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)

Growth arrest-specific protein 6 (gas6) activity is mediated through the receptor tyrosine kinase family members Axl, Rse, and Mer, all of which are expressed in human oligodendrocytes. In this study, we examined whether recombinant human (rh) gas6 protects oligodendrocytes from growth factor (insulin) withdrawal or tumor necrosis factor-alpha (TNFalpha) cytotoxicity. In addition, we examined whether the effect was caspase-dependent, which receptor mediated the protective effect, and whether survival required Akt1 activation. Oligodendrocyte viability was assessed by O4 staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling. Addition of rhgas6 to insulin-depleted cultures resulted in a significant increase in oligodendrocyte viability. Rhgas6 and caspase inhibitors also reduced active caspase-3 immunoreactivity relative to TNFalpha-only-treated cultures. In cultures treated with TNFalpha (100 ng/ml), the oligodendrocyte survival rate was 18% compared with cultures treated with TNFalpha and rhgas6 (64%) or the caspase inhibitors IETD-fmk [z-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone] (65%) and zVAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) (63%). Increased phosphoAkt (Ser473) immunoreactivity was detected 15 min after administration of gas6 and TNFalpha to oligodendrocyte cultures but not in TNFalpha-treated cultures. The gas6 protective effect was abrogated by the Axl decoy receptor Axl-Fc, by the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one], and in Akt1(-/-) oligodendrocytes. Oligodendrocyte cultures established from wild-type and Rse(-/-) mice, but not from Axl(-/-) mice, were also protected from TNFalpha-induced cell death when maintained in rhgas6. We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death.
 ...
PMID:Gas6/Axl signaling activates the phosphatidylinositol 3-kinase/Akt1 survival pathway to protect oligodendrocytes from tumor necrosis factor alpha-induced apoptosis. 1672 20

SU11248 is an orally available type III and V receptor tyrosine kinase inhibitor. Clinical studies have shown the efficacy of SU11248 in individuals with gastrointestinal stromal tumors (GIST); however, the molecular mechanisms by which SU11248 inhibits the proliferation of these tumor cells remains to be fully elucidated. Taking advantage of GIST-T1 cells, which possess an activating mutation in exon 11 of the c-KIT gene, we examined the medicinal action of SU11248 in GIST cells. Clonogenic and MTT assays showed that SU11248 potently inhibited the proliferation of GIST-T1 cells with IC50 of approximately 1 nM and 40 nM, respectively. SU11248 (10 or 20 nM, 48 h) activated caspase-3 and induced apoptosis of GIST-T1 cells as measured by caspase assay, annexin V staining and cleavage of poly (ADP-ribose) polymerase. Western blot analyses found that SU11248 blocked autophosphorylation of c-KIT in association with inhibition of its downstream effectors, including Akt and extracellular signal-regulated kinase, but not signal transducers and activators of transcription. Interestingly, when phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling was blocked simultaneously by either LY294002 or rapamycin, growth inhibition mediated by SU11248 was potentiated. Taken together, this study supports clinical studies of SU11248 for individuals with GIST, and the combination of SU11248 and inhibitors of 3-kinase/Akt/mammalian target of rapamycin signaling represents a promising novel treatment strategy.
 ...
PMID:Effect of SU11248 on gastrointestinal stromal tumor-T1 cells: enhancement of growth inhibition via inhibition of 3-kinase/Akt/mammalian target of rapamycin signaling. 1691 20

