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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis plays a critical role in metastasis and tumor growth. Human tumors, including colorectal adenocarcinoma, secrete angiogenic factors, inducing proliferation and chemotaxis of microvascular endothelial cells, eventually leading to tumor neovascularization. The chemokine interleukin 8 (IL-8; CXCL8) exerts potent angiogenic properties on endothelial cells through interaction with its cognate receptors CXCR1 and CXCR2. As CXCR1 and CXCR2 expression is differentially regulated in tissue-specific endothelial cells and effects of IL-8 on intestinal endothelial cells are not defined, we characterized the potential IL-8-induced angiogenic mechanisms in primary cultures of human intestinal microvascular endothelial cells (HIMEC) and IL-8 receptor expression in human intestinal microvessels. CXCR1 and CXCR2 expression on HIMEC were defined using reverse transcriptase-PCR, immunohistochemistry, flow cytometry, and Western blot analysis. IL-8-induced downstream signaling events were assessed using immunoblot analysis and immunofluorescence. The angiogenic effects of IL-8 on HIMEC were determined using proliferation and chemotaxis assays. HIMEC responded to IL-8 with rapid stress fiber assembly, chemotaxis, enhanced proliferation, and phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2). HIMEC express CXCR2, but not CXCR1. Neutralizing antibodies to CXCR2 diminished IL-8-induced chemotaxis and stress fiber assembly. Specific inhibitors of ERK 1/2 and phosphoinositide 3-kinase abrogated endothelial tube formation and IL-8-induced chemotaxis in HIMEC. IL-8 elicits angiogenic responses in microvascular endothelial cells isolated from human intestine by engaging CXCR2. We confirmed tissue expression of CXCR2 in human intestinal microvessels. Supported by the notion that malignant colonic epithelial cells overexpress IL-8, CXCR2 blockade may be a novel target for anti-angiogenic therapy in colorectal adenocarcinoma.
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PMID:Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. 1249 58

PTEN (phosphatase and tensin homologue deleted on chromosome-10), a dual specificity phosphatase, is a tumor suppressor gene whose inactivation has been associated with many different types of cancer including prostate cancer. Prostate adenocarcinoma is one of the most commonly diagnosed malignancies afflicting the male population in both the United States and Europe. The frequency of PTEN inactivation appears to increase during the progression of prostatic cancer. The physical loss of the PTEN genetic locus in prostate cancer progression has been well characterized, however the molecular implication of this loss of PTEN remains enigmatic. The purpose of this review is to describe the functional role of PTEN in the molecular pathogenesis of prostatic disease. We review the function of PTEN discussing its association with the phosphoinositol 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signal transduction pathways. Additionally, we discuss the role of PTEN in the regulation of apoptotic pathways involving the anti-apoptotic gene bcl-2 and the pro-apoptotic ligand TRAIL. We also review the mechanisms that can lead to the loss of PTEN function. We describe genetic inactivation including loss of heterozygosity, haploinsufficiency and mutation. We conclude by outlining epigenetic loss including methylation, post-translational modifications and oxidative stress.
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PMID:The role of PTEN in the progression and survival of prostate cancer. 1271 46

Using cDNA microarray with double dots of 4096 human genes, P18(INK4C), a member of CKI, was found down-regulated in a gastric adenocarcinoma metastatic cell line (RF-48), compared with the corresponding primary cancer cell line (RF-1), which implied that P18(INK4C) might be involved in cell invasion and metastatic progression of human gastric adenocarcinoma. Antisense RNA expression plasmid was applied to inhibit P18(INK4C) expression to study the effect of decreased P18(INK4C) expression on cell migration, invasion and proliferation ability and cell cycle of RF-1. Results showed that inhibition of P18(INK4C) expression could obviously enhance cell invasion ability of RF-1, but had little effect on its cell cycle and cell migration and proliferation ability. These results implied that P18(INK4C) might play a pivotal role in regulating cell invasion, rather than regulating cell cycle and proliferation in the progression of human gastric adenocarcinoma as expected before.
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PMID:The effects of inhibiting P18(INK4C) expression on the invasion of gastric adenocarcinoma cell line. 1279 10

