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

A cDNA encoding mouse hepatocyte growth factor (HGF) has been cloned and completely sequenced by use of reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent cloning. Sequence analysis reveals that mouse HGF, similar to its human and rat counterparts, consists of 728 amino acids, and both the alpha- and beta-chains are encoded in a single open reading frame. Strong homology exists in the primary structure of HGF among the three species of mouse, rat and human (more than 90%), especially in Kringle 1 of the alpha chain which is assumed to be an essential domain for binding of HGF to its receptor, c-MET, a proto-oncogene product. Our results suggest the existence of evolutionary pressure to conserve the distinct structure, and presumably the biological functions, of HGF.
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PMID:Molecular cloning and characterization of cDNA encoding mouse hepatocyte growth factor. 824 Dec 72

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

Delavirdine mesylate (U-90152T) is a highly specific nonnucleoside reverse transcriptase inhibitor currently under development for the treatment of AIDS. The excretion, disposition, and metabolism of delavirdine were investigated in Sprague-Dawley rats after oral administration of [14C]delavirdine mesylate at single doses ranging from 10 to 250 mg/kg and multiple doses ranging from 20 to 250 mg/kg/day. Excretion studies showed that feces was the major route of elimination, delavirdine was well absorbed (>80%) after a 10 mg/kg single dose, and excretion was dose-dependent. The metabolism of delavirdine in the rat was extensive. The following metabolites were identified (% of dose in rats given 10 and 100 mg/kg, respectively): 6'-hydroxy delavirdine (7.1% and 15.6%) and its glucuronide (12.2% and 6.2%) and sulfate (5.5% and 3.2%) conjugates, despyridinyl delavirdine (12.1% and 11.7%) and its conjugate (13.0% and 11.7%), desalkyl delavirdine (16.5% and 13.4%), and its N-sulfamate, 6'- and 4'-sulfate conjugates (2.9% and 3.9%). Cleavage of the amide bond in delavirdine to give N-isopropylpyridinepiperazine and indole carboxylic acid constituted a minor pathway. Degradation of 6'-hydroxy delavirdine generated despyridinyl delavirdine and the pyridine-ring opened MET-14. The metabolic pathway of delavirdine involved N-desalkylation, pyridine ring hydroxylation, pyridine ring cleavage, and amide bond cleavage.
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PMID:Metabolism of the human immunodeficiency virus type 1 reverse transcriptase inhibitor delavirdine in rats. 902 54

Hepatocyte growth factor/scatter factor (HGF/SF) is secreted by mesenchymal cells and elicits proliferation, motility, differentiation, and morphogenesis of epithelia and other cells. These effects are mediated by binding to MET, a receptor tyrosine kinase. Genetically engineered mice lacking HGF/SF die in utero due to a failure of placental and hepatocyte differentiation, but little information exists regarding the expression of this signaling system in human development. Using reverse transcriptase-polymerase chain reaction, Western blots, and immunohistochemistry, we report that HGF/SF and MET are expressed during critical early periods of human organogenesis from 6 to 13 wk of gestation. Organs that expressed both genes included liver, metanephric kidney, intestine, and lung, each of which develop by inductive interactions between mesenchyme and epithelia. Of all organs studied, the placenta contained the highest levels of HGF/SF protein, and MET was detected in trophoblastic cells of chorionic villi as early as the 5th wk of gestation. Finally, examination of a human multicystic dysplastic kidney demonstrated that malformed, hyperproliferative tubules expressed MET, whereas HGF/SF protein was immunolocalized to the same epithelia and also to the surrounding undifferentiated cells. Hence HGF/SF might be an important growth factor in normal human embryogenesis and may additionally play a role in human organ malformations.
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PMID:Expression of hepatocyte growth factor/scatter factor and its receptor, MET, suggests roles in human embryonic organogenesis. 912 88

