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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tyrosine kinase receptor c-kit and its ligand [kit ligand (KL) or stem cell factor (SCF)] exert a broad range of biological activities during organogenesis and normal cell development. Recent studies have revealed that altered c-kit levels occur in a variety of malignancies and cancer cell lines. KL has also been shown to stimulate the growth of malignant cells, as well as to promote chemotaxis. We had previously reported expression of KL in stroma cells of normal human prostate. The present study was undertaken in order to analyze the patterns of expression of c-kit and KL in a well characterized set of prostatic tissues, including normal prostate (n=4), benign prostatic hyperplasia (BPH) (n=53) and adenocarcinoma (n=46) samples. The distribution of c-kit and KL proteins was studied by immunohistochemical analyses, while transcript levels were determined by in situ hybridization with specific RNA probes on a subset of the benign and malignant tissues referred above. In addition, reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to determine levels of c-kit and KL expression in cultures of epithelial and stroma cells, as well as in the prostate cancer cell lines LNCaP, DU145 and PC3. c-kit protein in normal prostate was exclusively detected in mast cells by immunohistochemistry and in situ hybridization. However, c-kit transcripts, but not c-kit protein, were detected in low levels and with an heterogeneous pattern in basal epithelial cells of ducts and acini. c-kit in BPH was detected in epithelial cells in 9 of 53 (17%) specimens. c-kit protein expression in malignant epithelial cells was identified in 1 of 46 (2%) tumors. However, c-kit transcripts were detected in low levels by in situ hybridization in most of the tumors analyzed. KL protein and transcripts in normal prostate were detected in high levels in stroma cells. However, epithelial cells were unreactive for anti-KL antibody, but showed low levels of KL transcripts mainly in cells of the basal layer. Basal epithelial cells in hyperplastic glands showed KL expression in 13 of 53 (24%) specimens. KL protein in tumor cells was noted in 18 of 46 (39%) cases. c-kit transcripts were not found in normal prostate and in the 3 cancer cell lines analyzed by RT-PCR, however, it was present in cultured epithelial cells of BPH, and in cultures of stroma cells from both normal and BPH. The majority of cultured cell lines of epithelial and stromal origin displayed considerable levels of KL. In addition all prostate cell lines studied showed significant levels of KL transcripts. In summary, co-expression of c-kit and KL in a subset of BPH cases may suggest an autocrine mode of signaling. Data from this study reveals that altered patterns of c-kit and KL expression are associated with BPH and adenocarcinoma of prostate. It appears that KL induces mast cells proliferation and maturation and enhances their release of protease. This could explain the accumulation of mast cells at tumor sites, a phenomenon that was not observed in normal prostate or BPH samples.
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PMID:Expression of c-kit and kit-ligand in benign and malignant prostatic tissues. 1080 54

The regression of experimental and clinical pancreatic cancers by treatment with gonadotropin-releasing hormone (GnRH) agonists or antagonists has been repeatedly reported and is usually presumed to result from the creation of a sex steroid deficiency. There are, however, indications that GnRH analogs can also suppress the growth of the tumor cells in vitro and that specific binding sites for GnRH are present on membranes of these cells. The regulatory role of GnRH in rat pancreatic adenocarcinoma was investigated by examining the gene for GnRH and GnRH receptor (GnRH-R) in two pancreatic tumor cell lines (AR42J and ARIP). Reverse transcriptase polymerase chain reaction and Southern blot analysis indicated both GnRH-mRNA and GnRH-R-mRNA transcripts in the two cell lines. This is the first report raising the possibility of an autocrine/paracrine role for GnRH in rodent malignant pancreas.
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PMID:Gene expression of gonadotropin-releasing hormone and its receptor in rat pancreatic cancer cell lines. 1144 28

