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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We established 2 novel human cell lines (GCCOT-1, GCCRK) from glassy cell carcinoma. Both cell lines showed dual tendencies of glandular and squamous differentiation, and thus possess the characteristics resembling reserve cells, the putative origin of most carcinomas arising from the uterine cervix. HPV type 18 DNA including E6-E7, which is commonly found in cell types other than squamous cell carcinoma of uterine cervix, was detected in both cell lines. We analyzed gene copy number alterations of the 2 cell lines using conventional comparative genomic hybridization (CGH) coupled with array-based CGH. Among the putative oncogenes demonstrating copy number gain in both cell lines, FGR(SRC2) at 1p36.2-1 and LAMC2 at 1q25-31 have not been reported to show amplification in previous analyses of conventional cervical cell lines. These oncogenes are thus speculated to be directly associated with oncogenesis of glassy cell carcinoma. On the other hand, among the putative suppressor genes demonstrating copy number loss in both cell lines, the 9q region, ATM at 11q22.3, and CYLD at 16q12-13 have not been reported to show loss in conventional cervical cancer cell lines. These sites are speculated to be important as tumor suppressors directly associated with oncogenesis of glassy cell carcinoma. This study suggests for the first time that together with the presence of HPV type 18, alterations at the above sites are closely associated with oncogenesis of glassy cell carcinoma, a special type of carcinoma in the uterine cervix.
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PMID:Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix. 1501 Aug 38

Intracellular levels of phosphorylation are regulated by the coordinated action of protein kinases and phosphatases. Disregulation of this balance can lead to cellular transformation. Here we review knowledge of the mechanisms of one protein phosphatase, the tumour suppressor PTEN/MMAC/TEP 1 apropos its role in tumorigenesis and signal transduction. PTEN plays an important role in the phosphatidyl-inositol-3-kinase (PI3-K) pathway by catalyzing degradation of phosphatidylinositol-(3,4,5)-triphosphate generated by PI3-K. This inhibits downstream targets mainly protein kinase B (PKB/Akt), cell survival and proliferation. PTEN contributes to cell cycle regulation by blockade of cells entering the S phase of the cell cycle, and by upregulation of p27(Kip1) which is recruited into the cyclin E/cdk2 complex. PTEN also modulates cell migration and motility by regulation of the extracellular signal-related kinase - mitogen activated protein kinase (ERK-MAPK) pathway and by dephosphorylation of focal adhesion kinase (FAK). We also emphasize the increasingly important role that PTEN has from an evolutionary point of view. A number of PTEN functions have been elucidated but more information is needed for utilization in clinical application and potential cancer therapy.
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PMID:The mechanism of action of the tumour suppressor gene PTEN. 1503 1

The late stages of human breast cancer development are poorly understood complex processes associated with the expression of genes by cancers that promote specific tumorigenic activities, such as angiogenesis. Here, we describe the identification of periostin as a mesenchyme-specific gene whose acquired expression by human breast cancers leads to a significant enhancement in tumor progression and angiogenesis. Undetectable in normal human breast tissues, periostin was found to be overexpressed by the vast majority of human primary breast cancers examined. Tumor cell lines engineered to overexpress periostin showed a phenotype of accelerated growth and angiogenesis as xenografts in immunocompromised animals. The underlying mechanism of periostin-mediated induction of angiogenesis was found to derive in part from the up-regulation of the vascular endothelial growth factor receptor Flk-1/KDR by endothelial cells through an integrin alpha(v)beta(3)-focal adhesion kinase-mediated signaling pathway. These findings demonstrate the presence of a novel mechanism by which tumor angiogenesis is acquired with the expression of a mesenchyme-specific gene as a crucial step in late stages of tumorigenesis.
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PMID:Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression. 1508 92

Versican is highly expressed in many types of tumors. In a previous study, we found that a G3 mutant [G3DeltaEGF; a versican G3 domain lacking two epidermal growth factor (EGF)-like motifs] exerted a dominant-negative effect on versican secretion and binding. Here, we report that astrocytoma U87 cells expressing the versican G3 mutant lost the hallmark of cell transformation and tumorigenesis in vitro and in vivo. U87 cells expressing G3DeltaEGF had enhanced cell adhesion and spreading, but lost the tumor characteristic of anchorage-independent growth. When U87 cells were deprived of serum, FAK was quickly dephosphorylated, integrin/EGF-receptor (EGFR) complexes dissociated and the cells retained an appropriate level of EGFR phosphorylation. These cells quickly detached, migrated, rounded, reorganized and survived. However, after serum withdrawal from G3DeltaEGF-transfected U87 cells, sustained FAK phosphorylation and integrin-EGFR association were observed, but a greatly reduced EGFR phosphorylation. These cells remained spread and continued to grow before undergoing massive apoptosis. The addition of EGF promoted U87 cell rounding but had little effect on G3DeltaEGF-transfected cells owing to reduced EGFR phosphorylation. Our study sheds light on the question of how the matrix molecule versican modulates tumorigenesis by affecting integrin and EGFR signals.
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PMID:Overexpression of the C-terminal PG-M/versican domain impairs growth of tumor cells by intervening in the interaction between epidermal growth factor receptor and beta1-integrin. 1512 24

