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)

Tissue inhibitors of metalloproteinases (TIMPs) are important regulators of matrix metalloproteinase (MMP) and adamalysin metalloproteinase activity. We previously reported that overexpression of TIMP-3 inhibits MMPs and induces apoptotic cell death in a variety of cell types and demonstrated that apoptosis is mediated through the N terminus of TIMP-3, which harbors the MMP inhibitory domain. However, little is known about the mechanisms underlying TIMP-3-induced apoptosis. Here we demonstrate that overexpression of TIMP-3 induced activation of initiator caspase-8 and -9 and promoted caspase-mediated cleavage of the death substrates poly(ADP-ribose) polymerase and focal adhesion kinase. Furthermore, TIMP-3 induced mitochondrial activation as demonstrated by loss of mitochondrial membrane potential and release of cytochrome c. Intervention studies demonstrated that overexpression of Bcl-2, the anti-apoptotic mitochondrial membrane protein, or CrmA, a viral serpin inhibitor of caspase-8, completely inhibited TIMP-3-induced apoptosis. Furthermore, a dominant-negative Fas-associated death domain mutant inhibited TIMP-3-induced death substrate cleavage and apoptotic death. Taken together, these results indicate that TIMP-3 overexpression induces a type II apoptotic pathway initiated via a Fas-associated death domain-dependent mechanism.
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PMID:Tissue inhibitor of metalloproteinase-3 induces a Fas-associated death domain-dependent type II apoptotic pathway. 1182 69

B cell susceptibility to Fas-mediated apoptosis is regulated in a receptor-specific fashion. CD40 engagement produces marked sensitivity to Fas killing, whereas surface Ig (sIg) engagement blocks Fas signaling for cell death in otherwise sensitive, CD40-stimulated B cell targets, and thus, induces a state of Fas resistance. The signaling mediator, Bruton's tyrosine kinase (Btk), is required for certain sIg-triggered responses, and Btk is reported to directly bind Fas and block Fas-mediated apoptosis. For these reasons, the role of Btk as a mediator of sIg-induced Fas resistance was examined. Dysfunction of Btk through mutation, and absence of Btk through deletion did not interfere with induction of Fas resistance by anti-Ig. This may be due, at least in part, to induction of Btk-dependent Bcl-2 family members by anti-Ig after CD40 ligand treatment. However, the susceptibility to Fas-mediated apoptosis of B cell targets stimulated by CD40 ligand alone was increased in the absence of Btk. These results indicate that Fas resistance produced by sIg triggering does not require Btk, but suggests that in certain situations Btk modulates B cell susceptibility to Fas killing.
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PMID:BCR engagement induces Fas resistance in primary B cells in the absence of functional Bruton's tyrosine kinase. 1188 37

Genetic instability is a characteristic feature of the malignant Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin's lymphoma and the lymphocytic and histiocytic (L&H) cells in lymphocyte predominant Hodgkin's lymphoma. Genetic instability can be classified into four major categories: distinct DNA mutations (microsatellite instability); numerical aberrations (chromosomal instability); structural aberrations (translocation instability); and gains and losses of chromosomal regions. In Hodgkin's lymphoma (HL), HRS cells and L&H cells show somatically mutated clonally rearranged immunoglobulin genes, thus characterizing these cells genetically as germinal center B cells. These cells furthermore show mutations of oncogenes and tumor suppressor genes in some cases (p53, IkappaBalpha, CD95/Fas). They do not, however, display microsatellite instability, as they have a proficient mismatch repair machinery. In contrast, HRS and L&H cells frequently harbor recurrent but not specific numerical and structural aberrations as detected by classical cytogenetics and fluorescence in situ hybridization analysis. Results from molecular genetic studies using comparative genomic hybridization and allelotyping (LOH) indicate typical genetic patterns in HL with gains and losses of distinct chromosomal regions. In some instances, candidate genes possibly involved in the malignant transformation of HRS cells and L&H cells have been characterized (JAK2, c-REL, MDM2). In summary, using molecular genetics it might be possible in the near future to elucidate some of the complex genetic instabilities observed in HL.
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PMID:Genetic instability in Hodgkin's lymphoma. 1207 97