Actively dividing cells show progressive loss of telomeric DNA during successive rounds of replication due to end-replication problem. Telomere shortening has been proposed as a regulatory mechanism that controls the replicative capacity of primary cells before undergoing cellular senescence. In immortal cells including cancer, cellular senescence can be overcome by reactivation of telomerase or by a telomerase-independent mechanism for lengthening telomeres. In this work, we present a novel example of telomere elongation mechanism in a human stomach adenocarcinoma cell line which was selected for resistance to adriamycin. The resistant cell line (MKN/ADR) had long terminal restriction fragments (TRFs) of up to approximately 50 kb, while its parent cell line (MKN-45) had the TRFs, consisting of a smear extending from approximately 4 to approximately 25 kb. The very large TRFs in MKN/ADR cell line were proven to be telomeric by digestion with the exonuclease Bal31. When telomerase activity was examined using the PCR-based telomeric repeat amplification protocol (TRAP) assay, MKN/ADR cell line showed reduced activity to about 10% of that in MKN-45 cell line. The correlation between reduced telomerase activity and mRNA expression of telomerase subunits in MKN/ADR cell line was assessed by the reverse transcriptase-PCR analysis. The level of human telomerase reverse transcriptase (hTERT) mRNA was lower in MKN/ADR cell line than in MKN-45 cell line. This observation correlates with the finding that telomerase activity is reduced about 10-fold in MKN/ADR cell line. Reverse transcriptase-PCR analysis also revealed a close correlation between telomerase-associated protein (TP1) mRNA expression and telomerase activity in MKN/ADR cell line. In contrast, expression levels of human telomerase RNA (hTR) were identical in both MKN/ADR and MKN-45 cell lines. Taken together, these data suggest that telomeres in MKN/ADR cell line may be regulated through a novel mechanism other than telomerase. Although the basis for telomere elongation mechanism in MKN/ADR cell line is not yet understood, the occurrence of alternative mechanism for telomere elongation in drug-resistant cancer cells may have an important implication for use of telomerase inhibitors in human cancer treatment.
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PMID:A novel telomere elongation in an adriamycin-resistant stomach cancer cell line with decreased telomerase activity. 1201 44

A blood assay for detection of lung cancer biomarkers could significantly improve cancer patient prognosis and survival rates. Amplified fragment length polymorphism-differential display (AFLP-DD) was used to identify gene transcripts found in lung cancer tissue and the peripheral blood of lung cancer patients. The clones were evaluated for gene expression in lung cancer tissue, peripheral blood of lung cancer patients and healthy volunteers' blood. The isolated gene transcript clones were found to be from the syndecan 1 gene, collagen 1 gene and 2 novel genes. All 4 transcripts were expressed in normal lung tissue, 4 cultured primary lung cells and 6 lung cancer cell lines. RNA was isolated from peripheral blood samples of 69 lung cancer patients. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to test for the presence of cytokeratin 19 and the 4 gene mRNA transcripts in blood RNA. The positive detection rate of at least 1 of the 5 transcripts was 79% for lung adenocarcinoma and 62% for squamous carcinoma. Using RT-PCR, at least 1 of the markers was found in 53% of stage I patients, 100% of stage II, 71% of stage III and 81% of stage IV lung cancer patients. Blood samples from 20 healthy volunteers were also tested, but only 1 of the 5 transcripts was found in 1 patient. These new molecular markers may aid early detection, staging and follow-up of lung cancer patients by RNA isolated from blood.
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PMID:Application of differential display to identify genes for lung cancer detection in peripheral blood. 1212 10

The 5-lipoxygenase (5-LOX) pathway is critical for pancreatic cancer cell growth and escape from apoptosis. Inhibition of 5-LOX blocks proliferation and induces apoptosis in human pancreatic cancer cells. However, the expression of 5-LOX and its downstream signaling pathway have not been investigated in human pancreatic adenocarcinoma. Reverse transcriptase-polymerase chain reaction revealed expression of 5-LOX mRNA in all pancreatic cancer cell lines tested including, PANC-1, AsPC-1, and MiaPaCa2 cells, but not in normal pancreatic ductal cells. The expression of 5-LOX protein in pancreatic cancer cell lines was demonstrated by Western blotting. Finally, 5-LOX up-regulation in human pancreatic cancer tissues was verified by intense positive staining in cancer cells by immunohistochemistry. Staining for the 5-LOX protein was particularly evident in the ductal components of the more differentiated tumors but not in ductal cells in normal pancreatic tissues from cadaver donors. Immunohistochemistry also revealed strong staining of cancer tissues with an antibody to the receptor of the downstream 5-LOX metabolite, leukotriene B(4). The current study demonstrated marked expression of 5-LOX and the leukotriene B(4) receptor in human pancreatic cancer tissues. These findings provide further evidence of up-regulation of this pathway in pancreatic cancer and that LOX inhibitors are likely to be valuable in the treatment of this dreadful disease.
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PMID:5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. 1216 67

