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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secondary tumors and leukemias are major complications in Hodgkin lymphoma (HL). They likely arise from clonal selection of cells that have accumulated genomic lesions induced by chemo- and radiotherapy and may be further promoted by the loss of DNA repair and/or other pathways ensuring the fidelity of replicated DNA. To distinguish genomic imbalances associated with the development of acute myeloid leukemia (AML) in HL we used an array-based comparative genomic hybridization (aCGH) strategy on whole lymph node biopsies of HL patient. Genomic imbalances (amplifications and deletions) associated with AML outcome in 3 classic HL patients, at clinical diagnosis they exhibited a discrete individual variability. Three amplifications and 5 deletions were shared by all 3 patients. They involved AFM137XA11, a 9p11.2 pericentric region; FGFR1, the FGF receptor most frequently translocated in AML; PPARBP, a co-activator of nuclear receptors RARalpha, RXR and TRbeta1; AFM217YD10, a 17q25 telomeric region; FGR, an SRC2 kinase involved in cytokine production by NK and CD4+ NKT cells; GATA3, a Th2-specific transcription factor; TOP1, involved in DNA recombination and repair; WT1, a transcription factor involved in CD8+ T cell response against leukaemic blasts. Immunohistochemistry confirmed aCGH results and distinguished the distribution of either amplified or deleted gene products in neoplastic Reed Sternberg (RS) cells and non-neoplastic lymph node components.
...
PMID:Genomic imbalances associated with secondary acute leukemias in Hodgkin lymphoma. 1798 26

In budding yeast, telomeres, the ribosomal DNA array, and HM loci are transcriptionally silenced by chromatin complexes containing Sir proteins. Hek2, a protein containing three evolutionary conserved RNA-binding K-homology domains, was identified as a suppressor of telomeric silencing [telomeric position effect (TPE)]. To explore the mechanisms of Hek2p action in gene silencing, we examined its relationship with Sir proteins. This search revealed an epistatic interaction between HEK2 and SIR1 at telomeres. Both single mutations, sir1Delta and hek2Delta, enhanced TPE, whereas the effect of double mutation, sir1Delta hek2Delta, did not exceed that of the single mutations. The results of chromatin immunoprecipitation analysis demonstrate that the TPE enhancement observed in these mutants is associated with increased binding of Sir2 protein to telomeres. At the HMR locus, hek2Delta rescues the silencing defect caused by sir1Delta mutation and reverses the loss of Sir2p and Sir3p. These data suggest that the epistatic interaction of HEK2 and SIR1 reflects competition between telomeres and HMR for Sir2/3 factors where HEK2 acts to suppress silencing. Because chromatin immunoprecipitation analysis reveals the presence of Hek2p at a subtelomeric region and HMR, its silencing effects at these loci are likely direct. These observations suggest that HEK2 regulates the composition of Sir complexes at HMR and telomeres.
...
PMID:Epistatic interaction between the K-homology domain protein HEK2 and SIR1 at HMR and telomeres in yeast. 1806 21

The pathological classification of gliomas constitutes a critical step of the clinical management of patients, yet it is frequently challenging. To assess the relationship between genetic abnormalities and clinicopathological characteristics, we have performed a genetic and clinical analysis of a series of gliomas. A total of 112 gliomas were analyzed by comparative genomic hybridization on a BAC array with a 1 megabase resolution. Altered regions were identified and correlation analysis enabled to retrieve significant associations and exclusions. Whole chromosomes (chrs) 1p and 19q losses with centromeric breakpoints and EGFR high level amplification were found to be mutually exclusive, permitting identification of 3 distinct, nonoverlapping groups of tumors with striking clinicopathological differences. Type A tumors with chrs 1p and 19q co-deletion exhibited an oligodendroglial phenotype and a longer patient survival. Type B tumors were characterized by EGFR amplification. They harbored a WHO high grade of malignancy and a short patient survival. Finally, type C tumors displayed none of the previous patterns but the presence of chr 7 gain, chr 9p deletion and/or chr 10 loss. It included astrocytic tumors in patients younger than in type B and whose prognosis was highly dependent upon the number of alterations. A multivariate analysis based on a Cox model shows that age, WHO grade and genomic type provide complementary prognostic informations. Finally, our results highlight the potential of a whole-genome analysis as an additional diagnostic in cases of unclear conventional genetic findings.
...
PMID:BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas. 1807 69

