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)

The tight skin (Tsk/+) mouse represents a murine model of heritable fibrosis with some similarities to the skin fibrosis seen in human scleroderma. Tsk/+ animals display alterations in connective tissue in some internal organs. Skin fibrosis can be adoptively transferred to normal recipients with Tsk/+ bone marrow or spleen cells and older Tsk/+ animals develop autoantibodies against topoisomerase suggesting that some of the pathogenesis in the Tsk/+ mouse may be mediated by autoimmunity. To determine the role of T cell subsets in the pathogenesis of fibrotic disease, Tsk/+ mice were bred with CD4- and CD8-deficient (CD4-/- and CD8-/-) mice. Tsk/+ CD4-/- mice showed a marked reduction in skin fibrosis as well as decreased cellularity and only mild collagen disorganization as compared to Tsk/+ CD4+ CD8+ control mice yet did not differ from Tsk controls in the level of serum anti-topoisomerase activity. In contrast, Tsk/+ CD8-/- mice exhibited the same histology in the skin as Tsk/+ controls yet had significantly reduced levels of serum anti-topoisomerase activity. Lung pathology, i.e. emphysema, was unaffected by both the CD4 or CD8 mutations. These data show that only some of the pathological effects of the Tsk mutation are T cell dependent and that different T cell subsets affect different parameters in this multi-organ model of fibrotic disease.
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PMID:A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice. 791 25

Hybridization with cDNA arrays was used to obtain expression profiles of 214 protein-tyrosine kinase, protein-tyrosine phosphatase, dual-specific phosphatase, and other genes for kidney carcinomas (KC) and normal kidney tissues of 34 patients and for seven carcinoma cell lines. Computer analysis revealed three clusters of genes coexpressed in KC. A proliferating-cell gene cluster included MET, VIM, MYC, TOP2A, PCNA, etc. A neoangiogenesis and blood-cell gene cluster included LCK, HCK, FGR, MMP9, CSFR1, VEGF, FLT1, and KDR. A cluster corresponding to normal, differentiated kidney cells included ERBB2 (HER2) for receptor protein-tyrosine kinase, several phosphatase genes (PTPRE, PTPRB, DUSP9), and EGF. The results suggested that MET, DUSP9, PCNA, TOP2A, and VIM may serve as diagnostic and prognostic markers in KC. Tubulin and topoisomerase II were assumed to be promising targets for cell proliferation inhibitors in KC.
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PMID:[Molecular portrait of human kidney carcinomas: the gene expression profiling of protein-tyrosine kinases and tyrosine phosphatases which controlled regulatory signals in the cells]. 1206 34

Expression of BCR-ABL is the leading cause of chronic myelogenous leukemia. In chronic myelogenous leukemia cells, c-Abl expression is silenced by promoter methylation. In addition, the level of c-Abl needs to be tightly and constantly regulated due to its cytotoxicity and its rapid degradation after activation. Yet the regulation of c-Abl expression remains unclear. In an effort to gain better understanding of c-Abl function, we performed a glutathione S-transferase-Abl pull-down screen and identified TopBP1, a topoisomerase IIbeta-binding protein that contains Brca1 C-terminal motifs and has been implicated in DNA damage response. Their physical interaction was verified by in vitro and in vivo assays with TopBP1 found as a substrate of Abl proteins. TopBP1 could repress the expression of c-Abl at both mRNA and protein levels. Reporter assays indicate that TopBP1 directly repressed the promoter activity of c-Abl. Furthermore, TopBP1 repressed expression of c-Abl through a novel mechanism that involved histone deacetylation and DNA methylation. This transcriptional repression was inhibited by c-Abl in a kinase-dependent manner. The dual antagonistic interplay between c-Abl and TopBP1 may also provide a mechanism for fine-tuning of c-Abl levels.
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PMID:Identification of TopBP1 as a c-Abl-interacting protein and a repressor for c-Abl expression. 1596 88

