Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor (scatter factor) (HGF/SF) is a pleiotrophic mediator of epithelial cell motility, morphogenesis, angiogenesis, and tumorigenesis. HGF/SF protects cells against DNA damage by a pathway from its receptor c-Met to phosphatidylinositol 3-kinase (PI3K) to c-Akt, resulting in enhanced DNA repair and decreased apoptosis. We now show that protection against the DNA-damaging agent adriamycin (ADR; topoisomerase IIalpha inhibitor) requires the Grb2-binding site of c-Met, and overexpression of the Grb2-associated binder Gab1 (a multisubstrate adapter required for epithelial morphogenesis) inhibits the ability of HGF/SF to protect MDCK epithelial cells against ADR. In contrast to Gab1 and its homolog Gab2, overexpression of c-Cb1, another multisubstrate adapter that associates with c-Met, did not affect protection. Gab1 blocked the ability of HGF/SF to cause the sustained activation of c-Akt and c-Akt signaling (FKHR phosphorylation). The Gab1 inhibition of sustained c-Akt activation and of cell protection did not require the Gab1 pleckstrin homology or SHP2 phosphatase-binding domain but did require the PI3K-binding domain. HGF/SF protection of parental MDCK cells was blocked by wortmannin, expression of PTEN, and dominant negative mutants of p85 (regulatory subunit of PI3K), Akt, and Pak1; the protection of cells overexpressing Gab1 was restored by wild-type or activated mutants of p85, Akt, and Pak1. These findings suggest that the adapter Gab1 may redirect c-Met signaling through PI3K away from a c-Akt/Pak1 cell survival pathway.
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PMID:The multisubstrate adapter Gab1 regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNA repair. 1143 54

The cytokine hepatocyte growth factor/scatter factor (HGF/SF) has been found to protect a variety of epithelial and cancer cell types against cytotoxicity and apoptosis induced by DNA damage, but the specific apoptotic signaling events and the levels at which they are blocked by HGF/SF have not been identified. We found that treatment of MDA-MB-453 human breast cancer cells with adriamycin (also known as doxorubicin, a DNA topoisomerase IIalpha inhibitor) induced a series of time-dependent events, including the mitochondrial release of cytochrome c and apoptosis-inducing factor, mitochondrial membrane depolarization, activation of a set of caspases (caspase-9, -3, -7, -2, and -8), cleavage of poly(ADP-ribose) polymerase (PARP), and up-regulation of expression of the Fas ligand. All of these events were blocked by preincubation of the cells with HGF/SF. In contrast, the pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone blocked some of these events (e.g. caspase-3 activation and PARP cleavage) but did not block cytochrome c release or mitochondrial depolarization. These findings suggest that HGF/SF functions, in part, upstream of the mitochondria to block mitochondrial apoptosis signaling, prevent activation of multiple caspases, and protect breast cancer cells against apoptosis.
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PMID:Hepatocyte growth factor/scatter factor blocks the mitochondrial pathway of apoptosis signaling in breast cancer cells. 1157 Dec 97

The cytokine hepatocyte growth factor/scatter factor (HGF/SF) protects epithelial and cancer cells against DNA-damaging agents via a pathway involving signaling from c-Met --> phosphatidylinositol-3- kinase --> c-Akt. However, the downstream alterations in gene expression resulting from this pathway have not been established. On the basis of cDNA microarray and semiquantitative RT-PCR assays, we found that MDA-MB-453 human breast cancer cells preincubated with HGF/SF and then exposed to Adriamycin (ADR), a DNA topoisomerase II inhibitor, exhibit an altered pattern of gene expression, as compared with cells treated with ADR only. [HGF/SF+ADR]-treated cells showed altered expression of genes involved in the DNA damage response, cell cycle regulation, signal transduction, metabolism, and development. Some of these alterations suggest mechanisms by which HGF/SF may exert its protective activity, e.g., up-regulation of polycystic kidney disease-1 (a survival-promoting component of cadherin-catenin complexes), down-regulation of 51C (an inositol polyphosphate-5-phosphatase), and down-regulation of TOPBP1 (a topoisomerase IIB binding protein). We showed that enforced expression of the cdc42-interacting protein CIP4, a cytoskeleton-associated protein for which expression was decreased in [HGF/SF+ADR]-treated cells, inhibited HGF/SF-mediated protection against ADR. The cDNA microarray approach may open up new avenues for investigation of the DNA damage response and its regulation by HGF/SF.
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PMID:Altered gene expression pattern in cultured human breast cancer cells treated with hepatocyte growth factor/scatter factor in the setting of DNA damage. 1169 28