The hepatocyte growth factor (HGF)/c-MET signaling system plays an important role in the carcinogenesis of various organs. We investigated the expression of HGF and its receptor c-MET by immunohistochemistry (IHC) in 69 cases of synovial sarcoma and compared the findings with clinicopathologic parameters, proliferating activities evaluated by MIB-1 labeling index (MIB-1 LI), and patients' prognosis. Furthermore, mRNA analysis of HGF, c-MET, and SYT-SSX fusion gene was performed by reverse transcriptase-polymerase chain reaction (RT-PCR) in 22 concordant frozen materials. Twenty-one of 69 (30.4%) tumors showed positive reaction for c-MET, whereas 22 tumors (31.9%) were positive for HGF. In 10 cases, co-expression of HGF and c-MET was observed; however, there was no significant correlation between HGF and c-MET expression. HGF expression was correlated with female patients, large tumors (more than 5 cm), the presence of rhabdoid cells, low frequency of mast cells (<20/10 HPF), high nuclear grade (grade III), and high American Joint Committee (AJC) stage (III and IV). Conversely, c-MET expression was only correlated with large tumors. However, the coexpression of HGF and c-MET was significantly correlated with large tumor size, the existence of rhabdoid cells, and high AJC stage. Both the expression of HGF and the co-expression of HGF and c-MET showed a significantly high MIB-1 LI and were correlated with poor prognosis according to univariate analysis. Multivariate Cox analysis showed that high AJC stage, the expression of HGF, and a high MIB-1 LI (12.0>) independently had a negative impact on overall survival. In 22 frozen material cases evaluated by both IHC and RT-PCR, a statistically significant correlation was found between the 2 techniques. SYT-SSX fusion transcripts were detected in all 22 cases. Three tumors had SYT-SSX2 fusion transcripts, whereas 19 had SYT-SSX1 phenotype. Our results suggest that HGF/c-MET paracrine signaling may contribute to tumorigenesis and progression in synovial sarcoma.
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PMID:Expression of hepatocyte growth factor (HGF)/scatter factor and its receptor c-MET correlates with poor prognosis in synovial sarcoma. 1068 32

Papillary thyroid carcinoma (PTC) is clinically heterogeneous. Apart from an association with ionizing radiation, the etiology and molecular biology of PTC is poorly understood. We used oligo-based DNA arrays to study the expression profiles of eight matched pairs of normal thyroid and PTC tissues. Additional PTC tumors and other tissues were studied by reverse transcriptase-PCR and immunohistochemistry. The PTCs showed concordant expression of many genes and distinct clustered profiles. Genes with increased expression in PTC included many encoding adhesion and extracellular matrix proteins. Expression was increased in 8/8 tumors for 24 genes and in 7/8 tumors for 22 genes. Among these genes were several previously known to be overexpressed in PTC, such as MET, LGALS3, KRT19, DPP4, MDK, TIMP1, and FN1. The numerous additional genes include CITED1, CHI3L1, ODZ1, N33, SFTPB, and SCEL. Reverse transcriptase-PCR showed high expression of CITED1, CHI3L1, ODZ1, and SCEL in 6/6 additional PTCs. Immunohistochemical analysis detected CITED1 and SFTPB in 49/52 and 39/52 PTCs, respectively, but not in follicular thyroid carcinoma and normal thyroid tissue. Genes underexpressed in PTC included tumor suppressors, thyroid function-related proteins, and fatty acid binding proteins. Expression was decreased in 7/8 tumors for eight genes and decreased in 6/8 tumors for 19 genes. We conclude that, despite its clinical heterogeneity, PTC is characterized by consistent and specific molecular changes. These findings reveal clues to the molecular pathways involved in PTC and may provide biomarkers for clinical use.
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PMID:Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. 1175 53