The t(9;22) BCR/ABL fusion is associated with over 90% of chronic myelogenous and 25% of acute lymphocytic leukemia. Chromosome 11q23 translocations in acute myeloid and lymphoid leukemia cells demonstrate myeloid lymphoid leukemia (MLL) fusions with over 40 gene partners, like AF9 and AF4 on chromosomes 9 and 4, respectively. Therapy-related leukemia is associated with the above gene rearrangements following the treatment with topoisomerase II (topo II) inhibitors. BCR, ABL, MLL, AF9 and AF4 have defined patient breakpoint cluster regions. Chromatin structural elements including topo II and DNase I cleavage sites and scaffold attachment sites have previously been shown to closely associate with the MLL and AF9 breakpoint cluster regions, implicating these elements in non-homologous recombination (NHR). In this report, using cell lines and primary cells, chromatin structural elements were analyzed in BCR, ABL and AF4 and, for comparison, in MLL2, which is a homolog to MLL, but not associated with chromosome translocations. Topo II and DNase I cleavage sites associated with all breakpoint cluster regions, whereas SARs associated with ABL and AF4, but not with BCR. No close breakpoint clustering with the topo II/DNase I sites were observed; however, a statistically significant 5' or 3' distribution of patient breakpoints to the topo II DNase I sites was found, implicating DNA repair and exonucleases. Although MLL2 was expressed in all cell lines tested, except for the presence of one DNAse I site in the promoter, no other structural elements were found in MLL2. A NHR model presented demonstrates the importance of chromatin structure in chromosome translocations involved with leukemia.
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PMID:Common chromatin structures at breakpoint cluster regions may lead to chromosomal translocations found in chronic and acute leukemias. 1657 68

Current therapy for acute myeloid leukaemia (AML) is suboptimal with a high incidence of relapse. There is strong evidence that constitutive phosphoinositide 3-kinase (PI3K) activity plays a significant role in the pathophysiology of AML. PI3K products are derived from the activity of a number of PI3K catalytic isoforms (class I, II and III) but the relative contribution of these enzymes in AML remains unknown. As non-isoform-selective inhibitors of PI3K such as LY294002 may produce unwanted toxicity to normal tissues, we have investigated the role of the leukocyte-restricted p110delta PI3K isoform in 14 cases of AML. p110delta was detected in all cases whereas the expression levels of the other class I PI3Ks varied more widely, and were often undetectable. The p110delta-selective compound IC87114 inhibited constitutive phosphorylation of the PI3K target Akt/PKB and reduced cell number to a mean of 66+/-5% (range 14-88%). In eight cases, the combination of IC87114 and VP16 (a topoisomerase II inhibitor) was synergistic in reducing viable cell number, and was associated with a reduction in constitutive NF-kappaB activity. IC87114 did not have direct adverse effects or enhance the activity of VP16 on the proliferation and survival of normal haemopoietic progenitors. Overall, our results identify the p110delta isoform as a potential therapeutic target in AML and support a clinical approach to use isoform-selective over broad-spectrum PI3K inhibitors.
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PMID:A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. 1670 48

A novel amidine analogue of melphalan (AB4) was compared to its parent drug, melphalan in respect to cytotoxicity, DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. It was found that AB4 was more active inhibitor of DNA and collagen synthesis as well more cytotoxic agent than melphalan. The topoisomerase I/II inhibition assay indicated that AB4 is a potent catalytic inhibitor of topoisomerase II. Data from the ethidium displacement assay showed that AB4 intercalated into the minor-groove at AT sequences of DNA. The greater potency of AB4 to suppress collagen synthesis was found to be accompanied by a stronger inhibition of prolidase activity and expression compared to melphalan. The phenomenon was related to the inhibition of beta(1)-integrin and IGF-I receptor mediated signaling caused by AB4. The expression of beta(1)-integrin receptor, as well as Sos-1 and phosphorylated MAPK, ERK(1) and ERK(2) but not FAK, Shc, and Grb-2 was significantly decreased in cells incubated for 24h with 20 microM AB4 compared to the control, not treated cells, whereas in the same conditions melphalan did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the amidine analogue of melphalan, AB4 represent multifunctional inhibitor of breast cancer cells growth and metabolism.
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PMID:Novel amidine analogue of melphalan as a specific multifunctional inhibitor of growth and metabolism of human breast cancer cells. 1673 Jun 67

