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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor (scatter factor) and its receptor, the c-met proto-oncogene product (c-MET), have been implicated in embryogenesis, tissue reorganization, and tumor progression. Little is known, however, of the expression and functional significance of these molecules in prostatic cells and tissue. In this investigation, we assessed the expression of hepatocyte growth factor (HGF) and c-MET in prostatic tissues and cell lines and also determined the effect of purified recombinant HGF on cell proliferation and scattering of prostatic carcinoma cell lines. HGF was expressed by human prostatic stromal myofibroblasts in primary culture but not by three human prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3) as assessed by Northern blot analysis. HGF was also detected by reverse transcriptase-polymerase chain reaction in both benign and malignant tissues from radical prostatectomy specimens. c-MET transcripts were identified by Northern blot in two androgen-insensitive human prostatic carcinoma cell lines (DU 145 and PC-3) but not the androgen-sensitive LNCaP cell line. Additional evidence of linkage of androgen responsiveness and c-MET was provided by experiments in which androgen deprivation of normal rat prostates via castration produced a marked up-regulation of c-MET expression as determined by Northern blot and immunohistochemistry. c-MET protein was detected by immunohistochemical analysis in a substantial percentage (58 of 128 or 45%) of prostatic carcinomas and was found more often in metastatic growths of human prostatic carcinoma (15 of 20 patients) compared with primary tumors (43 of 108 patients; P < 0.005). Moreover, in Dunning R-3327 rat prostatic carcinoma cell lines, c-MET expression was highest in the androgen-insensitive subline with the highest metastatic capacity. Purified recombinant human HGF induced dose-dependent cellular proliferation and scattering in the DU 145 carcinoma cell line. These data indicate that HGF may function in the prostate gland as a paracrine growth factor, with synthesis by stromal cells and with biological target cells being the epithelial cells. Expression of the HGF receptor, c-MET, is up-regulated by androgen deprivation and c-MET appears to be preferentially expressed on androgen-insensitive, metastatic cells, suggesting a possible linkage of c-MET expression with prostatic carcinoma progression.
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PMID:Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. 763 32

Highly purified progenitors (including erythroid [BFU-E], granulo-monocytic [CFU-GM], multipotent [CFU-GEMM] progenitors, as well as multipotent progenitors with self-renewal capacity [CFU-B]) express high-affinity growth factor receptors (GFRs), with prevalent interleukin-3 receptors (IL-3Rs) (2,700/cell), a > or = 10-fold lower number of IL-6Rs (145/cell) and granulocyte-macrophage colony-stimulating factor receptors (GM-CSFRs) (300/cell), and a barely detectable level of erythropoietin (Ep) receptors (75/cell). Hematopoietic growth factor (HGF) dosages inducing peak clonogenetic effects are associated with partial/subtotal occupancy of the homologous HGF receptor (HGFR). Cross-reactivity between GFRs and heterologous GFs (including IL-6, IL-3, GM-CSF, Ep, and the kit ligand [KL]) was explored by competition experiments on purified progenitors with radiolabeled and excess cold HGFs at +4 degrees C. No cross-reaction was observed between IL-6R, IL-3R, EpR, and the heterologous GFs, whereas the GM-CSFR showed cross-reactivity with IL-3 and, to a lesser extent, KL. Modulation of GFRs was examined after 18 or 40 hours of incubation with GF(s) at 37 degrees C, followed by ligand-binding assay at 20 degrees C. IL-6, IL-3, GM-CSF, and Ep induce a marked down-modulation of their own receptors. Interestingly, each GF induces the transactivation of the R(s) for the "distal" GF(s): (1) IL-6 induces transactivation of IL-3R, but not of GM-CSFR/EpR; (2) IL-3 causes a rapid upmodulation of GM-CSFR/EpR ("pure" progenitors treated with IL-3 show upmodulation of GM-CSFR alpha-chain mRNA by reverse transcriptase-polymerase chain reaction); whereas (3) GM-CSF induces the transactivation of the EpR. This chain upmodulation of HGFRs may underlie the synergistic interactions between the HGFs in clonogenetic culture. It is emphasized that KL does not induce upmodulation of the other GFRs. Finally, Ep, GM-CSF, and IL-3 do not modulate the expression of the "proximal" HGFRs (ie, GM-CSFR/IL-3R/IL-6R, IL-3R/IL-6R, and IL-6R, respectively). These results allow insight into the cellular basis of hematopoiesis, ie, the complex and coordinate interactions between HGFs and their receptors. They are compatible with a model of cascade transactivation via upmodulation of GFRs in the initial key steps of hematopoietic differentiation, whereby the action of each GF enhances the effect of the distal GF(s) by a multistep chain-potentiation mechanism.
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PMID:Cascade transactivation of growth factor receptors in early human hematopoiesis. 845 93

