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)

Ovarian carcinoma (OC) is a leading cause of death among women throughout the world. A number of cancer-associated genes have been shown to be inactivated by hypermethylation of CpG islands during tumorigenesis. We tested the hypothesis that methylation status of MGMT, CDH1, RAR-beta and SYK could be important in the ovarian tumorigenic process and can lead to the gene(s) inactivation. Therefore, we assessed the promoter hypermethylation of MGMT, CDH1, RAR-beta and SYK in 43 ovarian granulosa cell tumours (GCTs) (adult type) using methylation-specific PCR. These tumours are relatively rare, accounting for approximately 3% of all ovarian cancers. Hypermethylation of MGMT (in 14 tumours), CDH1 (in nine tumours), RAR-beta (in eight tumours) and SYK (in seven tumours) have been found. Selective loss of RAR-beta and RAR-beta2 mRNA has been found in seven patients, while that of MGMT and SYK in three patients who also show aberrant methylation in promoter region of RAR-beta in addition to MGMT, SYK and CDH1 genes. Promoter CpG hypermethylation may be an alternative to mutation(s) to inactivate tumour suppressor genes such as MGMT, CDH1, RAR-beta and SYK, and this can also be an early event in the pathogenesis of OCs. Moreover, hypermethylation of the MGMT and CDH1, MGMT and RAR-beta and CDH1 and RAR-beta promoters occurred concordantly (P< 0.001, 0.0421 and 0.0005 respectively; Fischer's exact test). In addition to this, monosomy 22 and trisomy 14 have also been found in 10 tumours. It is clear from the results that hypermethylation of the promoter region of these tumour suppressor genes, monosomy 22 and trisomy 14, may be critical steps in the tumorigenesis, which consequently play a permissive role for tumour aggressiveness. All these events might play an important role in the early clinical diagnosis of the disease. Our results, therefore, suggest a potential role for epigenetic modification of these critical tumour suppressor genes in pathways relevant to the transformation and differentiation of rare type of ovarian cancer (GCTs).
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PMID:Promoter hypermethylation of MGMT, CDH1, RAR-beta and SYK tumour suppressor genes in granulosa cell tumours (GCTs) of ovarian origin. 1497 Aug 67

Caulobacter crescentus is a gram negative, non-pathogenic bacterium, common in aquatic and soil environments. One feature of note is a protein surface layer (S-layer) composed of a single protein, organized as a self-assembled crystalline array that coats the bacterium. In the course of efforts to express cancer-associated peptides as genetic insertions into the S-layer, we noted a tumor suppressive effect of the unmodified bacterium. C. crescentus was examined for anti-tumor activity against three transplantable tumor mouse models: Lewis lung carcinoma cells transfected with the MUC1 gene in C57BL/6, murine mammary carcinoma (EMT-6) in BALB/c (both in prophylactic and therapeutic mode) and murine leukemia cells (L1210) in DBA2. Mice were immunized three times i.p. with C. crescentus (2 x 10(7) cells/mouse). In prophylactic mode, the mice were challenged with tumor cells two weeks after the last immunization. Immunization with live C. crescentus resulted in anti-tumor activity in all three transplantable tumor models, as measured by prolonged survival, reduced tumor mass or reduced number of lung nodules, compared to saline control groups. In the Lewis lung and the EMT-6 mammary carcinoma murine models the number of lung nodules as well as the tumor weight was lower in mice treated with C. crescentus, compared to the control group; for EMT-6, this was observed in prophylactic and therapeutic modes. In the murine leukemia and Lewis lung carcinoma models prolonged survival was observed in the groups of mice immunized with Caulobacters. In most cases the live C. crescentus cells were markedly more efficacious than heat killed or formalin fixed cells, despite the fact that they do not grow or persist in mice. The results suggest that C. crescentus may be a safe, bacterial immunomodulator for the treatment of tumors.
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PMID:Anti-tumor effects of the bacterium Caulobacter crescentus in murine tumor models. 1658 92

The close link between alcohol and other drug abuse and STD morbidity and the positive impact of AOD intervention services in reducing STD morbidity, led the New York State Office of Alcoholism and Substance Abuse Services (OASAS) and the New York City Bureau of STD Control (BSTDC) to assess the prevalence of AOD problems among STD clinic patients. Assessing problematic AOD involvement among STD patients was of interest to BSTDC for STD prevention and to OASAS, for new AOD case-finding and early intervention. During fall, 2000, 100 STD patients in each of the 7 full-time BSTDC clinics in New York City were solicited in clinic waiting rooms; eligible patients were screened individually and anonymously with a modified CAGE-A (mCA). The mCA asks 4 questions about problematic AOD use "ever" (i.e., "lifetime") and currently (i.e., "in the past 30 days) rather than "in the past 12 months" of the CAGE and uses two or more "Yes" answers as a "positive" screen. The mCA also asks for age, sex, ethnicity, prior AOD treatment, and interest in an AOD referral. Only 2 of 704 eligible patients refused mCA screening, n = 702. Sixty percent were male, 87.7% Black and/or Hispanic, and 69%, <or=35 years old. Of the sample screened, 30.5% were "positive" on the "ever" and 16.5%, on "the past 30 days," mCA questions. 13.2% reported prior AOD treatment, 1.4% were in AOD treatment or about to start, and <1% wanted an AOD referral. Eight of 10 STD patients currently in AOD treatment screened positive on the "ever" mCA questions. The AOD prevalence rates observed here were deemed high since: 1) CAGE (and CAGE-A) data on general hospital and emergency room admissions showed positive screening rates of only 5-14 % and 2) only an estimated 6-7% of adults in New York have received any formal intervention with an AOD problem, less than half the rate found for treatment alone with the STD patients in this study. The results support implementing AOD screening and intervention services in STD clinics since an estimated 11,000 patients annually would screen positive but now are undetected and untreated. As AOD intervention services also can reduce risky sexual behavior, providing them could expand STD prevention services significantly. Policy, funding, and evaluation issues related to implementing AOD intervention services in STD and other public health clinics also are discussed.
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PMID:Assessing alcohol and other drug problems (AOD) among sexually transmitted disease (STD) clinic patients with a modified CAGE-A: implications for AOD intervention services and STD prevention. 1659 25