Recurring chromosome abnormalities are strongly associated with certain subtypes of leukemia, lymphoma and sarcomas. More recently, their potential involvement in carcinomas, i.e. prostate cancer, has been recognized. They are among the most important factors in determining disease prognosis, and in many cases, identification of these chromosome abnormalities is crucial in selecting appropriate treatment protocols. Chromosome translocations are frequently observed in both de novo and therapy-related acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The mechanisms that result in such chromosome translocations in leukemia and other cancers are largely unknown. Genomic breakpoints in all the common chromosome translocations in leukemia, including t(4;11), t(9;11), t(8;21), inv(16), t(15;17), t(12;21), t(1;19) and t(9;22), have been cloned. Genomic breakpoints tend to cluster in certain intronic regions of the relevant genes including MLL, AF4, AF9, AML1, ETO, CBFB, MYHI1, PML, RARA, TEL, E2A, PBX1, BCR and ABL. However, whereas the genomic breakpoints in MLL tend to cluster in the 5' portion of the 8.3 kb breakpoint cluster region (BCR) in de novo and adult patients and in the 3' portion in infant leukemia patients and t-AML patients, those in both the AML1 and ETO genes occur in the same clustered regions in both de novo and t-AML patients. These differences may reflect differences in the mechanisms involved in the formation of the translocations. Specific chromatin structural elements, such as in vivo topoisomerase II (topo II) cleavage sites, DNase I hypersensitive sites and scaffold attachment regions (SARs) have been mapped in the breakpoint regions of the relevant genes. Strong in vivo topo II cleavage sites and DNase I hypersensitive sites often co-localize with each other and also with many of the BCRs in most of these genes, whereas SARs are associated with BCRs in MLL, AF4, AF9, AML1, ETO and ABL, but not in the BCR gene. In addition, the BCRs in MLL, AML1 and ETO have the lowest free energy level for unwinding double strand DNA. Virtually all chromosome translocations in leukemia that have been analyzed to date show no consistent homologous sequences at the breakpoints, whereas a strong non-homologous end joining (NHEJ) repair signature exists at all of these chromosome translocation breakpoint junctions; this includes small deletions and duplications in each breakpoint, and micro-homologies and non-template insertions at genomic junctions of each chromosome translocation. Surprisingly, the size of these deletions and duplications in the same translocation is much larger in de novo leukemia than in therapy-related leukemia. We propose a non-homologous chromosome recombination model as one of the mechanisms that results in chromosome translocations in leukemia. The topo II cleavage sites at open chromatin regions (DNase I hypersensitive sites), SARs or the regions with low energy level are vulnerable to certain genotoxic or other agents and become the initial breakage sites, which are followed by an excision end joining repair process.
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PMID:Chromatin structural elements and chromosomal translocations in leukemia. 1689 85

Integrin-mediated adhesion to the extracellular matrix plays a fundamental role in tumor metastasis. Salvicine, a novel diterpenoid quinone compound identified as a nonintercalative topoisomerase II poison, possesses a broad range of antitumor and antimetastatic activity. Here, the mechanism underlying the antimetastatic capacity of salvicine was investigated by exploring the effect of salvicine on integrin-mediated cell adhesion. Salvicine inhibited the adhesion of human breast cancer MDA-MB-435 cells to fibronectin and collagen without affecting nonspecific adhesion to poly-l-lysine. The fibronectin-dependent formation of focal adhesions and actin stress fibers was also inhibited by salvicine, leading to a rounded cell morphology. Furthermore, salvicine down-regulated beta(1) integrin ligand affinity, clustering and signaling via dephosphorylation of focal adhesion kinase and paxillin. Conversely, salvicine induced extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation. The effect of salvicine on beta(1) integrin function and cell adhesion was reversed by U0126 and SB203580, inhibitors of MAPK/ERK kinase 1/2 and p38 MAPK, respectively. Salvicine also induced the production of reactive oxygen species (ROS) that was reversed by ROS scavenger N-acetyl-l-cysteine. N-acetyl-l-cysteine additionally reversed the salvicine-induced activation of ERK and p38 MAPK, thereby maintaining functional beta(1) integrin activity and restoring cell adhesion and spreading. Together, this study reveals that salvicine activates ERK and p38 MAPK by triggering the generation of ROS, which in turn inhibits beta(1) integrin ligand affinity. These findings contribute to a better understanding of the antimetastatic activity of salvicine and shed new light on the complex roles of ROS and downstream signaling molecules, particularly p38 MAPK, in the regulation of integrin function and cell adhesion.
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PMID:Salvicine inactivates beta 1 integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling. 1831 80

