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)

Bruton's tyrosine kinase (BTK) is a member of the Src-related Tec family of protein tyrosine kinases. Mutations in the btk gene have been linked to severe developmental blocks in human B-cell ontogeny leading to X-linked agammaglobulinemia. Here, we provide unique biochemical and genetic evidence that BTK is an inhibitor of the Fas/APO-1 death-inducing signaling complex in B-lineage lymphoid cells. The Src homology 2, pleckstrin homology (PH), and kinase domains of BTK are all individually important and apparently indispensable, but not sufficient, for its function as a negative regulator of Fas-mediated apoptosis. BTK associates with Fas via its kinase and PH domains and prevents the FAS-FADD interaction, which is essential for the recruitment and activation of FLICE by Fas during the apoptotic signal. Fas-resistant DT-40 lymphoma B-cells rendered BTK-deficient through targeted disruption of the btk gene by homologous recombination knockout underwent apoptosis after Fas ligation, but wild-type DT-40 cells or BTK-deficient DT-40 cells reconstituted with wild-type human btk gene did not. Introduction of an Src homology 2 domain, a PH domain, or a kinase domain mutant human btk gene into BTK-deficient cells did not restore the resistance to Fas-mediated apoptosis. Introduction of wild-type BTK protein by electroporation rendered BTK-deficient DT-40 cells resistant to the apoptotic effects of Fas ligation. BTK-deficient RAMOS-1 human Burkitt's leukemia cells underwent apoptosis after Fas ligation, whereas BTK-positive NALM-6-UM1 human B-cell precursor leukemia cells expressing similar levels of Fas did not. Treatment of the anti-Fas-resistant NALM-6-UM1 cells with the leflunomide metabolite analog alpha-cyano-beta-methyl-beta-hydroxy-N-(2, 5-dibromophenyl)propenamide, a potent inhibitor of BTK, abrogated the BTK-Fas association without affecting the expression levels of BTK or Fas and rendered them sensitive to Fas-mediated apoptosis. The ability of BTK to inhibit the pro-apoptotic effects of Fas ligation prompts the hypothesis that apoptosis of developing B-cell precursors during normal B-cell ontogeny may be reciprocally regulated by Fas and BTK.
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PMID:Bruton's tyrosine kinase as an inhibitor of the Fas/CD95 death-inducing signaling complex. 988 May 44

CML is the myeloproliferative disorder connected with the specific chromosome translocation (9;22) and occurrence of the fusion gene/protein BCR-ABL. BCR-ABL protein is believed to inhibit apoptosis and to cause drug resistance. We investigated the correlation of two different forms of BCR-ABL mRNA in 94 pts with their overall survival. It was found that b2a2 (but not b2a3) mRNA expression correlates with longer survival of patients treated with chemotherapy. We did not find an influence of different types of BCR/ABL mRNA on the survival of pts treated with interferon-alpha. FAS/APO-1 antigen was expressed by the cells of 34% of the pts in CML blast crisis (BC) and directly correlated with the the expression of CD34, CD13 and CD14 differentiation antigens. FAS/APO-1 non-expression correlated with higher rate of remissions in BC. We investigated P-glyco-protein (Pgp) expression and functional activity in 40 BC CML pts. 2-fold shorter survival was found in the pts with Pgp expression. Pgp expression strongly correlated with CD13 antigen. Consecutive studies of pts in BC CML show that Pgp expressing cells often do not multiply in the course of BC CML. We postulate that Pgp may be regarded as differentiation marker of the cells and the unfavorable prognostic factor in BC CML.
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PMID:Studies of some mechanisms of drug resistance in chronic myeloid leukemia (CML). 1050 Aug 25