Focal adhesion kinase (FAK) gene encodes focal adhesion kinase that localizes at contact points of cells with extracellular matrix. It was shown that FAK expression is increased in a variety of malignancies, both at early and advanced stages of tumorigenesis. To understand mechanisms of FAK gene expression and regulation, we cloned and characterized the 5' promoter region of the FAK gene. The 1.2-kb fragment with FAK promoter was placed upstream of the luciferase reporter gene in a pGL3-Basic vector and transfected into different cell lines. Endogenous high-FAK-expressing cell lines showed high levels of luciferase activity in contrast to low-FAK-expressing cells, indicating on transcriptional level of FAK regulation. Serial deletion constructs revealed that a approximately 600 base pair region (-564 to +47) is required for the maximal FAK promoter activity. The 5'-flanking region of FAK is GC-rich and contains several potential transcription factor binding sites, including two NF-kappa B and p53 binding sites. Inhibition of NF-kappa B with NF-kappa B super-repressor decreased FAK luciferase activity. Induction with TNF-alpha increased luciferase activity confirming a role of NF-kappa B transcription factor in the FAK transcriptional activation. The binding of NF-kappa B and p53 transcription factors to the FAK promoter region was demonstrated by electrophoretic mobility shift assay (EMSA). Cotransfection of NF-kappa B and p53 plasmids with FAK promoter luciferase constructs demonstrate induction and inhibition, respectively, of FAK luciferase activity. The results provide a molecular basis for analysis of FAK transcriptional regulation.
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PMID:Cloning and characterization of the promoter region of human focal adhesion kinase gene: nuclear factor kappa B and p53 binding sites. 1515 37

Bovine type I collagen (Col-I) is utilized for medical purposes such as cosmetic surgery and wrinkle removal. Cyclooxygenase-2 (COX-2) plays roles in pathophysiological processes including inflammation and tumorigenesis. This study examines the effects of Col-I on the COX-2 expression and the signaling pathways in macrophages. Col-I increased the levels of COX-2 protein and mRNA in serum-stimulated Raw264.7 cells in a time- and concentration-dependent manner. Treatment of cells with Col-I increased CCAAT/enhancer binding protein (C/EBP) DNA binding. Antibody supershift experiments revealed that C/EBP DNA binding activity induced by Col-I depended largely on C/EBPbeta and C/EBPdelta. Immunocytochemistry showed that Col-I induced nuclear translocation of C/EBPbeta and C/EBPdelta, whose activation contributes to COX-2 induction. Overexpression of the dominant-negative mutant form of C/EBP abolished COX-2 induction by Col-I. Col-I also increased cyclic-AMP response element binding protein (CREB) binding to DNA. Inhibition of focal adhesion kinase (FAK) or downstream phosphoinositide 3-kinase and p70S6 kinase by specific chemical inhibitors prevented COX-2 induction by Col-I, and C/EBP and CREB from binding to their consensus DNA oligonucleotides. Experiments using chemical inhibitors or dominant-negative mutant vectors showed that the mitogen-activated protein (MAP) kinase pathways including p38-kinase and extracellular signal-regulated kinase (ERK1/2), but not c-Jun N-terminal kinase (JNK1), simultaneously regulated COX-2 induction by Col-I. This was in agreement with inhibition of Col-I-inducible C/EBP and CREB DNA binding by concomitant treatment with SB203580 and PD98059. These results provide evidence that Col-I induces COX-2 in serum-stimulated macrophages and that the multiple cell signaling pathways involving Src-focal adhesion kinase, phosphoinositide 3-kinase, and MAP kinases regulate COX-2 induction by Col-I via C/EBP and CREB activation.
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PMID:Induction of cyclooxygenase-2 by bovine type I collagen in macrophages via C/EBP and CREB activation by multiple cell signaling pathways. 1516 55