Apoptosis is regulated by several pathways, such as caspases, mitogen activated protein kinase (MAPK) and cAMP/cAMP-dependent protein kinase A (PKA) cascade. This study investigated the effect of beta(2)-adrenoceptor activation on Shiga toxin (Stx)2-induced apoptosis in renal tubular cells and the contribution of these signalling pathways. Cultured human adenocarcinoma-derived tubular cells were exposed to Stx2 (64 pg/mL) for 2-24hr following the addition of the beta(2)-adrenoceptor agonist (terbutaline) to the incubation medium. Stx2-induced apoptosis and its amelioration by beta(2)-adrenoceptor activation was confirmed using DNA degradation assays and by flow cytometry for annexin V, mitochondrial membrane potential and caspase(-3 and -7) activity. Exposure of cells to Stx2 for 24hr increased the DNA fragmentation to 11.6+/-0.9%, compared to 3.3+/-0.2% in control cells (P<0.05) but was decreased to approximately 5-7% (P<0.05) in the presence of terbutaline. Furthermore, Stx2-stimulated apoptosis, detected by TUNEL, annexin V and mitochondrial potential, was inhibited by terbutaline (P<0.05) which was prevented by cAMP-PKA inhibitors and a beta(2)-adrenoceptor antagonist. However, inhibition of Stx2-mediated caspase activity by terbutaline was partially blocked by cAMP-PKA inhibitors. On the other hand, p38MAPK inhibition by terbutaline prevented Stx2-induced apoptosis and caspase activity through a cAMP-independent pathway via beta(2)-adrenoceptor. These data indicate that beta(2)-adrenoceptor activation can inhibit Stx2-induced apoptosis of the cells, which may be caused by a reduction in caspase activity through cAMP-PKA activation and the p38MAPK pathway.
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PMID:Beta2-adrenoceptor activation inhibits Shiga toxin2-induced apoptosis of renal tubular epithelial cells. 1282 77

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Deregulation of cell-cycle control is thought to be a crucial event in malignant transformation, and CDC25 phosphatases are a family of cyclin-dependent kinase activators, which act at different points of the cell cycle, including G1-S and G2-M transition. Here, we investigated the expression and functional significance of CDC25s in PDAC. CDC25B mRNA expression levels in human pancreatic tissue samples were analysed by cDNA array, quantitative PCR and Northern blotting. Immunohistochemistry was carried out to localize and quantify CDC25B expression. Two specific CDC25B inhibitors were utilized to determine the functional relevance of CDC25B. By quantitative RT-PCR, CDC25B mRNA was overexpressed in pancreatic cancer (7.5-fold) in comparison to the normal pancreas. Strong nuclear CDC25B immunoreactivity was present in both pancreatic and metastatic cancer samples, and there was a marked increase of the percentage of positive cells in primary cancer (48.6+/-16.3%) and metastatic tissues (71.7+/-3.1%) compared to normal samples (8.3+/-1.8%). Two CDC25B inhibitors reduced the growth of pancreatic cancer cell lines, resulting in the accumulation of phosphorylated CDC2 and G2/M arrest. These findings demonstrate an important role of CDC25B in cell-cycle progression, raising the possibility that inhibition of CDC25B may have therapeutic potential in pancreatic cancer.
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PMID:Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. 1471 12