Myeloma cell line supernatants were screened for their ability to inhibit the activity of transforming growth factor-beta (TGFbeta) in the mink lung cell (Mv-1-Lu) bioassay. Supernatant from the human myeloma cell line JJN-3 contained potent TGFbeta antagonistic activity. This activity was isolated and found to be associated with a 72-78-kDa glycoprotein. Specific polyclonal and monoclonal antibodies were generated toward the 72-78-kDa protein, and these antibodies precipitated the TGFbeta inhibitory activity from JJN-3 supernatant. Upon amino acid sequencing the protein appeared to be identical to hepatocyte growth factor (HGF), and some of the generated antibodies directly blocked the action of recombinant HGF in various assays. By HGF-specific polymerase chain reaction we demonstrated that HGF mRNA was expressed in five out of five tested myeloma cell lines. The level of HGF protein in supernatants showed great variation from >500 ng/ml in JJN-3 supernatant to a few ng/ml in the supernatants from other myeloma cell lines. The same five cell lines were also screened for expression the HGF receptor c-MET. Four of them expressed the receptor as shown by reverse transcriptase-polymerase chain reaction and Western blot. The receptor was shown to be constitutively phosphorylated in the human myeloma cell line JJN-3. This receptor could be dephosphorylated by anti-HGF antibodies, indicating the existence of an autocrine HGF loop in this cell line. We propose that HGF/c-MET may play a role in multiple myeloma.
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PMID:Concomitant expression of hepatocyte growth factor/scatter factor and the receptor c-MET in human myeloma cell lines. 879 32

Scatter factor (SF), also known as hepatocyte growth factor, is angiogenic in systemic tissue, and SF titers correlate with the malignancy and metastatic phenotype of certain systemic cancers. Human gliomas express SF and its receptor c-met, but their role in the malignant progression of these tumors has not been defined. To examine this, 9L glioma cells that express c-met but not SF were transfected with human SF cDNA, and their behavior in vitro and in vivo was examined. SF gene expression was detected in conditioned medium of 9L-SF but not in control 9L-neo-transfected cell lines, by reverse transcriptase-PCR, immunoblot, ELISA, and scatter activity assays. Gliomas derived from 9L-SF and control 9L-neo cell lines implanted in the caudate/putamen of Fisher 344 rats (intracranially) and in the flanks of SCID/Beige mice (subcutaneously) were examined. Extracts from intracranial (i.c.) gliomas contained elevated levels of SF protein as determined by ELISA (1 to 5.5 ng SF/mg protein), whereas no SF was detected in control tumors. Reverse transcriptase-PCR of RNA from i.c. gliomas revealed that only 9L-SF gliomas expressed SF and both 9L-neo and 9L-SF gliomas expressed the c-met SF receptor. By postimplantation Day 14, 9L-SF i.c. gliomas were approximately 5-fold larger than 9L-neo control tumors (p < 0.001). Subcutaneous 9L-SF glioma growth was also greater than that in controls, although the differences were more variable. SF-producing i.c. gliomas contained elevated levels of 48-kd urokinase (3.5-fold) and 92-kd type IV collagenase (2.8-fold), both enzymes that correlate with the malignant progression of human gliomas (p < 0.001). SF-producing and control 9L cell lines did not differ in rates of proliferation, thymidine incorporation, or adhesion-independent growth in vitro. Conditioned medium from 9L-SF cells stimulated thymidine incorporation into microvessel brain endothelial cells 3- to 4-fold higher than did CM from 9L-neo controls (p < 0.001). Intracranial 9L-SF gliomas were more angiogenic than controls based on elevated peak (2.25-fold; p < 0.005) and mean (1.7-fold; p < 0.008) blood vessel densities. These results suggest that SF production by glioma cells enhances glioma malignancy in vivo, in part, by paracrine mechanisms involving glioma-associated angiogenesis.
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PMID:Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo. 911 17