Pediatric ependymomas are enigmatic tumors, and their clinical management remains one of the more difficult in pediatric oncology. The identification of biological correlates of outcome and therapeutic targets remains a significant challenge in this disease. We therefore analyzed a panel of potential biological markers to determine optimal prognostic markers. We constructed a tissue microarray from 97 intracranial tumors from 74 patients (WHO grade II-III) and analyzed the candidate markers nucleolin, telomerase catalytic subunit (hTERT; antibody clone 44F12), survivin, Ki-67, and members of the receptor tyrosine kinase I (RTK-I) family by immunohistochemistry. Telomerase activity was determined using the in vitro-based telomere repeat amplification protocol assay, and telomere length was measured using the telomere restriction fragment assay. Primary tumors with low versus high nucleolin protein expression had a 5-year event-free survival of 74%+/-13% and 31%+/-7%, respectively. Multivariate analysis identified low nucleolin expression to be independently associated with a more favorable prognosis (hazard ratio=6.25; 95% confidence interval, 1.6-24.2; p=0.008). Ki-67 and survivin correlated with histological grade but not with outcome. Immunohistochemical detection of the RTK-I family did not correlate with grade or outcome. Telomerase activity was evident in 19 of 22 primary tumors, with telomere lengthening and/or maintenance occurring in five of seven recurrent cases. Low nucleolin expression was the single most important biological predictor of outcome in pediatric intracranial ependymoma. Furthermore, telomerase reactivation and maintenance of telomeric repeats appear necessary for childhood ependymoma progression. These findings require corroboration in a clinical trial setting.
...
PMID:Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma. 1870 11

Neuroblastoma in advanced stages is one of the most intractable paediatric cancers, even with recent therapeutic advances. Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of heterozygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma. However, the scarcity of reliable molecular targets has hampered the development of effective therapeutic agents targeting neuroblastoma. Here we show that the anaplastic lymphoma kinase (ALK), originally identified as a fusion kinase in a subtype of non-Hodgkin's lymphoma (NPM-ALK) and more recently in adenocarcinoma of lung (EML4-ALK), is also a frequent target of genetic alteration in advanced neuroblastoma. According to our genome-wide scans of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, the ALK locus, centromeric to the MYCN locus, was identified as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed eight novel missense mutations in 13 out of 215 (6.1%) fresh tumours and 8 out of 24 (33%) neuroblastoma-derived cell lines. All but one mutation in the primary samples (12 out of 13) were found in stages 3-4 of the disease and were harboured in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wild-type kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumours in nude mice. Furthermore, we demonstrate that downregulation of ALK through RNA interference suppresses proliferation of neuroblastoma cells harbouring mutated ALK. We anticipate that our findings will provide new insights into the pathogenesis of advanced neuroblastoma and that ALK-specific kinase inhibitors might improve its clinical outcome.
...
PMID:Oncogenic mutations of ALK kinase in neuroblastoma. 1892 3

Most of human gastrointestinal stromal tumors (GIST) are driven by activating mutations in the proto-oncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumor regrowth occurs as a result of the development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus, kinase resistance may be circumvented. A naphthalene diimide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilizes both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (approximately 1 microM) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modeling studies with a telomeric quadruplex have been used to rationalize aspects of the experimental quadruplex melting data.
...
PMID:Targeting human gastrointestinal stromal tumor cells with a quadruplex-binding small molecule. 1946 47

Rare breast neoplasms resembling the tall-cell variant of papillary thyroid carcinoma have been reported. In addition, papillary carcinoma of the breast occasionally displays nuclear features reminiscent of papillary thyroid carcinoma. In this study, we evaluated 33 intraductal/intracystic papillary carcinomas of the breast for the presence and extent of nuclear overlap, grooves, clearing, and inclusions, as well as features of the tall-cell or columnar-cell variants of papillary thyroid carcinoma. RET rearrangements were assessed in a subset of these cases. Paired probes localizing to the centromeric and telomeric ends of the RET gene on chromosome 10 were used for FISH using a break-apart approach. Single round and nested PCR was performed to detect RET/PTC1, RET/PTC2, RET/PTC3 and ELKS-RET fusion transcripts. Nuclear overlap, grooves, stratification, and clearing were identified in 24 (73%), 14 (42%), 11 (33%), and 9 (27%) cases respectively, whereas nuclear inclusions and 'tall-cell' features were each seen in only one (3%) and two (6%) cases, respectively. Four of 19 tested cases displayed split FISH signals in a low percentage of cells and were considered borderline for RET rearrangement. All 19 tested cases with amplifiable RNA were negative for the four RET fusion transcripts evaluated by RT-PCR. Although papillary carcinomas of breast often display one or more cytoarchitectural features of papillary thyroid carcinoma, there is no evidence that RET rearrangements are involved.
...
PMID:Papillary carcinoma of the breast lacks evidence of RET rearrangements despite morphological similarities to papillary thyroid carcinoma. 1954 46

