Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small cell lung cancer (SCLC) is a difficult disease to treat and sometimes has overexpression or mutation of c-Met receptor tyrosine kinase. The effects of c-Met/hepatocyte growth factor (c-Met/HGF, ligand for c-Met) on activation of reactive oxygen species (ROS) was determined. HGF stimulation of c-Met-overexpressing H69 SCLC cells (40 ng/ml, 15 min) resulted in an increase of ROS, measured with fluorescent probe 2'-7'-dichlorofluorescein diacetate (DCFH-DA) or dihydroethidine (DHE) but not in c-Met-null H446 cells. ROS was increased in juxtamembrane (JM)-mutated variants (R988C and T1010I) of c-Met compared with wild-type c-Met-expressing cells. ROS was significantly inhibited by preincubation of SCLC cells with pyrrolidine dithiocarbamate (PDTC, 100 microM) and/or SU11274 (small molecule c-Met tyrosine kinase inhibitor, 2 microM) for 3 h. PDTC and SU11274 also abrogated the HGF proliferative signal and cell motility in a cooperative fashion. H(2)O(2) treatment of SCLC cells (over 15 min) led to phosphorylation of c-Met receptor tyrosine kinase and further upregulated downstream phosphorylation of phospho-AKT, ERK1/2, and paxillin in a dose-dependent manner (125 microM to 500 microM). c-Met is an important target in lung cancer, and the pathways responsible for ROS generation together may provide novel therapeutic intervention.
Am J Physiol Lung Cell Mol Physiol 2007 Jun
PMID:Activation of HGF/c-Met pathway contributes to the reactive oxygen species generation and motility of small cell lung cancer cells. 1732 84

Alterations in the c-Met/HGF system are frequently observed in various types of tumors and can directly influence tumor progression. In particular, the c-Met/HGF system can influence progression of lung tumors. The altered c-Met and HGF expression occurs in non-small-cell lung carcinomas. In this work we analyzed changes in c-Met and HGF expression in non-small-cell lung carcinomas by comparing expression levels with those in adjacent non-malignant tissues using semi-quantitative PCR. The c-Met transcript was detected in 50% of squamous cell carcinoma samples with an elevated level observed in 2 out of 25 cases (8%). HGF expression was detected only in two squamous cell carcinomas. At the same time, the c-Met transcript was observed in all 5 studied adenocarcinoma samples with an increased level compared to adjacent non- malignant tissue in 3 cases. HGF transcript was found in 2 adenocarcinoma samples. Therefore, c-Met rather than HGF transcript is frequently observed in non-small-cell lung carcinomas, especially in adenocarcinomas. According to the results of other studies, the c-Met transcript can serve as an indicator of the aggressive behavior and progression of non-small-cell lung carcinomas.
Mol Gen Mikrobiol Virusol 2007
PMID:[c-Met and HGF expression in non-small-cell lung carcinomas]. 1759 53