The effects of all trans retinoic acid and hyperthermia were studied in the human colon adenocarcinoma cell line HT29. Cell cytotoxicity after exposure to ATRA or heat-shock, alone or in association, was evaluated by the MTT assay while cell surface and ultrastructure modifications and actin fibre assembly changes were investigated by electron microscopy and by the FITC-phalloidin method. Apoptosis was evaluated by flow cytofluorimetry and electron microscopy. Reverse transcriptase-polymerase chain reaction was employed to study mRNA expression of genes involved in apoptosis, differentiation and growth arrest. Joint treatments were more effective in reducing the vital cell yield, being this effect only partially due to apoptosis. A marked up-regulation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 expression, not followed by any differentiation process, was responsible for growth arrest. Modulation of Hsp-70 expression, involved in cell response to treatments, was considered. Our results demonstrate that cell treatment with ATRA followed by heat-shock may elicit useful effects to treat tumours, which are responsive to retinoids, as well as those malignant cells which may be constitutively thermotolerant.
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PMID:All trans retinoic acid sensitizes colon cancer cells to hyperthermia cytotoxic effects. 1279 92

Conjugated linoleic acid (CLA) has chemoprotective properties in a variety of experimental cancer models. We have previously observed that dietary CLA inhibits colon tumorigenesis induced by 1,2-dimethylhydrazine in rats. In addition, our in vitro studies have shown that CLA inhibits DNA synthesis and induces apoptosis in HT-29 cells, the human colon adenocarcinoma cell line. The insulin-like growth factor (IGF) system regulates the growth of HT-29 cells by an autocrine mechanism. The present study examined whether the growth inhibitory effect of CLA is related to changes in the IGF system in HT-29 cells. To determine whether CLA inhibits IGF-II production, HT-29 cells were incubated in serum-free medium in the presence of various concentrations of CLA. CLA decreased protein levels of both mature and pro IGF-II and IGF-II transcripts. Whereas exogenous IGF-I and IGF-II produced an increase in cell number, neither IGF-I nor IGF-II counteracted the negative growth regulatory effect of CLA. Reverse transcriptase-polymerase chain reaction and Western blot analysis of total cell lysates revealed that CLA decreased IGF-I receptor (IGF-IR) transcript and protein levels in a dose-dependent manner. Immunoprecipitation/Western blot studies revealed that CLA inhibited IGF-I-induced phosphorylation of IGF-IR and insulin-receptor substrate (IRS)-1, recruitment of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) to IGF-IR, IGF-IR-associated PI3K activity, and phosphorylated Akt and extracellular signal-regulated kinase (ERK)-1/2 levels. In conclusion, the inhibition of cell proliferation and induction of apoptosis by CLA in HT-29 cells may be mediated in part by its ability to decrease IGF-II synthesis and to downregulate IGF-IR signaling and the PI3K/Akt and ERK-1/2 pathways.
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PMID:Conjugated linoleic acid downregulates insulin-like growth factor-I receptor levels in HT-29 human colon cancer cells. 1288 57

The prevalence of esophageal adenocarcinoma in the setting of Barrett's metaplasia continues to increase in Western nations at a rate greater than any other cancer. The trophic properties of gastrin have been documented in gastric, pancreatic and colon cancer cell lines, suggesting a potential role for this regulatory peptide in the growth of these malignancies. The aims of these studies were to identify and characterize the presence of functional cholecystokinin type-2 (gastrin) receptors on the membranes of human esophageal adenocarcinoma cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated the presence of cholecystokinin type-2 receptor transcripts in human esophageal adenocarcinoma cell lines. Competitive binding assays revealed specific binding of gastrin in SEG-1 cells (IC50 of 2.4 x 10(-8) M). This finding was confirmed by laser scanning confocal microscopy through internalization of rhodamine green labeled gastrin heptapeptide in SEG-1 cells. Gastrin caused a dose-dependent increase in proliferation of SEG-1 cells when compared to controls. This effect was abolished by co-incubation with L365,260, a CCK-2-specific receptor antagonist. Gastrin-induced phosphorylation of the p44 and p42 mitogen-activated protein kinases was demonstrated by Western blot analysis. In conclusion, the studied human esophageal adenocarcinoma cell lines possess cholecystokinin type-2 (gastrin) receptors. Receptors bind gastrin, resulting in increased proliferation in SEG-1 cells.
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PMID:Gastrin stimulates receptor-mediated proliferation of human esophageal adenocarcinoma cells. 1517 38