The cancer-associated gene (CAGE) is a novel cancer/testis antigen. Over-expression of it increased phosphorylation of focal adhesion kinase (FAK) and enhanced motility of SNU387 cells. Focal adhesion, kinase-related non-kinase (FRNK), an endogenous inhibitor of FAK, was significantly suppressed. This suggests that CAGE-promoted motility requires FAK. The inhibition of Rho-Associated coiled-coil-containing protein kinase (ROCK), an activator of FAK, also suppressed CAGE-promoted motility.
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PMID:Cancer/testis antigen cancer-associated gene (CAGE) promotes motility of cancer cells through activation of focal adhesion kinase (FAK). 1702 76

The preferred Cu(+) sites and formation of mono-, di-, and tricarbonyl complexes in the Cu-FER were investigated at the periodic density functional theory level and by means of FTIR spectroscopy. The site-specificity of adsorption enthalpies of CO on Cu-FER and of vibrational frequencies of polycarbonyl complexes were investigated for various Cu(+) sites in Cu-FER. Large changes in the Cu(+) interaction with the zeolite framework were observed upon the formation of carbonyl complexes. The dicarbonyl complexes formed on Cu(+) in the main channel or on the intersection of the main and perpendicular channels are stable and both, adsorption enthalpies and CO stretching frequencies are not site-specific. The fraction of Cu(+) ions in the FER cage, that cannot form dicarbonyl can be determined from IR spectra (about 7% for the Cu-FER with Si/Al = 27.5 investigated here). The tricarbonyl complexes can be formed at the Cu(+) ions located at the 8-member ring window at the intersection of main and perpendicular channel. The stability of tricarbonyl complexes is very low (DeltaH degrees (0 K)>or=-4 kJ mol(-1)).
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PMID:On the site-specificity of polycarbonyl complexes in Cu/zeolites: combined experimental and DFT study. 1713 68

Chromosome deletions do abound in cancer and are detected in certain regions in a non-random manner. Although their relevance remains elusive, it is a general agreement that segmental losses provide the cell with selective growth advantage. Consequently these may contain genes and/or regulatory sequences that control normal growth and inhibit malignancy. We have developed a monochromosomal hybrid based experimental model for the generation and functional analysis of deletions, that is called "elimination test" (Et). Focused on human chromosome 3 - that was known to carry multiple 3p deletions - the Et was expected to restrict a 3p tumor suppressor region to a sufficiently small segment that permits the selection of a critically important candidate gene. Surprisingly, we detected three regions that were lost in all or majority of tumors: CER1 (3p21.3, Mb: 43.32-45.74), CER2 (3p22, Mb: 37.83-39.06) and FER (3p14.3-p21.2, Mb: 50.12-58.03). In contrast a 3q26-qter region (CRR) was regularly retained. CER1 - our main focus - contains multiple genes that may inhibit tumor growth, but 3 genes, RIS1, LF (LTF) and LIMD1 have already the necessary experimental support to be considered bona fide tumor suppressors. Tumor suppressor region borders display instability features including: (1) they break in evolution and in tumors, (2) they evolve horizontally, and (3) they are enriched with pseudogene insertions. The most remarkable features at the breakpoint cluster regions were segmental duplications that drive horizontal evolution and contribute to cancer associated instability.
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PMID:Modeling non-random deletions in cancer. 1717 4