p27Kip1 belongs to the family of small polypeptides collectively termed cyclin-dependent kinase inhibitors, which negatively regulate the cell cycle progression. In various human cancers, the reduced p27Kip1 expression correlates well with poor prognosis. Recently, Jab1/CSN5, the fifth component of the COP9 signalosome complex, was found to specifically translocate p27Kip1 from the nucleus to the cytoplasm, and reduce the protein level of p27Kip1 by accelerating its degradation. In this study, we investigated the expression of p27Kip1 and Jab1 in 61 cases with pancreatic ductal adenocarcinoma. The p27Kip1 expression was positive in 41% (25/61) of the tumors. Of the 25 positive tumors, 12 cases had p27Kip1 positive expression mainly in the nucleus of the tumor cells, while 13 cases had p27Kip1 in the cytoplasm as well as in the nucleus. Among a variety of clinicopathological factors, only tumor status was inversely correlated with p27Kip1 expression (p=0.019). The Jab1 expression was detected both in the nucleus and the cytoplasm in almost all pancreatic cancer cells. The intensity of Jab1 expression in tumor cells, especially in the cytoplasm, was much stronger than in normal pancreatic ductal epithelial cells. The patients with positive p27Kip1 expression had significantly better prognosis than ones with negative p27Kip1 expression (p=0.008). Furthermore, 12 patients with exclusively nuclear p27Kip1 expression, but not 13 patients with both nuclear and cytoplasmic p27Kip1 expression, had significantly better prognosis than 36 patients with negative p27Kip1 expression (p=0.009). In multivariate survival analysis, localized p27Kip1 expression was an independent prognostic factor (p=0.016). The results of our study suggested that the mislocalization as well as the downregulation of p27Kip1 had significant prognostic value in pancreatic cancer and that Jab1 might play an important role in carcinogenesis of pancreatic cancer. Cell cycle control targeting p27Kip1 might be a promising future therapeutic modality against pancreatic cancer.
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PMID:Prognostic significance of localized p27Kip1 and potential role of Jab1/CSN5 in pancreatic cancer. 1471 54

Endometrial cancer is the most common gynecological cancer in Western industrialized countries. Cables, a cyclin-dependent kinase binding protein, plays a role in proliferation and/or differentiation. Cables mutant mice are viable, but develop endometrial hyperplasia and carcinoma in situ at a young age. Exposure to chronic low levels of estrogen results in development of endometrial cancer, similar to that observed in the postmenopausal female. In vitro and in vivo studies demonstrate that levels of Cables mRNA in benign human endometrial epithelium are up-regulated by progesterone and down-regulated by estrogen. Furthermore, nuclear immunostaining for Cables is lost in a high percentage of cases of human endometrial hyperplasia and adenocarcinoma, which are likely the product of unopposed estrogen. The loss of Cables immunostaining in the human endometrial cancer samples correlates with a marked decrease in Cables mRNA. Ectopic expression of Cables in human endometrial cells dramatically slows cell proliferation. Collectively, these data provide evidence that Cables is hormonally regulated and is involved in regulating endometrial cell proliferation. In addition, loss or suppression of Cables may be an early step in the development of endometrial cancer.
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PMID:Loss of cables, a cyclin-dependent kinase regulatory protein, is associated with the development of endometrial hyperplasia and endometrial cancer. 1472 25

Lung cancer from radon or (239)plutonium exposure has been linked to alpha-particles that damage DNA through large deletions and point mutations. We investigated the involvement of an epigenetic mechanism, gene inactivation by promoter hypermethylation in adenocarcinomas from plutonium-exposed workers at MAYAK, the first Russian nuclear enterprise established to manufacture weapons plutonium. Adenocarcinomas were collected retrospectively from 71 workers and 69 non-worker controls. Lung adenocarcinomas were examined from workers and non-worker controls for methylation of the CDKN2A (p16), O(6)-methylguanine-DNA methyltransferase (MGMT), death associated protein kinase (DAP-K), and Ras effector homolog 1 genes (RASSF1A). The prevalence for methylation of the MGMT or DAP-K genes did not differ between workers and controls, while a higher prevalence for methylation of the RASSF1A gene was seen in tumors from controls. In marked contrast, the prevalence for methylation of p16, a key regulator of the cell cycle, was increased significantly (P = 0.03) in tumors from workers compared with non-worker controls. Stratification of plutonium exposure into tertiles also revealed a striking dose response for methylation of the p16 gene (P = 0.008). Workers in the plutonium plant where exposure to internal radiation was highest had a 3.5 times (C.I. 1.5, 8.5; P = 0.001) greater risk for p16 methylation in their tumors than controls. This increased probability for methylation approximated the 4-fold increase in relative risk for adenocarcinoma in this group of workers exposed to plutonium. In addition, a trend (P = 0.08) was seen for an increase in the number of genes methylated (> or =2 genes) with plutonium dose. Here we demonstrate that exposure to plutonium may elevate the risk for adenocarcinoma through specifically targeting the p16 gene for inactivation by promoter methylation.
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PMID:Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma. 1474 12