The von Hippel-Lindau (VHL) gene is located on the short arm of chromosome 3, the mutations of which lead to the development of von Hippel-Lindau disease. The VHL gene is a putative tumour suppressor gene in VHL and a few other conditions, possibly by negative regulation of hypoxia- inducible factor-1 (HIF-1) and the stromal-derived factor-1 (SDF-1) receptor, CXCR4, via which the VHL protein negates angiogenesis and tumour cell migration. The current study investigated the expression of VHL at the mRNA and protein levels in clinical breast tumours and evaluated the impact of VHL on the invasion of human breast cancer cells in vitro. Primary breast cancer samples (n=124), adjacent non-cancerous breast tissues obtained from patients in cohort (n=33) and a panel of human breast cancer cells (n=12) were used. Tissue distribution of VHL protein in human breast cancer tissues was assessed using immunohistochemical analysis, and VHL transcript was determined using quantitative reverse transcription PCR. Breast cancer cell line MDA-MB-231 was transfected with a human VHL expression construct (pCR3-GFP/VHL) to allow forced overexpression of VHL in the cells. Invasiveness and migration of cancer cells were assessed using the Matrigel invasion and Cytodex-2 migration assays. Statistical analysis was performed using the Student's t-test. Our results showed that breast cancer cell lines MCF-7 and ZR-75-1 expressed very high levels of VHL transcripts, but the highly aggressive MDA-MB-231, MDA-MB-435 and MDA-MB-453 expressed either no VHL or a low level. The levels of VHL transcripts were significantly lower in grade 2 and grade 3 tumours (mean +/- SD, 1.36+/-0.55 and 0.9+/-0.37), compared with grade 1 tumours (12.3+/-7.6, p<0.002). Node-positive tumours had lower levels of VHL than node-negative tumours. Although tumours from patients with metastasis and from those who died of breast cancer had low levels of VHL, the most significant reduction in VHL was seen in tumours which developed local recurrence (p=0.03). The staining of VHL protein was most abundant in mammary epithelial cells and moderate in endothelial cells. Tumour cells in breast tissues had low to moderate VHL staining. pCR3-GFP/VHL-transfected MDA-MB-231 (MDA-MB-231VHL+) exhibited a reduced spontaneous in vitro invasiveness (14.8+/-2.7) compared with the control cells (18.4+/-1.4). MDA-MB-231VHL+ cells also lost their invasion response to HGF/SF, an invasion-inducing cytokine. The MDA-MB-231VHL+ cells had substantially reduced motility compared with that of the controls (14.8+/-0.7 for MDA-MB-231VHL+ and 20.7+/-1.2 for the control; p<0.001). Thus, VHL exerts inhibitory effects on the invasive and migratory capacity of breast cancer cells in vitro. Low levels of VHL occur in most aggressive breast tumours. Taken together, VHL is a powerful putative tumour suppressor gene in human breast cancer.
Int J Mol Med 2007 Oct
PMID:The expression of the von Hippel-Lindau gene product and its impact on invasiveness of human breast cancer cells. 1778 94

Therapeutic angiogenesis can be induced by the implantation of bone marrow cells (BMCs). However, the mechanism of BMC-mediated neovascularization remains to be clarified. We investigated the differential activities of bone marrow subpopulations in angiogenesis and cytokine production. BMCs were separated into positive and negative fractions by surface expression of Mac-1, Gr-1, CD19, and c-kit, respectively. After 7 days of culture in the presence of vascular endothelial growth factor (VEGF), the cells produced adherent cells which incorporate acetylated low-density lipoprotein (acLDL). Mac-1(+) and Mac-1(-) cells produced almost equal numbers of acLDL(+) cells, but only Mac-1(-) cells expressed endothelial markers, including Flk-1, vWF, and CD31. Similarly, the expression of endothelial markers was detected in Gr-1(-), CD19(-), and c-kit(+) BMC fractions at 7-day cultures, but not in Gr-1(+), CD19(+), or c-kit(-) cells. In contrast, freshly isolated Mac-1(+) and Gr-1(+) BMCs expressed higher levels of mRNAs for angiogenic cytokines (including VEGF-A, FGF-2, and HGF) than Mac-1(-) and Gr-1(-) cells, respectively. Moreover, Mac-1(+)/c-kit(+) BMC subpopulation expressed higher levels of VEGF-A and SDF-1 mRNAs than other subpopulations. These data demonstrate that a relatively small proportion of VEGF-cultured adherent cells are true endothelial cells with a Flk-1(+)/vWF(+)/CD31(+) phenotype. Moreover, endothelial stem/progenitor cells (EPCs) are limited primarily to Mac-1(-), Gr-1(-), and c-kit(+) BMC populations. In contrast, angiogenic cytokine mRNAs were also produced by Mac-1(+), Gr-1(+), and c-kit(-) BMCs, suggesting the heterogeneity of effector cell types for neovasculatization therapy.
J Mol Cell Cardiol 2007 Nov
PMID:Bone marrow subpopulations contain distinct types of endothelial progenitor cells and angiogenic cytokine-producing cells. 1790 Jun 10