In this report, the mechanism of the antitumor activities of Kushen flavonoids (KS-Fs) were explored. KS-Fs and kurarinone (Kur), a single flavonoid compound, were able to induce apoptosis of H460 and Eca-109 cells in vitro and H460 cells in vivo. The apoptosis inducing effect was enhanced in the presence of Taxol. In H460 xenograft mice treated with Kur, down-regulation of Bcl-2 and up-regulation of caspase 8 and caspase 3 in tumors were observed by immunohistochemical staining. In addition, KS-Fs and Kur were able to inhibit TNFalpha-induced NF-kappaB activation in 293 cells mediated by the decreased IkappaBalpha phosphorylation. Further the effects of KS-Fs and Kur on multiple receptor tyrosine kinase activities were explored. In cell-based assays, KS-Fs and Kur inhibited the EGF-induced EGF receptor phosphorylation in A431 cells and a constitutively activated Her-2 in MDA-MB-453s cells. In enzymatic assays, KS-Fs and Kur inhibited KDR, but not PDGF BR activities. In A431 xenograft mice treated with Kur, an inhibition of EGF receptor phosphorylation in tumors was observed. These results reveal a novel mechanism by which KS-Fs induces apoptosis in tumors by acting on multiple cellular targets including the inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities.
 ...
PMID:Kushen flavonoids induce apoptosis in tumor cells by inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities. 1718 93

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC(50) values, 5-20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers.
 ...
PMID:An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. 1748 55

Multiple myeloma (MM) is an invariably fatal plasma cell malignancy, primarily due to the therapeutic resistance which ultimately arises. Much of the resistance results from the expression of various survival factors. Despite this, the ribonucleoside analogue, 8-chloro-adenosine (8-Cl-Ado), is cytotoxic to a number of MM cell lines. Previously, we established that the analogue incorporates into the RNA and inhibits mRNA synthesis. Because 8-Cl-Ado is able to overcome survival signals present in MM cells and inhibits mRNA synthesis, it is likely that the drug induces cytotoxicity by depleting the expression of critical MM survival genes. We investigated this question using gene array analysis, real-time reverse transcription-PCR, and immunoblot analysis on 8-Cl-Ado-treated MM.1S cells and found that the mRNA and protein levels of the receptor tyrosine kinase MET decrease prior to apoptosis. To determine MET's role in 8-Cl-Ado cytotoxicity, we generated MM.1S clones stably expressing a MET ribozyme. None of the clones expressed <25% of the basal levels of MET mRNA, suggesting that a threshold level of MET is necessary for their survival. Additionally, the ribozyme knockdown lines were more sensitive to the cytotoxic actions of 8-Cl-Ado as caspase-3 activation and the induction of poly-ADP-ribose polymerase (PARP) cleavage were more pronounced and evident 12 h earlier than in the parental cells. We further established MET's role in MM cell survival by demonstrating that a retroviral MET RNA interference construct induces PARP cleavage in MM.1S cells. These results show that MET provides a survival mechanism for MM cells. 8-Cl-Ado overcomes MM cell survival by a mechanism that involves the depletion of MET.
 ...
PMID:Multiple myeloma cell killing by depletion of the MET receptor tyrosine kinase. 1794 23

Growth hormone (GH) is found in the developing eye, where it is synthesized by retinal ganglion cells (RGCs). In this location, GH variants appear to have an autocrine or paracrine anti-apoptotic neuroprotective role, and may contribute to the regulation of the developmental waves of apoptosis that characterize RGC differentiation. Here, we investigate the intracellular signaling pathways that are activated by GH as a neuroprotective agent in cultured chick embryo RGCs. We show that GH treatment reduces the cleavage of caspase-9, and that an inhibitor of caspase-9 cleavage can abrogate the pro-apoptotic effect of GH immunoneutralization. These findings complement previous results implicating caspase-3 in GH action on these cells. We had also previously shown that Akt pathways are involved in the neuroprotection of RGCs by GH. We now extend those findings to show that these pathways involve the activation of cytosolic tyrosine kinases (Trks) and extracellular-signal-related kinases (ERKs). Therefore, although the GH receptor, unlike other neurotrophin receptors, is not itself a receptor tyrosine kinase (receptor Trk), occupation of the receptor by GH involves downstream intracellular Trk pathways. Finally, we show that the Akt and Trk pathways converge on the activation of cAMP response element binding protein (CREB) which is able to initiate transcription of pro- or anti-apoptotic genes. These results indicate that the action of GH in the neuroprotection of embryonic RGCs involves pathways that are common to other neurotrophins, and that GH can be considered to be an authentic growth and differentiation factor in the development of the embryonic retina.
 ...
PMID:Growth hormone-mediated survival of embryonic retinal ganglion cells: signaling mechanisms. 1835 75