Missense variants are commonly identified in genomic sequence but only a small fraction directly contribute to oncogenesis. The ability to distinguish those missense changes that contribute to cancer progression from those that do not is a difficult problem usually only accomplished through functional in vivo analyses. Using two computational algorithms, Sorting Intolerant from Tolerant (SIFT) and the Pfam-based LogR.E-value method, we have identified features that distinguish cancer-associated missense mutations from other classes of missense change. Our data reveal that cancer mutants behave similarly to Mendelian disease mutations, but are clearly distinct from either complex disease mutations or common single-nucleotide polymorphisms. We show that both activating and inactivating oncogenic mutations are predicted to be deleterious, although activating changes are likely to increase protein activity. Using the Gene Ontology and data from the SIFT and LogR.E-value metrics, a classifier was built that predicts cancer-associated missense mutations with a very low false-positive rate. The classifier does remarkably well in a number of different experiments designed to distinguish polymorphisms from true cancer-associated mutations. We also show that recurrently observed mutations are much more likely to be predicted to be cancer-associated than rare mutations, suggesting that our classifier will be useful in distinguishing causal from passenger mutations. In addition, from an expressed sequence tag-based screen, we identified a previously unknown germ line change (P1104A) in tumor tissues that is predicted to disrupt the function of the TYK2 protein. The data presented here show that this novel bioinformatics approach to classifying cancer-associated variants is robust and can be used for large-scale analyses.
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PMID:Distinguishing cancer-associated missense mutations from common polymorphisms. 1723 53

Basic transcription factor 3 (BTF3) acts as a transcription factor and modulator of apoptosis, and is differentially expressed in colorectal cancer and glioblastomas. In the present study, the expression of BTF3, as well as its role in apoptosis and gene transcription, was analyzed in pancreatic ductal adenocarcinoma (PDAC). QRT-PCR, immunohistochemistry, immunoblotting, and immunofluorescence analyses were carried out to investigate BTF3 mRNA/protein expression and localization. BTF3 silencing in pancreatic cancer cells was performed using specific siRNA molecules. Functional analyses were carried out using cell growth assays, apoptosis assays, and DNA array analysis. BTF3 and BTF3a exhibited 1.3-fold and 4.6-fold increased median mRNA levels in PDAC tissues, compared to normal pancreatic tissues. BTF3 localized mainly in the cytoplasm and nuclei of tubular complexes and pancreatic cancer cells. Pancreatic cancer cell lines expressed the mRNA and protein of BTF3a (27 kDa) and BTF3b (22 kDa) isoforms. BTF3 silencing using specific siRNA molecules did not influence apoptosis induced by chemotherapy or radiotherapy. In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.
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PMID:Basic transcription factor 3 (BTF3) regulates transcription of tumor-associated genes in pancreatic cancer cells. 1731 87

Patients with malignant mesothelioma (MM), an aggressive cancer associated with asbestos exposure, usually present clinically with advanced disease and this greatly reduces the likelihood of curative treatment. MM is difficult to diagnose without invasive techniques; the development of non-invasively detectable molecular markers would therefore be highly beneficial. DNA methylation changes in cancer cells provide powerful markers that are potentially detectable non-invasively in DNA shed into bodily fluids. Here we examined the methylation status of 28 loci in 52 MM tumors to investigate their potential as molecular markers for MM. To exclude candidate MM markers that might be positive in biopsies/pleural fluid due to contaminating surrounding non-tumor lung tissue/DNA, we also examined the methylation of these markers in lung samples (age- or environmentally induced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM versus non-tumor lung samples was found for estrogen receptor 1 (ESR1; p = 0.0002), solute carrier family 6 member 20 (SLC6A20; p = 0.0022) and spleen tyrosine kinase (SYK; p=0.0003). Examination of associations between methylation levels of the 28 loci and clinical parameters suggest associations of the methylation status of metallothionein genes with gender, histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival.
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PMID:DNA methylation profile of 28 potential marker loci in malignant mesothelioma. 1765 10

Anxiety-related behaviors were evaluated across various tests in a large sample (n=787, both sexes) of genetically heterogeneous (N/Nih-HS) rats, derived from an eight-way cross of inbred strains. These tests either evoke unlearned (black-white box, BWB-; novel-cage activity, NACT-; elevated "zero" maze, ZM-; baseline acoustic startle response, BAS-) or learned (fear-potentiated startle, FPS-; two-way active-shuttle box-avoidance acquisition, SHAV-) anxious/fearful responses. The results showed that, with the exception of fear-potentiated startle, almost all (unlearned and learned) behaviors assessed fit with a pattern of sex effects characterized by male rats as being more fearful than females. We applied factor analyses (oblique rotation) to each sex, with the final two-factor solution showing: (1) a first factor (labelled as "Timidity") comprising BWB, NACT and ZM variables in both sexes, plus SHAV responding in the case of males, and (2) a second factor (called "Defensive Flight") which grouped BAS, FPS, and SHAV responding in both sexes. An additional regression analysis showed significant influences of (unlearned) risk assessment (i.e. stretch-attendance) behavior on SHAV in males, while FPS was the main variable positively influencing SHAV (in the intermediate and advanced phases of acquisition) in females. This indicates, for the first time, that fear-potentiated startle may have a facilitating role in the rat's active responses (at least in females) to the cue in the intermediate to advanced phases (i.e. when the initial "passive avoidance/active avoidance" begins to fade) of shuttle box avoidance acquisition. The results of this first extensive behavioral evaluation of N/Nih-HS rats are discussed in terms of their potential usefulness for present and future neurobehavioral and genetic studies of fearfulness/anxiety.
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PMID:Fearfulness in a large N/Nih genetically heterogeneous rat stock: differential profiles of timidity and defensive flight in males and females. 1807 10


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