We have previously determined that the HGF promoter can be transactivated by a combination of activated Src and wild-type Stat3 in the mouse breast cell lines HC11 and SP1. To determine if this pathway is of relevance for the human disease, a series of human breast and other human cells lines were examined, and the status of key proteins in these cells determined. All of the human breast cell lines exhibited strong transactivation by a combination of activated Src and Stat3. This activation was dependent on a Stat3 recognition element present at nt-95. The exception was the ErbB2 over-expressing cell line SK-BR-3 where Stat3 alone could transactivate HGF though Src augmented this effect. Increased phosphorylation of Stat3 tyrosine 705 was also observed in this line. Analysis of three ovarian cell lines revealed that Src/Stat3 expression was not able to activate the HGF promoter in two of these lines (SKOV3 and IOSE-80PC). Src/Stat3 expression did activate HGF transcription in OVCAR3 cells, but this effect was not mediated by the Stat3 site at nt-95. Stat3 phosphorylation at tyrosine 705 was observed in IOSE-80PC cells, but was insufficient to allow for activation of the HGF promoter. Human kidney (HEK293) and cervical carcinoma (HeLa) cells were also not Src/Stat3 permissive, despite high levels of Stat3 phospho-Y705. These results suggest that human breast cells are a uniquely permissive environment for HGF transactivation by Src/Stat3 which may allow for the inappropriate activation of HGF transcription during the early stages of breast transformation. This could lead to paracrine or autocrine activation of the Met receptor in breast carcinoma cells.
Mol Cancer 2007 Oct 29
PMID:A novel activating role of SRC and STAT3 on HGF transcription in human breast cancer cells. 1796 79

Uterine leiomyomas (fibroids) are benign tumors that are prevalent in women of reproductive age. Research suggests that activated receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in fibroids. In this study, a phospho-RTK array technique was used to detect RTK activity in leiomyomas compared with myometrial tissue. We found that fifteen out of seventeen RTKs evaluated in this study were highly expressed (P < 0.02-0.03) in the leiomyomas, and included the IGF-I/IGF-IR, EGF/EGFR, FGF/FGF-R, HGF/HGF-R, and PDGF/PDGF-R gene families. Due to the higher protein levels of IGF-IR observed in leiomyomas by us in earlier studies, we decided to focus on the activation of the IGF-IR, its downstream effectors, and MAPKp44/42 to confirm our earlier findings; and validate the significance of the increased IGF-IR phosphorylation observed by RTK array analysis in this study. We used immunolocalization, western blot, or immunoprecipitation studies and confirmed that leiomyomas overexpressed IGF-IRbeta and phosphorylated IGF-IRbeta. Additionally, we showed that the downstream effectors, Shc, Grb2, and MAPKp44/42 (P < 0.02-0.001) were also overexpressed and involved in IGF-IR signaling in these tumors, while IRS-I, PI3K, and AKT were not. In vitro studies showed that IGF-I (100 ng/mL) increased the proliferation of uterine leiomyoma cells (UtLM) (P < 0.0001), and that phosphorylated IGF-IRbeta, Shc, and MAPKp44/42 were also overexpressed in IGF-I-treated UtLM cells (P < 0.05), similar to the tissue findings. A neutralizing antibody against the IGF-IRbeta blocked these effects. These data indicate that overexpression of RTKs and, in particular, activation of the IGF-IR signaling pathway through Shc/Grb2/MAPK are important in mediating uterine leiomyoma growth. These data may provide new anti-tumor targets for noninvasive treatment of fibroids.
Mol Med
PMID:Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas. 1823 72

The growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor MET, the tyrosine kinase encoded by the c-MET proto-oncogene, exert major roles in cancer invasion and metastasis and are key targets for therapy. NK1 is an alternative spliced variant of HGF/SF that consists of the N-terminal (N) and first kringle (K1) domains and has partial agonistic activity. NK1 crystallizes as a head-to-tail dimer with an extensive inter-protomeric interface resulting from contacts between the two short interdomain linkers and reciprocal contacts between the N and K1 domains. Here we show that a subset of mutants at the NK1 dimer interface, such as the linker mutants Y124A or N127A or the kringle mutant V140A:I142A, bind the MET receptor with affinities comparable to wild-type NK1 but fail to assemble a dimeric, signalling competent NK1-MET complex. These NK1 variants have no detectable agonistic activity on, behave as bona fide receptor antagonists by blocking cell migration and DNA synthesis in target cells and have strong prospects as therapeutics for human cancer.
J Mol Biol 2008 Mar 28
PMID:Engineering the NK1 fragment of hepatocyte growth factor/scatter factor as a MET receptor antagonist. 1829 18