The mechanisms by which growth factors trigger signal transduction pathways leading to protection against apoptosis are of great interest. In this study, we investigated the effect of hepatocyte growth factor (HGF/SF) and epidermal growth factor (EGF) on adriamycin (ADR)-induced apoptosis. Treatment of human epithelial MKN74 cells with ADR, a DNA topoisomerase IIalpha inhibitor, caused apoptosis. However, cells pretreated with HGF/SF, but not those pretreated with EGF, were resistant to this apoptosis. The protective effect of HGF/SF against the ADR-induced apoptosis was abolished in the presence of either LY294002, an inhibitor of phosphatidylinositol-3'-OH kinase (PI3-K) or 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, an inhibitor of Akt, thus implicating the activation of PI3-K-Akt signaling in the antiapoptotic action of HGF/SF. Immunoblotting analysis revealed that HGF/SF stimulated the sustained phosphorylation of Akt for several hours but that EGF stimulated the phosphorylation only transiently. Furthermore, ADR-induced activation of caspase-9, a downstream molecule of Akt, was inhibited for at least 24 h after HGF/SF stimulation, but it was not affected by EGF stimulation. Cell-surface biotin-labeling analysis showed that the HGF/SF receptor remained on the cell surface until at least 30 min after HGF/SF addition but that the EGF receptor level on the cell surface was attenuated at an earlier time after EGF addition. These results indicate that HGF/SF, but not EGF, transmitted protective signals against ADR-induced apoptosis by causing sustained activation of the PI3-K-Akt signaling pathway. Furthermore, the difference in antiapoptotic capacity between HGF/SF and EGF is explained, at least in part, by the delayed down-regulation of the HGF/SF receptor.
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PMID:Suppression of adriamycin-induced apoptosis by sustained activation of the phosphatidylinositol-3'-OH kinase-Akt pathway. 1457 Sep 4

The cytokine scatter factor/hepatocyte growth factor (HGF/SF) protects epithelial, carcinoma, and other cell types against cytotoxicity and apoptosis induced by DNA-damaging agents such as ionizing radiation and adriamycin (ADR, a topoisomerase IIalpha inhibitor). We investigated the role of nuclear factor kappa B (NF-kappaB) signaling in HGF/SF-mediated protection of human prostate cancer (DU-145) and Madin-Darby canine kidney (MDCK) epithelial cells against ADR. HGF/SF caused the rapid nuclear translocation of the p65 (RelA) subunit of NF-kappaB associated with the transient loss of the inhibitory subunit IkappaB-alpha. Exposure to HGF/SF caused the activation of an NF-kappaB luciferase reporter that was blocked or attenuated by the expression of a mutant 'super-repressor' IkappaB-alpha. Electrophoretic mobility shift assay supershift assays revealed that HGF/SF treatment induced the transient binding of various NF-kappaB family proteins (p65, p50, c-Rel, and RelB) with radiolabeled NF-kappaB-binding oligonucleotides. The HGF/SF-mediated protection of DU-145 and MDCK cells against ADR (demonstrated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays) was abrogated by the IkappaB-alpha super-repressor. The ability of HGF/SF to activate NF-kappaB signaling was dependent on c-Akt --> Pak1 (p21-associated kinase-1) signaling (with Pak1 downstream of c-Akt) and was inhibited by the tumor suppressor PTEN (phosphatase and tensin homolog). Inhibitors of phosphatidylinositol-3'-kinase and Src family kinases significantly inhibited HGF/SF-mediated activation of NF-kappaB, while inhibitors of MEK, protein kinase C, and p70 S6 kinase had a modest effect or no effect on NF-kappaB activity. HGF/SF induced the expression of several known NF-kappaB target genes (cIAP-1 (cellular inhibitor of apoptosis-1), cIAP-2, and TRAF-2 (TNF receptor-associated factor-2)) in an NF-kappaB-dependent manner; HGF/SF blocked the inhibition of expression of these genes by ADR. Experimental manipulation of expression of these genes suggests that they (particularly TRAF-2 and cIAP-2) contribute to the protection against ADR by HGF/SF. These findings suggest that HGF/SF activates NF-kappaB through a c-Akt --> Pak1 signaling pathway that is also dependent on Src, and that NF-kappaB contributes to HGF/SF-mediated protection against ADR.
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PMID:Role of NF-kappaB signaling in hepatocyte growth factor/scatter factor-mediated cell protection. 1568 34