The potential efficacy of prodrug activation of a transduced suicide gene in a cancer cell may be impaired or enhanced by oncoproteins produced by that cell. In the context of a gene therapy protocol for chronic myeloid leukemia (CML) we examined whether the Bcr-Abl fusion protein would have either of these effects. Thus, the mechanism of cell killing by transfer of herpes simplex virus thymidine kinase (HSV-tk) and subsequent ganciclovir (GCV) treatment was examined in pre-B (TonB210.1) cells and myeloid cells (32D) and in their BCR-ABL-expressing counterparts. HSV-tk-transduced cell lines, either in the presence or in the absence of BCR-ABL expression, became susceptible to GCV at concentrations which were nontoxic to the nontransduced cells. This susceptibility was represented by apoptotic cell death in all cases. Apoptosis was observed after 24 h of treatment with GCV in the tk-transduced parental cells and in the BCR-ABL-expressing TonB210.1 cells but only after a delay of more than 24 h in the 32Dp210 cells compared to 32D. Cell death in the BCR-ABL-expressing clones was preceded by S- and G2/M-phase cell cycle arrest. Activation of FAS/APO-1 and caspase-8 was observed in all the tk-transduced cell lines after GCV treatment. However, the caspase-8 inhibitor Z-IETD-FMK only partially abrogated tk/GCV-induced apoptosis. A possible role for inhibition of Bcl-2 or Bcl-x(L) expression in the apoptosis induced by GCV was observed in the tk-transduced TonB210.1 cells but not in the 32D or 32Dp210 cells. The data demonstrate that expression of the Bcr-Abl oncoprotein does not block the apoptosis induced by the HSV-tk/GCV system, suggesting that this suicide gene therapy strategy could be considered for the treatment of CML in blast crisis.
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PMID:BCR-ABL-expressing cells transduced with the HSV-tk gene die by apoptosis upon treatment with ganciclovir. 1135 68

Recent experimental data suggest that one of the major effects of BCR-ABL gene expression in hematopoietic cells is the inhibition of apoptosis. Although the exact mechanisms of this phenomenon are not clear, it is thought to be related to the fact that BCR-ABL induces several signalling pathways also activated by growth factors. In order to determine the anti-apoptotic role of BCR-ABL in a hematopoietic cell line and to by-pass the influence of cytokine-dependence, BCR-ABL gene was expressed in the autonomously growing myelomonocytic U937 cell line using retroviral vectors. There was no resistance to apoptosis induced by either serum deprivation or different doses of etoposide in any U937 clones expressing BCR-ABL protein. In addition to serum deprivation and etoposide, BCR-ABL-expressing clones were not protected from apoptosis induced by TNF, ceramide-C2 and FAS-cross-linking. BCL2 expression was absent in U937 cells and BAX levels were identical between Neo and BCR-ABL clones. To further investigate the mechanisms of this phenomenon, band-shift assays were performed to detect activation of STAT molecules. No constitutive activation of STATs was detected in either NeoR or BCR-ABL-U937 cells, although both IFN-gamma and GM-CSF activated STAT1 and STAT5, respectively, with similar kinetics in both NeoR and BCR-ABL-U937 cells. In addition, the GM-CSF-induced-STAT5 activation was found to be weakened in all clones expressing BCR-ABL. In both control NeoR and BCR-ABL-transfected clones, band-shift assays revealed the presence of an abnormal truncated STAT5 recognized only by an anti-N-terminal but not by an anti-C-Terminal STAT5 antibody. These findings suggest a possible link between the absence of anti-apoptotic potential of BCR-ABL and abnormalities of the STAT5 pathway, including, absence of constitutive activation of STAT5, inhibition of GM-CSF-induced STAT5 activation and expression of a carboxyl-terminal-truncated STAT5.
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PMID:BCR-ABL fails to inhibit apoptosis in U937 myelomonocytic cells expressing a carboxyl-terminal truncated STAT5. 1169 9

