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)

Tumor invasion marks a critical point in cancer progression; it is a harbinger of morbidity and mortality. Thus, the cellular events that enable the invasive phenotype are under intense investigation. Epstein-Barr virus (EBV) is associated with a number of cancers, including Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC) and is suspected to contribute to their tumorigenesis. On average, 8% of gastric carcinomas have been shown to carry this virus. To explore whether the presence of EBV in gastric carcinoma contributes to tumor progression in this predominantly invasive carcinoma, we examined a panel of 2 in vitro EBV-infected human gastric cancer cell line sublines and their mock-infected AGS parental control line. We found EBV infection caused a marked increase in transmigration of a Matrigel barrier (415% and 303%, p < 0.05, for the 2 infected lines). This correlated with increased motility of these sublines (233% and 140%, p < 0.05). As this pattern of increased motility leading to a more pronounced enhancement of invasion has been noted in other tumor cells, we explored the roles of autocrine signaling pathways previously implicated in carcinoma motility and invasion. Inhibitors to the epidermal growth factor receptor (EGFR) (PD153035), phospholipase C (PLC) (U73122), extracellular-signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) (PD089035) and PI-3 kinase (Wortmannin) were not informative. These data suggest that EBV increases migration of AGS cells by a mechanism independent of these autocrine growth factor-induced pathways. Instead, we found that the EBV-infected cells presented increased focal adhesion kinase (FAK) phosphorylation. These findings suggest a role for integrin-mediated signaling in promoting EBV-associated invasiveness.
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PMID:EBV-expressing AGS gastric carcinoma cell sublines present increased motility and invasiveness. 1211 96

Oncogenes involved in the development of hematological malignancies were first discovered through the study of experimental leukemias induced in animals by retroviruses. The discovery that some of these genes were located at the breakpoints of chromosome rearrangements in human malignancies, such as the MYC gene in Burkitt's lymphoma and the ABL gene in chronic myeloid leukemia (CML) has suggested that chromosome abnormalities were causally implicated in the pathogenesis of human diseases. Numerous nonrandom somatically acquired chromosomal translocations or inversions have been identified in human leukemias. The molecular cloning of the genes located at the breakpoints of these rearrangements allowed to identify more than 100 new oncogenes, the products of which affect normal programs of cell proliferation, differentiation and survival. Chromosome translocations can lead to the deregulated expression of a normal gene product, but in most cases of leukemia, chromosome rearrangements result in the expression of a chimeric fusion protein. Oncogene products associated with acute leukemias are often transcription factors while tyrosine kinases and antiapoptotic proteins are more commonly activated or overexpressed in chronic leukemias and in lymphomas. Recent data indicated that gene rearrangements were not the sole gene alterations occurring in human leukemia since point mutations could also affect the function of transcription factors playing a key role in hematopoiesis such as C/EBP alpha, GATA1 and AML1. But the most exciting finding was the discovery of activating point mutations in tyrosine kinase receptors such as FLT3 and c-KIT in acute leukemia. Treatment of leukemia could therefore benefit from new therapeutic approaches targeting the function of specific oncogene products as already demonstrated for CML and acute promyelocytic leukemia.
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PMID:[Oncogenes and leukemia: history and perspectives]. 1283 14

To determine the specific gene expression in B-cell lymphoma subtypes, we compared expression profiles of cell lines from transformed follicular lymphoma (tFL), Epstein-Barr virus-negative (EBV(-)) Burkitt's lymphoma (BL) and EBV(+)BL. Complementary DNAs were synthesized from these cell lines and hybridized with the Atlas Human 1.2 Array membrane. Hierarchical clustering analysis based upon the levels of 43 genes highlighted characteristic expression patterns of the 3 lymphoma subtypes. Genes expressed at higher levels in tFL than EBV(-)BL and EBV(+)BL included calcium/calmodulin-dependent protein kinase I (CAMK1) and mitogen-activated protein kinase 10 (MAPK10). EBV(-)BL was characterized by high-level expression of amyloid beta precursor protein (APP), heat shock 27 kD protein 1 (HSPB1) and mothers against decapentaplegic homolog 1 (MADH1). Gardner-Rasheed feline sarcoma viral oncogene homolog (FGR) was the most significant gene to delineate EBV(+)BL. A subtype prediction algorithm using 34 genes correctly classified 22 (92%) of 24 lymphomas into FL/tFL, EBV(-)BL or EBV(+)BL. By comparison with normal reference B-cell materials, the expression patterns of the selected genes were characteristic of lymphomas. We extended the clustering analysis to cell lines from de novo diffuse large B-cell lymphoma (DLBCL). The DLBCL cell lines were either separated from the former 3 lymphoma subtypes or segregated with EBV(+)BL, possibly reflecting variable genetic abnormalities. The associations of CAMK1 with tFL, APP and MADH1 with EBV(-)BL, FGR with EBV(+)BL, and BCL2 with tFL and DLBCL were confirmed by real-time quantitative reverse transcriptase-mediated polymerase chain reaction assays. This study has provided new molecular markers, expressions of which are closely associated with B-cell lymphoma subtypes.
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PMID:Comparison of gene expression profiles of lymphoma cell lines from transformed follicular lymphoma, Burkitt's lymphoma and de novo diffuse large B-cell lymphoma. 1296 75