The Met protooncogene encodes the tyrosine kinase receptor for the hepatocyte growth factor (HGF), a potent mitogen for hepatocytes and other epithelial cells produced by mesenchymal cells. Many of the studies on the physiologic and neoplastic growth of the liver, as well as other organs, have been performed in the rat. Therefore, chromosomal mapping of the rat Hgf gene and the gene of its receptor is of particular value. To achieve this, a probe of the coding part of rat HGF cDNA was used to isolate four genomic probes from a lambda phage rat genomic library. These probes were used to map the Hgf gene to Chromosome (Chr) 4q12 by the FISH technique. To obtain a probe for the mapping of the HGF receptor/Met gene, we cloned the complete coding region of the rat HGF receptor mRNA. Complementary DNA (cDNA) was synthesized with reverse transcriptase from total RNA for use as a template for the PCR. The two PCR primers were designed based on human and mouse sequences and were located in the flanking regions of the open reading frame of the HGF receptor mRNA. Amplification resulted in a band of an estimated size of 4.1 kb, which was cloned and sequenced. The nucleotide sequence showed about 93% and 85% homology compared with mouse and human HGF receptor sequences, respectively. A full-length probe of the coding part of the cDNA was used to map the rat HGF receptor/Met gene to Chr 4q21 by the FISH technique. Therefore, the rat Hgf and HGF receptor/Met genes are located relatively close to each other, in a way similar to humans but not mice.
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PMID:Chromosomal localization of rat hepatocyte growth factor (Hgf) and HGF receptor (Met) and characterization of HGF receptor cDNA. 927 68

Hepatocyte growth factor acts differently depending on the organs or tumours involved. It may be produced simultaneously with its receptor, c-Met, in several types of malignant tumour cells and may exercise an autocrine regulation. To analyse the effect of hepatocyte growth factor in human prostate cancer, we conducted immunohistochemistry, in situ hybridization and the reverse transcriptase polymerase chain reaction. The first two techniques revealed the growth factor in prostate cancer cells, and the polymerase chain reaction confirmed this expression. c-Met is expressed in prostate cancer cells, but not in interstitial cells. Hepatocyte growth factor is expressed in interstitial cells, especially in hormone-treated cancer tissue, indicating that the growth factor pathway changes with the hormonal status. Low-grade tumours expressed c-Met at the plasma membrane. Higher grade tumours tended to express it in the cytoplasm, suggesting that the role of c-Met as the hepatocyte growth factor receptor was blocked in higher grade tumours. The relationship between the growth factor and its receptor is thus influenced by hormonal status and differentiation in prostate cancer and is not explained simply in terms of autocrine or paracrine action.
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PMID:Co-expression of hepatocyte growth factor and its receptor in human prostate cancer. 953 4

Met protein is a tyrosine kinase receptor for hepatocyte growth factor (HGF). c-Met has morphogenic, mitogenic, and motogenic properties and is overexpressed in many solid tumors. We studied c-met mRNA and protein expression in papillary thyroid carcinomas and nonneoplastic thyroid tissue. The c-met mRNA was detected in all biopsies by reverse transcriptase-polymerase chain reaction and by hybridization of complex cDNA probes to a c-met-specific DNA fragment in a dot blot array. Immunohistochemistry on fresh frozen biopsies showed Met protein localized along the basal cell membrane of normal thyrocytes in 32 of 35 nonneoplastic thyroid tissue specimens, sometimes associated with weak cytoplasmic reactivity but without apical cell membrane staining. In papillary carcinomas an increased Met protein expression was seen, comprising a cytoplasmic (33 of 49) and apical cell membrane (24 of 49) immunoreactivity, whereas only 1 of 49 biopsies showed basal cell membrane staining. A 145-kDa Met-specific band was detected by Western immunoblotting on protein extracts from papillary carcinomas. The tight junction protein zona occludens-1 (ZO-1), studied by immunohistochemistry, was weakly expressed along the apical cell membrane in 10 nonneoplastic biopsies. In contrast, increased and cytoplasmic/apical membranous ZO-1 immunostaining was seen in 11 of 15 papillary carcinomas. Nuclear ZO-1 staining was present in a few papillary carcinomas with partial dedifferentiation. The concomitant overexpression and subcellular redistribution of Met and ZO-1 proteins indicate a change in cell polarity in papillary carcinomas compared to nonneoplastic thyroid tissue. These observations may reflect an important feature of the tumorigenesis of papillary thyroid carcinomas. No significant association was found between semiquantitative immunohistochemical assessment of Met protein and clinical parameters in papillary carcinoma patients.
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PMID:Difference in patterns of Met expression in papillary thyroid carcinomas and nonneoplastic thyroid tissue. 1136 90