The Mre11 complex promotes DNA double-strand break repair and regulates DNA damage signaling via activation of the ataxia-telangiectasia mutated (ATM) kinase. The hypermorphic Rad50(S) allele encodes a variant of Rad50, a member of the Mre11 complex. Cells expressing Rad50(S) experience constitutive ATM activation, which leads to precipitous apoptotic attrition in hematopoietic cells. In this study, we show that ATM activation by the Rad50S-containing Mre11 complex enhances the proliferation of LSK cells, a population consisting of hematopoietic stem cells and multipotent progenitor cells. In Rad50(S/S) mice, enhanced LSK proliferation triggers apoptotic attrition. This phenotype is mitigated when Rad50(S/S) is combined with mutations that alter either LSK cell quiescence (myeloid elf-1-like factor/ELF4-deficient mice) or hematopoietic differentiation (p21- and p27-deficient mice), indicating that the LSK population is a primary target of Rad50(S) pathology. We show that cells from Rad50(S/S) mice are hypersensitive to camptothecin, a topoisomerase I inhibitor that causes DNA damage primarily during DNA replication. On this basis, we propose that apoptotic attrition of Rad50(S/S) hematopoietic cells results from enhanced proliferation in the context of topoisomerase-associated DNA damage. Impairment of apoptosis in Rad50(S/S) mice promotes hematopoietic malignancy, suggesting that primitive hematopoietic cells serve as a reservoir of potentially oncogenic lesions in Rad50(S/S) mice. These data provide compelling evidence that the Mre11 complex plays a role in the metabolism of topoisomerase lesions in mammals, and further suggest that such lesions can accumulate in primitive hematopoietic cells and confer significant oncogenic potential.
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PMID:DNA damage signaling in hematopoietic cells: a role for Mre11 complex repair of topoisomerase lesions. 1838 24

Advances in the therapy of malignancy have been accompanied by an increased frequency of cases of secondary acute myelogenous leukemia and related clonal cytopenias and oligoblastic (subacute) myelogenous leukemia (myelodysplastic syndromes). The acute myelogenous leukemia incidence can be increased by high-dose acute ionizing radiation exposure, alkylating agents, topoisomerase II inhibitors, possibly other DNA-damaging therapeutic agents, heavy, prolonged cigarette smoking, and high dose-time exposure to benzene, the latter less frequently seen in industrialized countries with worksite regulations. Acute myelogenous leukemia and myelodysplastic syndromes may result from innumerable primary types of chromosome damage. In the case of chronic myelogenous leukemia, a specific break in chromosome bands 9q34 and 22q11 must occur to result in the causal fusion oncogene (BCR-ABL). A review of 11 studies of the chromosomal abnormalities found in presumptive cases of cytotoxic therapy-induced leukemia and of 40 studies of the subtypes of leukemia that occur following cytotoxic therapy for other cancers has not provided evidence of an increased risk for chemically induced BCR-ABL-positive chronic myelogenous leukemia. Studies of the effects of alkylating agents, topoisomerase inhibitors, and benzene on chromosomes of hematopoietic cells in vitro, coupled with the aforementioned epidemiological studies of secondary leukemia after cytotoxic therapy or of persons exposed to high dose-time concentrations of benzene in the workplace, do not indicate a relationship among chemical exposure, injury to chromosome bands 9q34 and 22q11, and an increased risk for BCR-ABL-positive chronic myelogenous leukemia.
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PMID:Is there an entity of chemically induced BCR-ABL-positive chronic myelogenous leukemia? 1858 19


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