Increased transcriptional activity of the MYC gene is a characteristic feature of Burkitt's lymphoma. Aberrant MYC expression is caused by (1) chromosomal translocation to one of the loci carrying an immunoglobulin gene, (2) mutation within the translocated allele, (3) loss of the block to transcription elongation, or (4) promoter shift. To investigate the influence of breakpoint locations within the MYC gene on MYC transcript levels, we determined both the precise genomic MYC/IGH breakpoints and the amount of MYC mRNA in 25 samples of pediatric Burkitt's lymphoma with translocation t(8;14)(q24;q32). Patients with breakpoints that were 5' from MYC exon 1 had significantly lower expression of MYC than did patients who had a breakpoint within exon 1 or intron 1 (P < 0.05 and 0.005, respectively). The highest mRNA level of MYC (1,006 copies per 100 copies ABL1) was detected in patients with loss of the first exon and transcription initiation from a cryptic P3 promoter within the first intron of the MYC gene. In contrast, there was no obvious correlation between breakpoint locations within the IgH locus and the amount of MYC mRNA.
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PMID:Level of MYC overexpression in pediatric Burkitt's lymphoma is strongly dependent on genomic breakpoint location within the MYC locus. 1528 31

The review by D.T. Hughes examined the role of cytogenetics in cancer research in 1964. Despite the technical limitations of the day, he highlighted a number of known abnormalities which were to turn out to be crucial in our understanding of cancer genetics over the subsequent 40 years. These included the Philadelphia translocation and the Burkitt's lymphoma-associated marker chromosomes. In addition, he mentioned that a deleted chromosome had been observed in an example of retinoblastoma and double-minute chromosomes in neuroblastoma. The study of these events led to the identification of the key genes involved (BCR, ABL, C-MYC, RB1 and N-MYC) and served as models for substantial further work. We review some of the technical advances in the field of molecular cytogenetics and show how they can be applied to the events reviewed by Hughes.
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PMID:Understanding cancer at the chromosome level: 40 years of progress. 587 19

An HIV-1 infected patient on dual protease inhibitor treatment developed spontaneous vertebral fractures and avascular necrosis of the femoral bone after receiving combined chemotherapy for Burkitt's lymphoma including short-term prednisolone. The factors involved in the pathogenesis of osteopaenia and osteoporosis in this case are discussed and we propose the need for guidelines in order to reduce the incidence of such events in HIV-infected patients in the future.
Int J STD AIDS 2006 Aug
PMID:Severe osteoporosis and multiple fractures in an AIDS patient treated with short-term steroids for lymphoma: a need for guidelines. 1692 9

We report a novel t(7;9)(q11;p13) translocation in 2 patients with B-cell acute lymphoblastic leukemia (B-ALL). By fluorescent in situ hybridization and 3' rapid amplification of cDNA ends, we showed that the paired box domain of PAX5 was fused with the elastin (ELN) gene. After cloning the full-length cDNA of the chimeric gene, confocal microscopy of transfected NIH3T3 cells and Burkitt lymphoma cells (DG75) demonstrated that PAX5-ELN was localized in the nucleus. Chromatin immunoprecipitation clearly indicated that PAX5-ELN retained the capability to bind CD19 and BLK promoter sequences. To analyze the functions of the chimeric protein, HeLa cells were cotransfected with a luc-CD19 construct, pcDNA3-PAX5, and with increasing amounts of pcDNA3-PAX5-ELN. Thus, in vitro, PAX5-ELN was able to block CD19 transcription. Furthermore, real-time quantitative polymerase chain reaction (RQ-PCR) experiments showed that PAX5-ELN was able to affect the transcription of endogenous PAX5 target genes. Since PAX5 is essential for B-cell differentiation, this translocation may account for the blockage of leukemic cells at the pre-B-cell stage. The mechanism involved in this process appears to be, at least in part, through a dominant-negative effect of PAX5-ELN on the wild-type PAX5 in a setting ofPAX5 haploinsufficiency.
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PMID:A novel PAX5-ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on wild-type PAX5. 1717 30

Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that transmits signals through G-protein-coupled receptors to control cellular differentiation, survival, and several functions of immune cells. S1P is a chemoattractant for NK cells, which are critical members of the immunological tumor surveillance machinery. In this study we analyzed the influence of S1P on the interaction of NK cells with tumor cells such as the human melanoma cell line Hs294T and the Burkitt's lymphoma cell line Raji. We found that S1P inhibited the cytotoxic activity of NK cells. Analysis of signal transduction pathways revealed that S1P induced common signalling pathways of chemotaxins such as Gi protein-dependent actin reorganization and activation of the phosphatidylinositol 3-kinase (PI3K) dependent signal molecules, protein kinase B (PKB/Akt) and glycogen synthase kinase-3beta (GSK-3beta). In contrast to most chemotaxins, S1P is also able to activate Gs-dependent signalling molecules. This signalling cascade involves increase of cAMP levels and protein kinase A (PKA) activation. Additionally, blocking the regulatory subunits of PKA I abrogated the inhibitory effect of S1P, whereas the catalytic subunits were not involved. Our data indicate that S1P may contributes to the tumor escape from NK cell-dependent immunological surveillance machinery.
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PMID:Sphingosine-1-phosphate inhibits the cytotoxic activity of NK cells via Gs protein-mediated signalling. 1908

It is well known that translocation between chromosomes 2 and 8, t(2;8)(p12;q24), has a strong association with Burkitt's lymphoma. It has rarely been seen in indolent lymphoproliferative disorders. In this study, we report for the first time on 2 cases of chronic lymphocytic leukemia (CLL) with t(2;8). They were diagnosed as having typical CLL (case 1) and CLL/prolymphocytic leukemia (case 2), respectively, based on morphology and immunophenotyping. Karyotypic analysis of the bone marrow cells using the R-banding technique revealed a karyotype of 47,XY, t(2;8)(p12;q24), +4,[17]/46, XY[9] in case 1 and a karyotype of 45,X, t(Y;7)(q12;q21),t(2;8)(p12; q24),del(12)(p12),-17[5]/46,XY[9] in case 2. T(2;8) translocation was confirmed by whole chromosome painting. Rearrangement of the MYC gene and loss of one p53 allele were detected by FISH only in case 2. Both cases had negative ZAP70 and CD38 expressions; however, only case 1 showed good response to therapy. We consider that MYC rearrangement, loss of one p53 allele as well as other factors, such as more prolymphocytes in the blood and bone marrow and complex chromosome abnormalities, also had adverse effects on the poorer prognosis of case 2.
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PMID:Translocation t(2;8)(p12;q24) in two patients with B Cell chronic lymphocytic leukemia. 1924 86

Epstein-Barr virus (EBV) persists as a life-long latent infection within memory B cells, but how EBV may circumvent the innate immune response within this virus reservoir is unclear. Recent studies suggest that the latency-associated non-coding RNAs of EBV may actually induce type I (antiviral) interferon production, raising the question of how EBV counters the negative consequences this is likely to have on viral persistence. We addressed this by examining the type I interferon response in Burkitt lymphoma (BL) cell lines, the only in vitro model of the restricted program of EBV latency-gene expression in persistently infected B cells in vivo. Importantly, we observed no effect of EBV on interferon alpha-induced signaling or evidence of type I interferon production, suggesting that EBV in this latent state is silent to the cell's innate antiviral surveillance. We did uncover, however, a defect in the negative feedback control of interferon signaling in a subpopulation of BL lines as was revealed by prolonged interferon-stimulated gene transcription consistent with sustained tyrosine phosphorylation on STAT1 and STAT2. This was due to inadequate induction of expression of the ubiquitin-specific protease UBP43, which removes the ubiquitin-like ISG15 polypeptide conjugated to proteins (ISGylation) in response to type I interferons. Results here are consistent with previous findings in genetically engineered Ubp43(-/-) murine cells that UBP43 down-regulates interferon signaling, independent of its ISG15 isopeptidase activity, by precluding the protein kinase JAK1 from the interferon receptor. This natural deficiency in UBP43 expression may therefore provide a useful model to further probe the biological roles of UBP43 and ISGylation.
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PMID:Epstein-Barr virus independent dysregulation of UBP43 expression alters interferon-stimulated gene expression in Burkitt lymphoma. 1955 Nov 50


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