The T cell costimulatory molecule CD28 is important for T cell survival, yet both the signaling pathways downstream of CD28 and the apoptotic pathways they antagonize remain poorly understood. Here we demonstrate that CD4(+) T cells from CD28-deficient mice show increased susceptibility to Fas-mediated apoptosis via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. Protein kinase B (PKBalpha/Akt1) is an important serine/threonine kinase that promotes survival downstream of PI3K signals. To understand how PI3K-mediated signals downstream of CD28 contribute to T cell survival, we examined Fas-mediated apoptosis in T cells expressing an active form of PKBalpha. Our data demonstrate that T cells expressing active PKB are resistant to Fas-mediated apoptosis in vivo and in vitro. PKB transgenic T cells show reduced activation of caspase-8, BID, and caspase-3 due to impaired recruitment of procaspase-8 to the death-inducing signaling complex (DISC). Similar alterations are seen in T cells from mice which are haploinsufficient for PTEN, a lipid phosphatase that regulates phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) and influences PKBalpha activity. These findings provide a novel link between CD28 and an important apoptosis pathway in vivo, and demonstrate that PI3K/PKB signaling prevents apoptosis by inhibiting DISC assembly.
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PMID:CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. 1216 62

The focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) are protein-tyrosine kinases that are overexpressed and activated in human breast cancer. To determine the role of EGFR and FAK survival signaling in breast cancer, EGFR was stably overexpressed in BT474 breast cancer cells, and each signaling pathway was specifically targeted for inhibition. FAK and EGFR constitutively co-immunoprecipitated in EGFR-overexpressing BT474 cells. In low EGFR-expressing BT474-pcDNA3 vector control cells, inhibition of FAK by the FAK C-terminal domain caused detachment and apoptosis via pathways involving activation of caspase-3 and -8, cleavage of poly(ADP-ribose) polymerase, and caspase-3-dependent degradation of AKT. This apoptosis could be rescued by the dominant-negative Fas-associated death domain, indicating involvement of the death receptor pathway. EGFR overexpression did not inhibit detachment induced by the FAK C-terminal domain, but did suppress apoptosis, activating AKT and ERK1/2 survival pathways and inhibiting cleavage of FAK, caspase-3 and -8, and poly(ADP-ribose) polymerase. Furthermore, this protective effect of EGFR signaling was reversed by EGFR kinase inhibition with AG1478. In addition, inhibition of FAK and EGFR in another breast cancer cell line (BT20) endogenously overexpressing these kinases also induced apoptosis via the same mechanism as in the EGFR-overexpressing BT474 cells. The results of this study indicate that dual inhibition of FAK and EGFR signaling pathways can cooperatively enhance apoptosis in breast cancers.
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PMID:Dual inhibition of focal adhesion kinase and epidermal growth factor receptor pathways cooperatively induces death receptor-mediated apoptosis in human breast cancer cells. 1216 18

Intercellular adhesion molecule-1 (ICAM-1) works as one of the ligands for activating the killing activity of natural killer (NK) cells and cancer specific cytotoxic T lymphocytes (CTL). Expression of ICAM-1 enhances lymphocyte adhesion to the cancer cells in vivo. Cancer cell lines express significantly lower level of ICAM-1 than that of normal epithelium or benign cells. Overexpression of LIGHT (LIGHT: homologous to lymphotoxins, indicating inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator [HVEM/TR2]) in MDA-MB-231 human breast cancer cells was observed to suppress tumor growth in vivo. In order to elucidate the mechanisms how LIGHT overexpression could trigger tumor suppression, the expression level of a panel of cell surface makers CD54, CD56, CD95, and CD119 was investigated in a group of cancer cells. Flow cytometry analysis results demonstrate that LIGHT gene expression in cancer cells can greatly increase ICAM-1 expression level, IFNgamma alone can stimulate cancer cells to express ICAM-1, which can be highly augmented by LIGHT in a dose-dependent manner. This upregulation of ICAM-1 expression is not only at ICAM-1 protein trafficking level on cell surface as demonstrated by flow cytometry analysis, but also at ICAM-1 total protein level as confirmed by Western blot. There is no difference of expression level among these cancer cell lines for the other three cell surface markers: CD56, CD95 (Fas), and CD119. It was confirmed that LIGHT enhancement upregulation of ICAM-1 expression is at least STAT1 and JAK1 dependent by using STAT1-deficient U3A and JAK1-deficient E2A4 cells. These findings suggest that LIGHT-induced inhibition of tumor growth is highly correlated with its upregulation of ICAM-1 expression.
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PMID:Light stimulates IFNgamma-mediated intercellular adhesion molecule-1 upregulation of cancer cells. 1265 Oct 68