A new tumor cell line (SUIT-4) derived from ascites of a patient with carcinoma of the pancreas has been established in tissue culture and in nude mice, and maintained for over 7 years. In tissue culture, the cells grew as a confluent monolayer with piling up of cells in some areas. The population doubling time during the exponential phase of the cell growth was 43.9 h in vitro. Chromosome count ranged from 63 to 68 with a modal number of 67. Subcutaneous injection of cultured cells into the flanks of nude mice resulted in tumor formation with a doubling time of 88.8 h. Histopathologically, xenografts in nude mice were moderately differentiated tubular adenocarcinoma, and the tumor cells showed spontaneous metastasis to the regional lymph nodes in 6 of 21 nude mice and to the lung in 4 of 21. Transmission electron microphotographs confirmed the ductal cell origin of the carcinoma and revealed that the cells had abundant mitochondria and lysosomes. SUIT-4 cells released carcinoembryonic antigen (3.08 x 10(2) ng/1 x 10(6) cells/24 h) and carbohydrate antigen 19-9 (4.75 x 10(4) U/1 x 10(6) cells/24 h) during exponential cell growth in vitro. Reverse transcriptase-polymerase chain reaction studies revealed that SUIT-4 cells expressed matrix metalloproteinases 1, 3, 7, 10 and 14.
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PMID:Establishment and characterization of a novel human pancreatic cancer cell line (SUIT-4) metastasizing to lymph nodes and lungs in nude mice. 1545 75

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) promotes tumor progression through activation of matrix metalloproteinase (MMP) activity. MMP-9 is a gelatinase secreted by both cancer cells and surrounding stromal cells, and it contributes to TNF-alpha-stimulated tumor invasion and metastasis. Cyclin-dependent kinase 9 (CDK9), the catalytic component of positive transcription elongation factor-b, phosphorylates serine 2 residues in the C-terminal domain of RNA polymerase II for productive transcription elongation and is up-regulated upon exposure to various stresses. This study investigated roles of CDK9 in TNF-alpha-stimulated MMP-9 expression in human lung adenocarcinoma cells. CDK9 activity was inhibited using three different strategies, including the CDK9 pharmacological inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), a dominant-negative CDK9, and a CDK9-specific small interfering RNA. All three approaches reduced TNF-alpha-mediated accumulation of MMP-9 in the conditioned media as demonstrated by gelatin zymography. In contrast, transforming growth factor-beta1-induced accumulation of MMP-2 was unaffected by DRB. Expression of the MMP-9 gene was examined using reverse transcription real time PCR and using a transient transfection assay to evaluate MMP-9 promoter activity. DRB reduced the TNF-alpha-induced increase in MMP-9 mRNA levels but did not effect transforming growth factor-beta1-induced MMP-2 mRNA expression. Consistently DRB and dominant-negative CDK9 completely abrogated TNF-alpha-stimulated human MMP-9 promoter activity. TNF-alpha did not regulate expression or localization of CDK9 or its regulatory partner Cyclin T. However, TNF-alpha stimulated CDK9 binding to Cyclin T and MMP-9 gene occupancy by both CDK9 and the serine 2-phosphorylated form of RNA polymerase II. Our findings indicate that CDK9 mediates TNF-alpha-induced MMP-9 transcription. Disruption of TNF-alpha signaling using CDK9 inhibitors could serve as a potential therapeutic strategy against tumor invasion and metastasis.
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PMID:Cyclin-dependent kinase 9 is required for tumor necrosis factor-alpha-stimulated matrix metalloproteinase-9 expression in human lung adenocarcinoma cells. 1552 90


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