Temporal and spatial occurrence of hepatocyte growth factor (HGF) and its cognate receptor c-Met in the mouse mandibular development was investigated by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction. HGF was first recognized in the mesenchymal cells of the first branchial arch at the 10th day of gestation (E10), before tongue formation, whereas HGF receptor (c-Met) -positive myogenic cells first appeared at E11 in the center of mandibles. By E12, HGF turned to be colocalized with c-Met in the differentiating tongue myoblasts. Between E14 and E16, HGF disappeared, whereas c-Met remained, in the tongue myoblasts. The levels of HGF mRNA in the developing tongue decreased in accordance with the increase of desmin mRNA levels from E11 to E17. These in vivo results strongly suggest that the HGF/c-Met system takes part in the earlier stages of tongue development. To elucidate this hypothesis, the antisense oligodeoxyribonucleotide (A-ODN) for mouse HGF mRNA was added to the organ culture system of mandible with serumless, defined medium. Mandibular arches from E10 mouse embryos were cultured at 37 degrees C for 10 days in the absence or presence of A-ODN, control (sense) oligonucleotide (C-ODN), or A-ODN plus recombinant HGF. In the control mandibular explants cultured without HGF or ODN, the anterior two-third of the tongue derived from the first branchial arch was formed. It contained abundant desmin-positive myoblasts and was equivalent to the tongue of E14-E15. In contrast, in the presence of A-ODN in the medium, neither the swelling nor myogenic cells were found in the tongue-forming region of explants, and myogenic cells accumulated behind the tongue-forming region. Such dysplasia of tongue was never induced in the presence of C-ODN or A-ODN plus recombinant HGF in the medium. The effect of A-ODN appeared to be developmental stage-specific, because tongue dysplasia occurred when A-ODN was present during the earlier 4 days but not during the later 4 days of the culture. Furthermore, recombinant HGF added to the culture without ODNs during the earlier 4 days caused elevation in the number of mitotic myoblasts. These results suggest that HGF regulates both the migration and proliferation of myogenic cells during the earlier stages of tongue development.
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PMID:Hepatocyte growth factor is essential for migration of myogenic cells and promotes their proliferation during the early periods of tongue morphogenesis in mouse embryos. 1183 82

Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental cirrhosis is associated with hepatic cell hypoxia, we herein investigated whether hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver. Cirrhosis was induced by diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular hypoxia and proliferation 24 hours after a two-thirds partial hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to hypoxia using anaerobic jars. Hepatocyte growth factor (HGF) and c-Met expressions were determined by reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats, hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats, hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under hypoxia. Our results suggest that hepatocellular hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.
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PMID:Hepatocyte growth factor and c-Met inhibition by hepatic cell hypoxia: a potential mechanism for liver regeneration failure in experimental cirrhosis. 1183 82

Liver metastasis is one of the poor prognostic factors for gastric cancer. Hepatocyte growth factor (HGF) and its receptor, c-Met, have been reported to be related to the proliferation of carcinoma cells. We examined c-Met and HGF expression in stage IV gastric cancers (n = 121) and compared the results in groups with liver metastasis (n = 47, LM group) and without liver metastasis (n = 74, no-LM group). The survival rate for the LM group was significantly poorer than for the no-LM group (p < 0.01). We found a high frequency of c-Met expression in the LM group compared with the no-LM group at protein level detected by immunohistochemistry (p = 0.0005) and at mRNA level detected by semiquantitative reverse transcriptase-polymerase chain reaction (p = 0.0386) in primary gastric tumors. Furthermore, we evaluated HGF expression in both carcinoma cells and stromal cells in gastric cancers. There was no significant difference in the HGF expression between the LM and no-LM groups. The labeling index of proliferating cell nuclear antigen for the carcinomas in the LM group was higher than that in the no-LM group (47.1 +/- 24.5 vs. 26.2 +/- 24.5%, p < 0.0001). Thus, the high frequency of c-Met overexpression in carcinoma cells may be involved in the mechanism of liver metastasis in gastric cancers. Moreover, the evaluation of c-Met expression might be a useful indicator of liver metastasis in patients with gastric cancer.
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PMID:c-Met expression in gastric cancer with liver metastasis. 1238 9


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