We report the full genomic organization of the human gene for the corticotropin-releasing factor (CRF) receptor type 1 (CRFR1), with complete mapping of exons 1-14. The 5' flanking region (2.4 kb) of the gene encoding for human CRFR1 was isolated, sequenced, and characterized. Two major transcriptional start sites were determined at -265 and -238, relative to the ATG start site (+1). Transient expression of constructs containing sequentially deleted 5'-flanking sequences of CRFR1 fused to luciferase, revealed the minimal promoter sequence 370 bp in size, as shown by assays in neuroblastoma (SH-5YSY), teratocarcinoma (NT2), and adenocarcinoma (MCF 7) cell lines. CRF and UCN markedly increased promoter activity during transient CRFR1 expression studies. Similarly, CRF and UCN up-regulate the endogenous CRFR1 at the mRNA level in NT2 and MCF 7 cells. To dissect further the mechanisms involved, we have used primary myometrial cells transfected with the CRFR1 promoter. CRF and UCN increased the promoter activity, an effect blocked by protein kinase (PK)A and PKC inhibitors. Both CRF and UCN cause a positive feedback effect in primary cultures of human pregnant myometrial cells, by increasing mRNA expression of CRFR1. This effect appears to be dependent on activation of both PKA and PKC by CRF, whereas UCN's effect was mediated solely via PKC activation. Collectively, our data suggest that the CRFR1 gene is under the influence of both CRF and UCN, acting via distinct signaling pathways to create a positive feedback loop and regulate further the transcription of the receptor.
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PMID:Promoter analysis of human corticotropin-releasing factor (CRF) type 1 receptor and regulation by CRF and urocortin. 1514 84

A hybrid cell line, IOSE-Ov29, was created through fusion of cells from the human ovarian adenocarcinoma line OVCAR3 and the non-tumorigenic SV40 Tag-transfected human ovarian surface epithelial line IOSE-29. OVCAR3 cells exhibit a differentiated epithelial phenotype, whereas line IOSE-29 expresses mesenchymal characteristics that were acquired in culture by epithelio-mesenchymal transition. Microsatellite analysis, comparative genomic hybridization (CGH), and MFISH showed the genotype of the IOSE-Ov29 cells to contain components of both parent cell lines, but to be predominantly OVCAR3 derived. IOSE-Ov29 resembled OVCAR3 and differed from IOSE-29 as shown by its unlimited life span, tumorigenicity, epithelial morphology, keratin, occludin, E-cadherin and CA125 expression, increased expression of kinases of the PI3K pathway, and loss of cGMP-dependent protein kinase expression. IOSE-29-derived properties included SV40 Tag expression, growth inhibition by activin, collagen type III secretion, increased adhesion and spreading on tissue culture plastic, and increased growth rate. Proliferation of all three lines was stimulated by FSH and ATP and inhibited by GnRH I and GnRH II. Interestingly, IOSE-Ov29 was more anchorage independent than either parent line and was the only line that invaded Matrigel in Boyden chambers and formed invasive branches in collagen gels. The results indicate that IOSE-Ov29 is an IOSE-29/OVCAR3 hybrid, which differs from both parent lines genetically and phenotypically. Unexpectedly, fusion with the non-tumorigenic IOSE-29 cells enhanced malignancy-associated characteristics of OVCAR3, presumably as a result of the expression of IOSE-29-derived mesenchymal properties that are usually acquired by carcinoma cells through epithelio-mesenchymal transition during metastatic progression.
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PMID:Epithelio-mesenchymal transition in a neoplastic ovarian epithelial hybrid cell line. 1515 38


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