K562 cells express the fusion protein BCR-ABL and have been shown to be relatively more resistant to apoptosis induction by chemotherapeutic agents. We show that Actinomycin D (Act D) induces time- and dose-dependent apoptosis in K562 cells. Act D causes early activation of caspase-3 followed by inhibition of the expression of the anti-apoptotic proteins BCR-ABL and Bcl-xl. Act D-induced apoptosis is associated with cytoplasmic translocation and cleavage of the multifunctional nuclear protein RNA helicase A (RHA). RHA has roles in transcription and RNA metabolism and has been shown to be cleaved during Fas mediated apoptosis. These results suggest that Act D causes caspase-3 activation and apoptosis in BCR-ABL positive K562 cells and that RHA cytoplasmic translocation and cleavage occur in chemotherapy-induced apoptosis.
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PMID:The actinomycin D-induced apoptosis in BCR-ABL-positive K562 cells is associated with cytoplasmic translocation and cleavage of RNA helicase A. 1268 Feb 54

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

Canstatin, a 24-kDa peptide derived from the C-terminal globular non-collagenous (NC1) domain of the alpha2 chain of type IV collagen, was previously shown to induce apoptosis in cultured endothelial cells and to inhibit angiogenesis in vitro and in vivo. In this report, we demonstrate that canstatin inhibits the phosphorylation of Akt, focal adhesion kinase, mammalian target of rapamycin, eukaryotic initiation factor-4E-binding protein-1, and ribosomal S6 kinase in cultured human umbilical vein endothelial cells. It also induces Fas ligand expression, activates procaspases 8 and 9 cleavage, reduces mitochondrial membrane potential, and increases cell death (as determined by propidium iodide staining). Canstatin-induced activation of procaspases 8 and 9 as well as the induced reduction in mitochondrial membrane potential and cell viability were attenuated by the forced expression of FLICE-inhibitory protein. Canstatin-induced procaspase 8 activation and cell death were also inhibited by a neutralizing anti-Fas antibody. Collectively, these data indicate that canstatin-induced apoptosis is associated with phosphatidylinositol 3-kinase/Akt inhibition and is dependent upon signaling events transduced through membrane death receptors.
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PMID:Canstatin inhibits Akt activation and induces Fas-dependent apoptosis in endothelial cells. 1287 80

Crosslinking of Fas (APO-1/CD95) on the surface of T cells initiates a biochemical cascade leading to programmed cell death. We have previously shown that crosslinking of Fas with an apoptosis-inducing IgM anti-Fas mAb results in suppression of the CD3-initiated cell signaling including Ca2+ mobilization and protein tyrosine phosphorylation. We conducted experiments to decipher the mechanisms whereby the cross talk between the Fas- and CD3 signaling pathways occur. We used lysates from Jurkat T and examined the composition of the TCR zeta chain-precipitated immune complexes using immunoblots. While crosslinking of Fas affected the association of p59fyn and p56lck tyrosine kinases with the TCR zeta chain to a limited degree, it dramatically inhibited the association of the protein tyrosine kinase ZAP70 with the zeta chain. In cells that were preincubated with an apoptosis-inducing anti-Fas mAb, the binding of the protein tyrosine phosphatases SHP-1 to the TCR zeta chain was increased. These experiments indicate that crosslinking of Fas interferes with early T cell signaling events by promoting the recruitment of SHP-1 and decreasing the association of protein tyrosine kinases with TCR zeta chain. Therefore, crosslinking of Fas antigen may regulate the antigen-induced T cell response and play an active role in the T cell anergy.
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PMID:Crosslinking of Fas/CD95 suppresses the CD3-mediated signaling events in Jurkat T cells by inhibiting the association of the T-cell receptor zeta chain with src-protein tyrosine kinases and ZAP70. 1463 36


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