Interstitial cells of Cajal (ICC) are specialized mesenchyme-derived cells that regulate contractility and excitability of many smooth muscles with loss of ICC seen in a variety of gut motility disorders. Maintenance of ICC numbers is tightly regulated, with several factors known to regulate proliferation. In contrast, the fate of ICC is not established. The aim of this study was to investigate whether apoptosis plays a role in the regulation of ICC numbers in the normal colon. ICC were identified by immunolabelling for the c-Kit receptor tyrosine kinase and by electron microscopy. Apoptosis was detected in colon tissue by immunolabelling for activated caspase-3, terminal dUTP nucleotide end labelling and by ultrastructural changes in the cells. Apoptotic ICC were identified and counted in double-labelled tissue sections. They were identified in all layers of the colonic muscle. In the muscularis propria 1.5 +/- 0.2% of ICC were positive for activated caspase-3 and in the circular muscle layer 2.1 +/- 0.9% of ICC were positive for TUNEL. Apoptotic ICC were identified by electron microscopy. Apoptotic cell death is a continuing process in ICC. The level of apoptosis in ICC in healthy colon indicates that these cells must be continually regenerated to maintain intact networks.
 ...
PMID:Apoptotic cell death of human interstitial cells of Cajal. 1879 96

The epidermal growth factor (EGF) receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase that regulates diverse cell functions that are dependent upon cell type, the presence of downstream effectors, and receptor density. In addition to activating biochemical pathways, ligand stimulation causes the EGFR to enter the cell via clathrin-coated pits. Endocytic trafficking influences receptor signaling by controlling the duration of EGFR phosphorylation and coordinating the receptor's association with downstream effectors. To better understand the individual contributions of cell surface and cytosolic EGFRs on cell physiology, we used EGF that was conjugated to 900 nm polystyrene beads (EGF-beads). EGF-beads can stimulate the EGFR and retain the activated receptor at the plasma membrane. In MDA-MB-468 cells, a breast cancer cell line that over-expresses the EGFR, only internalized, activated EGFRs stimulate caspase-3 and induce cell death. Conversely, signaling cascades triggered from activated EGFR retained at the cell surface inhibit caspase-3 and promote cell proliferation. Thus, through endocytosis, the activated EGFR can differentially regulate cell growth in MDA-MB-468 cells.
 ...
PMID:Cellular localization of the activated EGFR determines its effect on cell growth in MDA-MB-468 cells. 1881 71

The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by EphA2 monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. In this report, we describe the isolation and characterization of a fully human monoclonal antibody (1C1) that selectively binds both the human and rodent EphA2 receptor. After cell binding, the antibody induces rapid tyrosine phosphorylation, internalization, and degradation of the EphA2 receptor. Because monoclonal antibodies that selectively bind tumor cells and internalize provide a vehicle for targeted delivery of cytotoxics, 1C1 was conjugated to the microtubule inhibitor monomethylauristatin phenylalanine using a stable maleimidocaproyl linker. The anti-EphA2 antibody-drug conjugate [1C1-maleimidocaproyl-MMAF (mcMMAF)] stimulated the activation of caspase-3/caspase-7 and the death of EphA2-expressing cells with IC(50) values as low as 3 ng/mL. Similarly, the conjugate induced degradation of the EphA2 receptor and inhibited tumor growth in vivo. Administration of 1C1-mcMMAF at doses as low as 1 mg/kg once weekly resulted in significant growth inhibition of EphA2-expressing tumors without any observable adverse effects in mouse xenograft and rat syngeneic tumor models. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of EphA2-expressing tumors.
 ...
PMID:A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. 1901 Sep 11

Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.
 ...
PMID:Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma. 1922 14


<< Previous 1 2 3 4 5 6 7 8 9 Next >>