MEK kinase 1 (MEKK1) induces apoptosis through the activation of caspases. The mechanism for MEKK1-induced apoptosis involves caspase-mediated cleavage of MEKK1, releasing a pro-apoptotic 91 kDa kinase fragment that serves to further amplify caspase activation in a feedback loop. Both cleavage of MEKK1 and increased expression of death receptor 4 (DR4, TRAILR1) and death receptor 5 (DR5, TRAILR2) occur following exposure of cells to genotoxins. Overexpression of kinase inactive MEKK1 inhibits MEKK1-mediated apoptosis and effectively blocks death receptor upregulation following etoposide treatment. Herein, we investigate the role of death receptor activation and the ability of AKT/PKB (AKT) to inhibit cell death in MEKK1-induced apoptosis. We show that by preventing DR4 and DR5 activation through expression of decoy receptor 1 (DcR1) and dominant negative FADD, we inhibit MEKK1-induced apoptosis. Furthermore, expression of 91 kDa MEKK1 increased DR4 and FAS mRNA and protein levels. MEKK1-induced apoptosis is amplified by blocking PI-3 kinase activation and overexpression of AKT blocked both MEKK1-induced apoptosis and caspase activation. AKT overexpression also prevented the cleavage of endogenous MEKK1 by genotoxins. AKT did not, however, block MEKK1-induced JNK activation, showing that regulation of the JNK pathway by MEKK1 is independent of its role in regulation of apoptosis. Thus, MEKK1-induced apoptosis requires TRAIL death receptor activation and is blocked by AKT through inhibition of MEKK1 cleavage.
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PMID:MEKK1-induced apoptosis requires TRAIL death receptor activation and is inhibited by AKT/PKB through inhibition of MEKK1 cleavage. 1224 63

IL-6 has emerged as an important cytokine upregulated in states of insulin resistance such as type 2 diabetes. We evaluated the chronic effect of IL-6 on insulin signaling in 3T3-F442A and 3T3-L1 adipocytes. First, cells responded to a chronic treatment with IL-6 by initiating an autoactivation process that increased IL-6 secretion. Second, IL-6-treated adipocytes showed a decreased protein expression of IR-beta subunit and IRS-1 but also an inhibition of the insulin-induced activation of IR-beta, Akt/PKB, and ERK1/2. Moreover, IL-6 suppressed the insulin-induced lipogenesis and glucose transport consistent with a diminished expression of GLUT4. IL-6-treated adipocytes failed to maintain their adipocyte phenotype as shown by the downregulation of the adipogenic markers FAS, GAPDH, aP2, PPAR-gamma, and C/EBP-alpha. IL-6 also induced the expression of SOCS-3, a potential inhibitor of insulin signaling. Finally, the effects of IL-6 could be prevented by rosiglitazone, an insulin-sensitizing agent. Thus, IL-6 may play an important role in the set-up of insulin resistance in adipose cell.
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PMID:Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. 1459 24

Perturbation of oxygen flow occurs in disease states such as diabetic retinopathy and cancer. To maintain oxygen homoeostasis, the mammalian microvascular endothelium undergoes a dramatic reorganization to assist in bringing oxygen and nutrients to oxygen-starved tissues. This process is termed angiogenesis and is common in certain cancers with hypoxic foci and in areas of focal ischaemia in the diabetic retina. In the present study, we report on the activation of the JAK2/STAT5 pathway (where JAK stands for Janus kinase and STAT stands for signal transduction and activator of transcription) by low oxygen in microvascular endothelial cells. This activation appears to occur downstream of VEGF (vascular endothelial growth factor), a well-known proangiogenic factor, and is related to repression of proapoptotic FAS(CD95)/FASL(CD95L). These results indicate that the JAK/STAT pathway may play a pivotal role during tumour-associated or retinal angiogenesis in which endothelial cell survival during tissue hypoxia is critical for maintaining either the growth of neoplasms or the inappropriate retinal neovascularization common in diabetic retinopathy.
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PMID:A VEGF/JAK2/STAT5 axis may partially mediate endothelial cell tolerance to hypoxia. 1591 95