Lung carcinoma development is accompanied by field changes that may have diagnostic significance. We have previously shown the importance of chromosomal aneusomy in lung cancer progression. Here, we tested whether genomic gains in six specific loci, TP63 on 3q28, EGFR on 7p12, MYC on 8q24, 5p15.2, and centromeric regions for chromosomes 3 (CEP3) and 6 (CEP6), may provide further value in the prediction of lung cancer. Bronchial biopsy specimens were obtained by LIFE bronchoscopy from 70 subjects (27 with prevalent lung cancers and 43 individuals without lung cancer). Twenty six biopsies were read as moderate dysplasia, 21 as severe dysplasia and 23 as carcinoma in situ (CIS). Four-micron paraffin sections were submitted to a 4-target FISH assay (LAVysion, Abbott Molecular) and reprobed for TP63 and CEP 3 sequences. Spot counts were obtained in 30-50 nuclei per specimen for each probe. Increased gene copy number in 4 of the 6 probes was associated with increased risk of being diagnosed with lung cancer both in unadjusted analyses (odds ratio = 11, p<0.05) and adjusted for histology grade (odds ratio = 17, p<0.05). The most informative 4 probes were TP63, MYC, CEP3 and CEP6. The combination of these 4 probes offered a sensitivity of 82% for lung cancer and a specificity of 58%. These results indicate that specific cytogenetic alterations present in preinvasive lung lesions are closely associated with the diagnosis of lung cancer and may therefore have value in assessing lung cancer risk.
...
PMID:Recurrent genomic gains in preinvasive lesions as a biomarker of risk for lung cancer. 1954 94

Previous studies have suggested that the ancestral haplotype 18.2 (AH18.2) carries additional susceptibility gene to Type 1 Diabetes (T1D) on the Major Histocompatibility Complex (MHC). We analyzed 10 DR3/TNFa1b5 homozygous subjects in order to establish the conservation of the AH18.2 and then compared this conserved region with other DR3 haplotype, the AH8.1. The Illumina's HumanHap550 Bead chip was used to perform an extensive genotyping of the MHC region. The AH18.2 was highly conserved between DDR1 and HLA-DQA1 genes; therefore most probably the second susceptibility gene is located within this region. We can exclude the region centromeric to HLA-DRA gene and telomeric to DDR1 gene. A comparison between the AH18.2 and AH8.1 haplotypes showed that 233 SNPs were different in the aforementioned conserved region. These data suggest that the 1.65 Mb MHC region between DDR1 and HLA-DRA genes is likely to carry additional susceptibility alleles for T1D on the AH18.2 haplotype.
...
PMID:Localization of Type 1 Diabetes susceptibility in the ancestral haplotype 18.2 by high density SNP mapping. 1959 19

Approximately 8% of breast cancers show increased copy numbers of chromosome 17 centromere (CEP17) by fluorescence in situ hybridization (FISH) (ie average CEP17 >3.0 per nucleus). Currently, this pattern is believed to represent polysomy of chromosome 17. HER2-amplified cancers have been shown to harbour complex patterns of genetic aberrations of chromosome 17, in particular involving its long arm. We hypothesized that aberrant copy numbers of CEP17 in FISH assays may not necessarily represent true chromosome 17 polysomy. Eighteen randomly selected CEP17 polysomic cases and a control group of ten CEP17 disomic cases, as defined by dual-colour FISH, were studied by microarray-based comparative genomic hybridization (aCGH), which was performed on microdissected samples using a 32K tiling-path bacterial artificial chromosome microarray platform. Additional FISH probes were employed for SMS (17p11.2) and RARA (17q21.2) genes, as references for chromosome 17 copy number. Microarray-based comparative genomic hybridization revealed that 11 out of the 18 polysomic cases harboured gains of 17q with involvement of the centromere, one displayed 17q gain sparing the centromeric region, and only one could be defined as polysomic. The remaining five cases displayed amplification of the centromeric region. Among these, one case, showing score 2+ by immunohistochemistry and 8.5 HER2 mean copy number, was classified as not amplified by HER2/CEP17 ratio and as amplified by HER2/SMS ratio. Our results suggest that true chromosome 17 polysomy is likely to be a rare event in breast cancer and that CEP17 copy number greater than 3.0 in FISH analysis is frequently related to gain or amplification of the centromeric region. Larger studies investigating the genetic profiles of CEP17 polysomic cases are warranted.
...
PMID:Does chromosome 17 centromere copy number predict polysomy in breast cancer? A fluorescence in situ hybridization and microarray-based CGH analysis. 1967 Feb 16


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---