KIT and platelet-derived growth factor receptors (PDGFRs) play critical oncogenic roles in a broad spectrum of hematologic and solid tumors. These receptor tyrosine kinases, as well as ABL and BCR-ABL, are inhibited by imatinib. Tumors caused by chromosomal translocations that lead to overexpression of PDGFR ligand, resulting in continuous activation of wild-type PDGFRs, are likely to respond to imatinib, as are malignancies caused by gene amplification and overexpression of wild-type PDGFR or KIT receptors. Malignancies linked to chromosomal translocations that express PDGFR or KIT fusion protein-tyrosine kinases are also likely to respond to imatinib. Malignant cell responses to imatinib depend on whether any of these tyrosine kinase activities play essential roles in the oncogenesis of a given tumor, as well as the precise molecular mechanism underlying oncogenesis. For example, imatinib efficacy for malignancies arising from constitutively activating point mutations in tyrosine kinases depends on the exact location of the mutation in the kinase molecule.
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PMID:Role of KIT and platelet-derived growth factor receptors as oncoproteins. 1517 98

HHV-8-GPCR is a chemokine-like receptor encoded by KSHV, the etiologic agent of KS. HHV-8-GPCR is constitutively active. Although it is homologous to mammalian CXCR2, it binds CXC and CC chemokines. Structure-function analysis showed that chemokines bind primarily to the amino terminus whereas signaling occurs in the absence of: the amino terminus, which is, therefore, not a tethered agonist. In in vitro systems, HHV-8-GPCR signals via multiple transduction pathways including, activation of phospholipase C and PKC, inhibition of adenylyl cyclase, activation of nuclear factor-kappaB; activation PI 3-kinase, p42/44 MAPK and Akt/PKB, and activation of JNK/SAPK, p38 MAPK and RAFTK. HHV-8-GPCR is important in the HHV-8 life cycle because HHV-8-GPCR-deficient viruses do not replicate in response to chemokines and exhibit, less efficient reactivation from latency. Although the role of HHV-8-GPCR in the pathogenesis of KS has not been defined, expression of HHV-8-GPCR resulted in the development of angioproliferative, KS-like tumors in transgenic mice. As endothelial cells may be targets of HHV-8 infection, HHV-8-GPCR has been studied in endothelial cells in vitro in which it affects cell adhesion and migration, increases cell survival, and stimulates secretion of proinflammatory cytokines and proangiogenic factors. Based on these findings and the observation that HHV-8-GPCR is expressed in only a few endothelial- like "spindle cells" within KS lesions, we propose that HHV-8-GPCR is involved in KS pathogenesis by stimulating secretion of proinflammatory/proangiogenic factors that act in a paracrine fashion to cause tumorigenesis.
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PMID:Insights into the viral G protein-coupled receptor encoded by human herpesvirus type 8 (HHV-8). 1520 3

Frequent deletions on 9q34.1-2 were reported in bladder transitional cell carcinoma. High deletion mapping studies delimited a critical interval between markers D9S61 and D9S66, which is highly susceptible to contain a tumor suppressor gene. Expression level of the 65 genes localized in this region was analyzed by real-time quantitative RT-PCR, comparing tumor to normal urothelium. Five genes exhibited a significantly reduced expression level: C9orf9, KIAA0625, ABL1, LAMC3 and KIAA1857-netrin-G2, which exhibited the most significant downregulation (p=0.0007). KIAA1857-netrin-G2 belongs to the netrins and might then be a tumor suppressor gene in bladder cancer, as netrin1 receptor DCC has been implicated in tumorigenesis.
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PMID:Expression in bladder transitional cell carcinoma by real-time quantitative reverse transcription polymerase chain reaction array of 65 genes at the tumor suppressor locus 9q34.1-2: identification of 5 candidates tumor suppressor genes. 1523 31

Rho GTPases are major regulators of cytoskeletal dynamics, but they also affect cell proliferation, transformation, and oncogenesis. RhoE, a member of the Rnd subfamily that does not detectably hydrolyze GTP, inhibits RhoA/ROCK signaling to promote actin stress fiber and focal adhesion disassembly. We have generated fibroblasts with inducible RhoE expression to investigate the role of RhoE in cell proliferation. RhoE expression induced a loss of stress fibers and cell rounding, but these effects were only transient. RhoE induction inhibited cell proliferation and serum-induced S-phase entry. Neither ROCK nor RhoA inhibition accounted for this response. Consistent with its inhibitory effect on cell cycle progression, RhoE expression was induced by cisplatin, a DNA damage-inducing agent. RhoE-expressing cells failed to accumulate cyclin D1 or p21(cip1) protein or to activate E2F-regulated genes in response to serum, although ERK, PI3-K/Akt, FAK, Rac, and cyclin D1 transcription was activated normally. The expression of proteins that bypass the retinoblastoma (pRb) family cell cycle checkpoint, including human papillomavirus E7, adenovirus E1A, and cyclin E, rescued cell cycle progression in RhoE-expressing cells. RhoE also inhibited Ras- and Raf-induced fibroblast transformation. These results indicate that RhoE inhibits cell cycle progression upstream of the pRb checkpoint.
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PMID:RhoE inhibits cell cycle progression and Ras-induced transformation. 1534 47


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