The aim of this study was to investigate the changes in expression pattern of the most important genes connected with apoptosis in proliferative apoptotic lesions (hyperplasia, adenoma), applying cDNA microarray technique, in order to promote the possible diagnostic or therapeutic utilisation of any difference in gene expression compared to the healthy (normal) parathyroid gland. Samples were taken from surgically removed 2 hyperplasias, 2 adenomas and 2 normal parathyroid glands. The Apoptosis Gene Array (Superarray) was used. This contains 112 genes, in tetraspot arrangement. The probes measured 250-600 base pairs. Streptavidin was bound to the array. CDP Star TM chemiluminescent substrate was used for detection. The samples deriving from hyperplasia or adenoma were compared to samples from normal parathyroid glands. The following genes were overexpressed in both hyperplasia and adenoma: CHEK1, ATM, BCL-XL, FAS, TNF, cIAP1, TRAIL, FADD, CASP 4,5,6,8, CD120b, CD137, LTA, TANK, TARF2, CAD, LIGHTR, DR3LG. CASP1,10, BFAR, BOD, BCL2L2, TRANCE were underexpressed in both hyperplasia and adenoma. Genes overexpressed only in hyperplasia were: MDM2, MCL1, BCL2A1, BLK, RIPK2, CD40LG, TRAF5, HUS1, BNIP3. Underexpressed only in hyperplasia: BOK, CIDEA, TRAF1, TRIP. Overexpressed only in adenoma: APOLLON, RIPK1, LTB, LTBR, CASP2,13, cIAP2, CIDEB. Underexpressed only in adenoma: TRAF4 and FASLG. Overexpresion or underexpression meant 1.5-fold difference from normal average values. As a result of this study, both pro-apoptotic and antiapoptotic genes were identified in hyperplasia and adenoma of the parathyroid gland. It seems that increased proliferation is connected also with increased apoptotic activity, but tumor cell candidates are able to survive, by activation of signal pathways resulting in overexpresion of anti-apoptotic genes.
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PMID:[Changes in gene expression in the course of proliferative processes in the parathyroid gland]. 1688 77

More complete knowledge of the molecular mechanisms underlying cancer will improve prevention, diagnosis and treatment. Efforts such as The Cancer Genome Atlas are systematically characterizing the structural basis of cancer, by identifying the genomic mutations associated with each cancer type. A powerful complementary approach is to systematically characterize the functional basis of cancer, by identifying the genes essential for growth and related phenotypes in different cancer cells. Such information would be particularly valuable for identifying potential drug targets. Here, we report the development of an efficient, robust approach to perform genome-scale pooled shRNA screens for both positive and negative selection and its application to systematically identify cell essential genes in 12 cancer cell lines. By integrating these functional data with comprehensive genetic analyses of primary human tumors, we identified known and putative oncogenes such as EGFR, KRAS, MYC, BCR-ABL, MYB, CRKL, and CDK4 that are essential for cancer cell proliferation and also altered in human cancers. We further used this approach to identify genes involved in the response of cancer cells to tumoricidal agents and found 4 genes required for the response of CML cells to imatinib treatment: PTPN1, NF1, SMARCB1, and SMARCE1, and 5 regulators of the response to FAS activation, FAS, FADD, CASP8, ARID1A and CBX1. Broad application of this highly parallel genetic screening strategy will not only facilitate the rapid identification of genes that drive the malignant state and its response to therapeutics but will also enable the discovery of genes that participate in any biological process.
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PMID:Highly parallel identification of essential genes in cancer cells. 1909 43

Colorectal cancers with mutations in the p53 gene have an invasive property, but its underlying mechanism is not fully understood. Through the screening of two data sets of the genome-wide expression profile, one for p53-introduced cells and the other for the numbers of cancer tissues, we report here X-linked ectodermal dysplasia receptor (XEDAR), a member of the TNFR superfamily, as a novel p53 target that has a crucial role in colorectal carcinogenesis. p53 upregulated XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. We also found a significant correlation between decreased XEDAR expressions and p53 gene mutations in breast and lung cancer cell lines (P=0.0043 and P=0.0122, respectively). Furthermore, promoter hypermethylation of the XEDAR gene was detected in 20 of 20 colorectal cancer cell lines (100%) and in 6 of 12 colorectal cancer tissues (50%), respectively. Thus, the XEDAR expression was suppressed to <25% of surrounding normal tissues in 12 of 18 colorectal cancer tissues (66.7%) due to either its epigenetic alterations and/or p53 mutations. We also found that XEDAR interacted with and subsequently caused the accumulation of FAS protein, another member of p53-inducible TNFR. Moreover, XEDAR negatively regulated FAK, a central component of focal adhesion. As a result, inactivation of XEDAR resulted in the enhancement of cell adhesion and spreading, as well as resistance to p53-induced apoptosis. Taken together, our findings showed that XEDAR is a putative tumor suppressor that could prevent malignant transformation and tumor progression by regulating apoptosis and anoikis.
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PMID:XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway. 1954 21


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