Loss of heterozygosity (LOH) on chromosome arm 7q31 is found in many prostate tumors. Such alterations are generally associated with inactivation of tumor suppressor genes. It has been shown previously that the main region of LOH at 7q31 spans the interval between the D7S486 and D7S2460 microsatellite loci, which contains several candidate tumor suppressor genes (TSG) such as TES, CAV2, CAV1, MET, CAPZA2, ST7 and WNT2. We tested 41 human sporadic prostate tumors for 7q31 LOH by using 5 polymorphic markers overlapping the critical region and used a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay to study the expression of the 7 candidate TSGs located in this genomic region. We found that CAV1, CAV2, MET and TES mRNA expression was lower in prostate tumors than in normal prostate tissues. Our immunohistochemical results and previously published data on the compartmental expression of these messenger RNAs in stromal and epithelial cells suggest that TES is the best candidate tumor suppressor gene at 7q31.
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PMID:Extensive analysis of the 7q31 region in human prostate tumors supports TES as the best candidate tumor suppressor gene. 1525 54

It has been demonstrated that exposure to cocaine increases cell death in the fetal CNS. To examine the molecular mechanisms of this effect, we employed mouse oligo microarrays followed by real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) to compare expressions of apoptosis-related genes in the cerebral wall of 18-day-old (E18) fetuses from cocaine-treated (20 mg/kg cocaine, s.c., b.i.d., E8th-E18th) and drug-naive (saline, s.c.) mice. Out of approximately 400 relevant genes in the arrays, 53 showed alterations in expression in cocaine-exposed fetuses. Upregulation was observed in 35 proapoptotic and 8 antiapoptotic genes; 4 proapoptotic and 6 antiapoptotic genes were down-regulated. The affected genes encode a wide range of apoptosis-related proteins, including death receptors (NTF-R1, NTF-R2, DR3, DR5, LTbeta-R, GITR, P57 TR-1) and their adaptor and regulatory proteins (MASGE-D1, TRAF-2, SIVA, MET, FLIP, FAIM, IAP1, ATFA), members of transcription regulatory pathways (JNK, NF-kappaB, P53), members of BCL-2 family of proteins (BID, BAD, BAX, BIK, NIP21, NIP3, NIX, BCL-2), DNA damage sensor (PARP-1), caspases and their substrates and regulatory proteins (caspases 8, 4, 9, and 3, ACINUS, CIDE-A, CIDE-B, GAS2), mitochondrially released factors (cytochrome c, AIF, PRG3), specific endoplasmic reticulum- and oxidative stress-associated factors (BACH2, ABL1, ALG2, CHOP), members of cell survival AKT and HSP70 pathways (PIK3GA, PTEN, HSP70, BAG1, BAG2), and others. This suggests that cocaine affects survival of developing cerebral cells via multiple apoptosis-regulating mechanisms.
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PMID:Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall. 1568 Nov 17

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma which is characterized by the presence of a specific chromosomal translocation encoding the chimeric transcription factor (ASPL-TFE3) that activates expression of MET. We reviewed the clinical features and treatment outcome of 12 ASPS patients. The presence of ASPL-TFE3 fusion transcripts was assessed by reverse transcriptase polymerase chain reaction. In addition, we performed immunohistochemical studies for MET, TFE3, Ki-67, and EGFR expression. Lower extremity was the most commonly affected primary site (2 thigh, 3 lower leg, and 1 foot). Of four patients who received primary cytotoxic chemotherapy, no patient demonstrated treatment response. With follow-up duration of 94.4 months, median overall survival was 53.2 (95% C.I. 40.9-65.5) months. The immunohistochemical staining demonstrated 100% TFE3 positivity (8 of 8), 75% MET positivity (6 of 8) with a strong association between TFE3 expression and MET positivity with correlation coefficient of 0.808 (P = 0.02). The high expression of MET in ASPL-TFE3 (+) ASPS may further support the potential role of targeted agents against MET in this rare, chemoresistant tumor.
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PMID:Expression of MET in alveolar soft part sarcoma. 1947 90


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