The c-Met receptor tyrosine kinase has been implicated in cellular transformation induced by mutant Ras, a commonly activated proto-oncogene in non-small cell lung cancer (NSCLC). However, the role of c-Met has not been defined in K-ras-mutant NSCLC, a disease for which no effective targeted therapeutic options currently exist. To acquire a greater understanding of its role, we used genetic and pharmacologic approaches to inhibit c-Met in mice and cultured cells. In Kras(LA1) mice, which develop premalignant lung lesions that progress to multifocal lung adenocarcinomas owing to somatic mutations in K-ras, c-Met was expressed in multiple cell types within premalignant lung lesions, and high concentrations of HGF were detected in bronchoalveolar lavage samples. Short-term treatment with PHA-665752, a c-Met inhibitor, decreased the numbers of premalignant lung lesions and induced apoptosis in tumor cells and vascular endothelial cells within lesions. In cell culture, PHA-665752 induced apoptosis of a lung adenocarcinoma cell line derived from Kras(LA1) mice (LKR-13) and a murine lung endothelial cell line (MEC). c-Met depletion by siRNA transfection induced apoptosis of MECs but not LKR-13 cells. Collectively, these findings suggest that apoptosis was an on-target effect of PHA-665752 in MECs but not in LKR-13 cells. We conclude that PHA-665752 inhibited lung tumorigenesis in Kras(LA1) mice and may provide a novel therapeutic approach to the prevention of K-ras-mutant NSCLC.
Mol Cancer Ther 2008 Apr
PMID:A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras. 1841 9

Bone marrow stromal stem cells (BMSSCs) may have potential to differentiate in vitro and in vivo into hepatocytes. Here, we investigated the effects of valproic acid (VPA) involved in epigenetic modification, a direct inhibitor of histone deacetylase, on hepatic differentiation of mouse BMSSCs. Following the treatment of 2.5 mM VPA for 72 hrs, the in vitro expanded, highly purified and functionally active mouse BMSSCs from bone marrow were either exposed to some well-defined cytokines and growth factors in a sequential way (fibroblast growth factor-4 [FGF-4], followed by HGF, and HGF + OSM + ITS + dexamethasone, resembling the order of secretion during liver embryogenesis) or transplanted (caudal vein) in mice submitted to a protocol of chronic injury (chronic i.p. injection of CCl4). Additional exposure of the cells to VPA considerably improved the in vitro differentiation, as demonstrated by a more homogeneous cell population exhibited epithelial morphology, increasing expression of hepatic special genes and enhanced hepatic functions. Further more, in vivo results indicate that the pre-treatment of VPA significantly increased the homing efficiency of BMSSCs to the site of liver injury and, additionally, for supporting hepatic differentiation as well as in vitro. We have demonstrated the usefulness of VPA in the transdifferentiation of BMSSCs into hepatocytes both in vitro and in vivo, and regulation of fibroblast growth factor receptors (FGFRs) and c-Met gene expression through post-translational modification of core histones might be the primary initiating event for these effects. This mode could be helpful for liver engineering and clinical therapy.
J Cell Mol Med 2009 Aug
PMID:Induction of hepatic differentiation of mouse bone marrow stromal stem cells by the histone deacetylase inhibitor VPA. 1870 98

We have recently established a clonal mesenchymal stem cell line (rBM25/S3) from adult rat bone marrow. The cells have practically unlimited proliferation capacity (over 300 PDL), maintaining multipotency for differentiation. In the present study, we examined the potential for rBM25/S3 cells to differentiate into insulin-secreting cells. When cultured in the presence of HGF and FGF-4 on Matrigel, rBM25/S3 cells expressed genes specific to pancreatic beta-cells as well as those specific to hepatocytes. They still maintained proliferation capacity with a doubling time of approximately 30 h. These hepato-pancreatic intermediate progenitor cells, but not the original undifferentiated rBM25/S3 cells, were induced by the overexpression of PDX-1 to produce significant amounts of insulin in a manner responding to glucose concentration in medium. The present culture system indicates a direction for further studies aimed at the realization of cell transplantation therapy for type I diabetes mellitus.
Int J Mol Med 2008 Oct
PMID:Derivation of hepato-pancreatic intermediate progenitor cells from a clonal mesenchymal stem cell line of rat bone marrow origin. 1881 50


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