465 73

Complestatin, a bicyclo hexapeptide from Streptomyces, was isolated as a possible regulator of neuronal cell death. In this study, we report an anti-apoptotic activity of complestatin and its underlying molecular mechanism. Complestatin blocked TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis and activation of caspase-3 and -8 at micromolar concentration levels without inhibiting the catalytic activities of these caspases. Complestatin potently induced a rapid and sustained AKT/PKB activation and Bad phosphorylation, resulting in inhibition of mitochondrial cytochrome c release. These anti-apoptotic activities of complestatin were significantly abrogated in cells expressing dominant negative AKT/PKB. Taken together, our results suggest that complestatin prevents apoptotic cell death via AKT/PKB-dependent inhibition of the mitochondrial apoptosis signal pathway. The novel property of complestatin may be valuable for developing new pharmaceutical means that will control unwanted cell death.
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PMID:Complestatin prevents apoptotic cell death: inhibition of a mitochondrial caspase pathway through AKT/PKB activation. 1467 17


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